Cancers

14 pages, 3623 KiB

Open AccessEditor’s ChoiceArticle

The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3

by Elly Marcq, Jonas R. M. Van Audenaerde, Jorrit De Waele, Céline Merlin, Patrick Pauwels, Jan P. van Meerbeeck, Scott A. Fisher and Evelien L. J. Smits

Cancers 2021, 13(2), 282; https://doi.org/10.3390/cancers13020282 - 14 Jan 2021

Cited by 18 | Viewed by 3660

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous asbestos exposure in most afflicted patients. The prognosis of patients remains dismal, with a median overall survival of only 9–12 months, due to the limited effectiveness of any conventional [...] Read more.

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous asbestos exposure in most afflicted patients. The prognosis of patients remains dismal, with a median overall survival of only 9–12 months, due to the limited effectiveness of any conventional anti-cancer treatment. New therapeutic strategies are needed to complement the limited armamentarium against MPM. We decided to focus on the combination of different immune checkpoint (IC) blocking antibodies (Abs). Programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3) blocking Abs were tested as monotherapies, and as part of a combination strategy with a second IC inhibitor. We investigated their effect in vitro by examining the changes in the immune-related cytokine secretion profile of supernatant collected from treated allogeneic MPM-peripheral blood mononuclear cell (PBMC) co-cultures. Based on our in vitro results of cytokine secretion, and flow cytometry data that showed a significant upregulation of PD-L1 on PBMC after co-culture, we chose to further investigate the combinations of anti PD-L1 + anti TIM-3 versus anti PD-L1 + anti LAG-3 therapies in vivo in the AB1-HA BALB/cJ mesothelioma mouse model. PD-L1 monotherapy, as well as its combination with LAG-3 blockade, resulted in in-vivo delayed tumor growth and significant survival benefit. Full article

(This article belongs to the Special Issue The Portrait of Cancer Immunotherapy: Tumor Microenvironment, Biomarkers and Immune Resistance)

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19 pages, 357 KiB

Open AccessEditor’s ChoiceReview

The Multiple Potential Biomarkers for Predicting Immunotherapy Response—Finding the Needle in the Haystack

by Tamiem Adam, Therese M. Becker, Wei Chua, Victoria Bray and Tara L. Roberts

Cancers 2021, 13(2), 277; https://doi.org/10.3390/cancers13020277 - 13 Jan 2021

Cited by 15 | Viewed by 4452

Abstract

Immune checkpoint inhibitors (ICIs) are being increasingly utilised in a variety of advanced malignancies. Despite promising outcomes in certain patients, the majority will not derive benefit and are at risk of potentially serious immune-related adverse events (irAEs). The development of predictive biomarkers is [...] Read more.

Immune checkpoint inhibitors (ICIs) are being increasingly utilised in a variety of advanced malignancies. Despite promising outcomes in certain patients, the majority will not derive benefit and are at risk of potentially serious immune-related adverse events (irAEs). The development of predictive biomarkers is therefore critical to personalise treatments and improve outcomes. A number of biomarkers have shown promising results, including from tumour (programmed cell death ligand 1 (PD-L1), tumour mutational burden (TMB), stimulator of interferon genes (STING) and apoptosis-associated speck-like protein containing a CARD (ASC)), from blood (peripheral blood mononuclear cells (PBMCs), circulating tumour DNA (ctDNA), exosomes, cytokines and metal chelators) and finally the microbiome. Full article

(This article belongs to the Special Issue Biomarkers of Immune Checkpoint Therapy Response and Resistance)

12 pages, 2943 KiB

Open AccessEditor’s ChoiceArticle

Lidocaine Suppresses Viability and Migration of Human Breast Cancer Cells: TRPM7 as a Target for Some Breast Cancer Cell Lines

by Hengrui Liu, James P. Dilger and Jun Lin

Cancers 2021, 13(2), 234; https://doi.org/10.3390/cancers13020234 - 10 Jan 2021

Cited by 33 | Viewed by 3300

Abstract

Background: The local anesthetic lidocaine suppresses some cancer cell lines but the mechanism is unclear. The melastatin-like transient receptor potential 7 (TRPM7) ion channel is aberrantly expressed in some cancers and may play a role in the disease. Hence, we suggested that lidocaine [...] Read more.

Background: The local anesthetic lidocaine suppresses some cancer cell lines but the mechanism is unclear. The melastatin-like transient receptor potential 7 (TRPM7) ion channel is aberrantly expressed in some cancers and may play a role in the disease. Hence, we suggested that lidocaine affects the viability and migration of breast cancer cells by regulating TRPM7. Methods: We measured the effects of lidocaine on TRPM7 function in HEK293 with exogenous TRPM7 expression (HEK-M7) using whole-cell patch-clamp and fura-2AM-based quench assay. We measured the effect of lidocaine on TRPM7 function, cell viability, and migration in TRPM7 expressing human breast cancer cell lines using fura-2AM-based quench, MTT, and wound-healing assays respectively. We compared cell viability and migration of wild type HEK293 cells (WT-HEK) with HEK-M7 and wild type MDA-MB-231 (WT-231) with TRPM7 knockout MDA-MB-231 (KO-231). Results: Lidocaine (1–3 mM) inhibited the viability and migration of all of these breast cancer cell lines. Functional evidence for TRPM7 was confirmed in the MDA-MB-231, AU565, T47D, and MDA-MB-468 cell lines where lidocaine at 0.3–3 mM suppressed the TRPM7 function. Lidocaine preferentially suppressed viability and migration of HEK-M7 over WT-HEK and WT-231 over KO-231. Conclusions: Lidocaine differentially reduced the viability and migration of human breast cancer cell lines tested. TRPM7 is one of the potential targets for the effects of lidocaine on viability and migration in MDA-MB-231, AU565, T47D, and MDA-MB-468. Full article

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22 pages, 1407 KiB

Open AccessEditor’s ChoiceArticle

Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma

by Tatiana Pazina, Alexander W. MacFarlane IV, Luca Bernabei, Essel Dulaimi, Rebecca Kotcher, Clinton Yam, Natalie A. Bezman, Michael D. Robbins, Eric A. Ross, Kerry S. Campbell and Adam D. Cohen

Cancers 2021, 13(2), 226; https://doi.org/10.3390/cancers13020226 - 10 Jan 2021

Cited by 35 | Viewed by 3898

Abstract

Accumulating evidence demonstrates important roles for natural killer (NK) cells in controlling multiple myeloma (MM). A prospective flow cytometry-based analysis of NK cells in the blood and bone marrow (BM) of MM patient subgroups was performed (smoldering (SMM), newly diagnosed (ND), relapsed/refractory, (RR) [...] Read more.

Accumulating evidence demonstrates important roles for natural killer (NK) cells in controlling multiple myeloma (MM). A prospective flow cytometry-based analysis of NK cells in the blood and bone marrow (BM) of MM patient subgroups was performed (smoldering (SMM), newly diagnosed (ND), relapsed/refractory, (RR) and post-stem cell transplantation (pSCT)). Assessments included the biomarker expression and function of NK cells, correlations between the expression of receptors on NK cells with their ligands on myeloma cells, and comparisons between MM patient subgroups and healthy controls. The most striking differences from healthy controls were found in RR and pSCT patients, in which NK cells were less mature and expressed reduced levels of the activating receptors DNAM-1, NKG2D, and CD16. These differences were more pronounced in the BM than in blood, including upregulation of the therapeutic targets TIM3, TIGIT, ICOS, and GITR. Their expression suggests NK cells became exhausted upon chronic encounters with the tumor. A high expression of SLAMF7 on blood NK cells correlated with shorter progression-free survival. This correlation was particularly evident in ND patients, including on mature CD56^dim NK cells in the BM. Thus, our NK cell analysis identified possible therapeutic targets in MM and a biomarker with prognostic potential for disease progression. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)

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22 pages, 3716 KiB

Open AccessEditor’s ChoiceReview

A 3D View of Colorectal Cancer Models in Predicting Therapeutic Responses and Resistance

by Eileen Reidy, Niamh A. Leonard, Oliver Treacy and Aideen E. Ryan

Cancers 2021, 13(2), 227; https://doi.org/10.3390/cancers13020227 - 10 Jan 2021

Cited by 42 | Viewed by 5577

Abstract

Although there have been many advances in recent years for the treatment of colorectal cancer (CRC), it still remains the third most common cause of cancer-related deaths worldwide. Many patients with late stage CRC display resistance to multiple different therapeutics. An important aspect [...] Read more.

Although there have been many advances in recent years for the treatment of colorectal cancer (CRC), it still remains the third most common cause of cancer-related deaths worldwide. Many patients with late stage CRC display resistance to multiple different therapeutics. An important aspect in developing effective therapeutics for CRC patients is understanding the interactions that take place in the tumor microenvironment (TME), as it has been shown to contribute to drug resistance in vivo. Much research over the past 100 years has focused on 2D monolayer cultures or in vivo studies, however, the efficacy in translating these to the clinic is very low. More recent studies are turning towards developing an effective 3D model of CRC that is clinically relevant, that can recapitulate the TME in vitro and bridge the gap between 2D cultures and in vivo studies, with the aim of reducing the use of animal models in the future. This review summarises the advantages and limitations of different 3D CRC models. It emphasizes how different 3D models may be optimised to study cellular and extracellular interactions that take place in the TME of CRC in an effort to allow the development of more translatable effective treatment options for patients. Full article

(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)

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12 pages, 267 KiB

Open AccessEditor’s ChoiceReview

Current Melanoma Treatments: Where Do We Stand?

by Alvaro Moreira, Lucie Heinzerling, Nina Bhardwaj and Philip Friedlander

Cancers 2021, 13(2), 221; https://doi.org/10.3390/cancers13020221 - 09 Jan 2021

Cited by 38 | Viewed by 4405

Abstract

Groundbreaking research in immunology and cancer biology in the last few decades has led to the discovery and development of novel therapeutics, such as immune checkpoint inhibitors and targeted therapies, which have revolutionized the clinical care of patients with metastatic melanoma. Updated data [...] Read more.

Groundbreaking research in immunology and cancer biology in the last few decades has led to the discovery and development of novel therapeutics, such as immune checkpoint inhibitors and targeted therapies, which have revolutionized the clinical care of patients with metastatic melanoma. Updated data from the largest clinical trials continue to support the use of these treatment modalities, both in the metastatic and in adjuvant settings, with studies showing the predicted plateau effect on survival curves. However, with growing evidence that neoadjuvant therapy is also associated with high rates of recurrence-free survival, the question about whether patients should receive adjuvant or neoadjuvant treatment raises new questions about therapeutic options. Finally, management after resistance and intervention with novel immunotherapies are newer challenges, particularly in the field of non-cutaneous melanoma. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Skin Cancer)

22 pages, 8957 KiB

Open AccessEditor’s ChoiceReview

The Role of Tumor Microenvironment in Multiple Myeloma Development and Progression

by Almudena García-Ortiz, Yaiza Rodríguez-García, Jessica Encinas, Elena Maroto-Martín, Eva Castellano, Joaquín Teixidó and Joaquín Martínez-López

Cancers 2021, 13(2), 217; https://doi.org/10.3390/cancers13020217 - 09 Jan 2021

Cited by 91 | Viewed by 8936

Abstract

Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and [...] Read more.

Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and occasionally extramedullary disease, is drastically affected by the tumor microenvironment (TME). Soluble factors and direct cell–cell interactions regulate MM plasma cell trafficking and homing to the BM niche. Mesenchymal stromal cells, osteoclasts, osteoblasts, myeloid and lymphoid cells present in the BM create a unique milieu that favors MM plasma cell immune evasion and promotes disease progression. Moreover, TME is implicated in malignant cell protection against anti-tumor therapy. This review describes the main cellular and non-cellular components located in the BM, which condition the immunosuppressive environment and lead the MM establishment and progression. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)

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24 pages, 5230 KiB

Open AccessEditor’s ChoiceReview

Treatment Strategies Considering Micro-Environment and Clonal Evolution in Multiple Myeloma

by Kazuhito Suzuki, Kaichi Nishiwaki and Shingo Yano

Cancers 2021, 13(2), 215; https://doi.org/10.3390/cancers13020215 - 08 Jan 2021

Cited by 21 | Viewed by 4565

Abstract

Multiple myeloma is an uncurable hematological malignancy because of obtained drug resistance. Microenvironment and clonal evolution induce myeloma cells to develop de novo and acquired drug resistance, respectively. Cell adhesion-mediated drug resistance, which is induced by the interaction between myeloma and bone marrow [...] Read more.

Multiple myeloma is an uncurable hematological malignancy because of obtained drug resistance. Microenvironment and clonal evolution induce myeloma cells to develop de novo and acquired drug resistance, respectively. Cell adhesion-mediated drug resistance, which is induced by the interaction between myeloma and bone marrow stromal cells, and soluble factor-mediated drug resistance, which is induced by cytokines and growth factors, are two types of de novo drug resistance. The microenvironment, including conditions such as hypoxia, vascular and endosteal niches, contributes toward de novo drug resistance. Clonal evolution was associated with acquired drug resistance and classified as branching, linear, and neutral evolutions. The branching evolution is dependent on the microenvironment and escape of immunological surveillance while the linear and neutral evolution is independent of the microenvironment and associated with aggressive recurrence and poor prognosis. Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibody agents (MoAbs), and autologous stem cell transplantation (ASCT) have improved prognosis of myeloma via improvement of the microenvironment. The initial treatment plays the most important role considering de novo and acquired drug resistance and should contain PIs, IMIDs, MoAb and ASCT. This review summarizes the role of anti-myeloma agents for microenvironment and clonal evolution and treatment strategies to overcome drug resistance. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)

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15 pages, 828 KiB

Open AccessEditor’s ChoiceReview

The Role of the Eph Receptor Family in Tumorigenesis

by Meg Anderton, Emma van der Meulen, Melissa J. Blumenthal and Georgia Schäfer

Cancers 2021, 13(2), 206; https://doi.org/10.3390/cancers13020206 - 08 Jan 2021

Cited by 38 | Viewed by 4751

Abstract

The Eph receptor tyrosine kinase family, activated by binding to their cognate ephrin ligands, are important components of signalling pathways involved in animal development. More recently, they have received significant interest due to their involvement in oncogenesis. In most cases, their expression is [...] Read more.

The Eph receptor tyrosine kinase family, activated by binding to their cognate ephrin ligands, are important components of signalling pathways involved in animal development. More recently, they have received significant interest due to their involvement in oncogenesis. In most cases, their expression is altered, affecting the likes of cell proliferation and migration. Depending on the context, Eph receptors have the potential to act as both tumour promoters and suppressors in a number of cancers, such as breast cancer, colorectal cancer, lung cancer, prostate cancer, brain cancer and Kaposi’s sarcoma (KS), the latter being intrinsically linked to EphA2 as this is the receptor used for endothelial cell entry by the Kaposi’s sarcoma-associated herpesvirus (KSHV). In addition, EphA2 deregulation is associated with KS, indicating that it has a dual role in this case. Associations between EphA2 sequence variation and KSHV infection/KS progression have been detected, but further work is required to formally establish the links between EphA2 signalling and KS oncogenesis. This review consolidates the available literature of the role of the Eph receptor family, and particularly EphA2, in tumorigenesis, with the aim to develop a better understanding of Eph signalling pathways for potential targeting in novel cancer therapies. Full article

(This article belongs to the Section Molecular Cancer Biology)

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34 pages, 2411 KiB

Open AccessEditor’s ChoiceReview

The Functional Crosstalk between Myeloid-Derived Suppressor Cells and Regulatory T Cells within the Immunosuppressive Tumor Microenvironment

by Maximilian Haist, Henner Stege, Stephan Grabbe and Matthias Bros

Cancers 2021, 13(2), 210; https://doi.org/10.3390/cancers13020210 - 08 Jan 2021

Cited by 83 | Viewed by 9345

Abstract

Immune checkpoint inhibitors (ICI) have led to profound and durable tumor regression in some patients with metastatic cancer diseases. However, many patients still do not derive benefit from immunotherapy. Here, the accumulation of immunosuppressive cell populations within the tumor microenvironment (TME), such as [...] Read more.

Immune checkpoint inhibitors (ICI) have led to profound and durable tumor regression in some patients with metastatic cancer diseases. However, many patients still do not derive benefit from immunotherapy. Here, the accumulation of immunosuppressive cell populations within the tumor microenvironment (TME), such as myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and regulatory T cells (Treg), contributes to the development of immune resistance. MDSC and Treg expand systematically in tumor patients and inhibit T cell activation and T effector cell function. Numerous studies have shown that the immunosuppressive mechanisms exerted by those inhibitory cell populations comprise soluble immunomodulatory mediators and receptor interactions. The latter are also required for the crosstalk of MDSC and Treg, raising questions about the relevance of cell–cell contacts for the establishment of their inhibitory properties. This review aims to outline the current knowledge on the crosstalk between these two cell populations, issuing particularly the potential role of cell adhesion molecules. In this regard, we further discuss the relevance of β2 integrins, which are essential for the differentiation and function of leukocytes as well as for MDSC–Treg interaction. Lastly, we aim to describe the impact of such bidirectional crosstalk for basic and applied cancer research and discuss how the targeting of these pathways might pave the way for future approaches in immunotherapy. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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17 pages, 6050 KiB

Open AccessEditor’s ChoiceArticle

Remodeling of the Lymph Node High Endothelial Venules Reflects Tumor Invasiveness in Breast Cancer and is Associated with Dysregulation of Perivascular Stromal Cells

by Tove Bekkhus, Teemu Martikainen, Anna Olofsson, Mathias Franzén Boger, Daniel Vasiliu Bacovia, Fredrik Wärnberg and Maria H. Ulvmar

Cancers 2021, 13(2), 211; https://doi.org/10.3390/cancers13020211 - 08 Jan 2021

Cited by 21 | Viewed by 5279

Abstract

The tumor-draining lymph nodes (TDLNs) are primary sites for induction of tumor immunity. They are also common sites of metastasis, suggesting that tumor-induced mechanisms can subvert anti-tumor immune responses and promote metastatic seeding. The high endothelial venules (HEVs) together with CCL21-expressing fibroblastic reticular [...] Read more.

The tumor-draining lymph nodes (TDLNs) are primary sites for induction of tumor immunity. They are also common sites of metastasis, suggesting that tumor-induced mechanisms can subvert anti-tumor immune responses and promote metastatic seeding. The high endothelial venules (HEVs) together with CCL21-expressing fibroblastic reticular cells (FRCs) are essential for lymphocyte recruitment into the LNs. We established multicolor antibody panels for evaluation of HEVs and FRCs in TDLNs from breast cancer (BC) patients. Our data show that patients with invasive BC display extensive structural and molecular remodeling of the HEVs, including vessel dilation, thinning of the endothelium and discontinuous expression of the HEV-marker PNAd. Remodeling of the HEVs was associated with dysregulation of CCL21 in perivascular FRCs and with accumulation of CCL21-saturated lymphocytes, which we link to loss of CCL21-binding heparan sulfate in FRCs. These changes were rare or absent in LNs from patients with non-invasive BC and cancer-free organ donors and were observed independent of nodal metastasis. Thus, pre-metastatic dysregulation of core stromal and vascular functions within TDLNs reflect the primary tumor invasiveness in BC. This adds to the understanding of cancer-induced perturbation of the immune response and opens for prospects of vascular and stromal changes in TDLNs as potential biomarkers. Full article

(This article belongs to the Section Tumor Microenvironment)

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Graphical abstract

21 pages, 1316 KiB

Open AccessEditor’s ChoiceReview

Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

by Kalpana K. Bhanumathy, Amrutha Balagopal, Frederick S. Vizeacoumar, Franco J. Vizeacoumar, Andrew Freywald and Vincenzo Giambra

Cancers 2021, 13(2), 184; https://doi.org/10.3390/cancers13020184 - 07 Jan 2021

Cited by 39 | Viewed by 8601

Abstract

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main [...] Read more.

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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35 pages, 1533 KiB

Open AccessEditor’s ChoiceReview

Resveratrol’s Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism

by Aranka Brockmueller, Saba Sameri, Alena Liskova, Kevin Zhai, Elizabeth Varghese, Samson Mathews Samuel, Dietrich Büsselberg, Peter Kubatka and Mehdi Shakibaei

Cancers 2021, 13(2), 188; https://doi.org/10.3390/cancers13020188 - 07 Jan 2021

Cited by 49 | Viewed by 7301

Abstract

Tumor cells develop several metabolic reprogramming strategies, such as increased glucose uptake and utilization via aerobic glycolysis and fermentation of glucose to lactate; these lead to a low pH environment in which the cancer cells thrive and evade apoptosis. These characteristics of tumor [...] Read more.

Tumor cells develop several metabolic reprogramming strategies, such as increased glucose uptake and utilization via aerobic glycolysis and fermentation of glucose to lactate; these lead to a low pH environment in which the cancer cells thrive and evade apoptosis. These characteristics of tumor cells are known as the Warburg effect. Adaptive metabolic alterations in cancer cells can be attributed to mutations in key metabolic enzymes and transcription factors. The features of the Warburg phenotype may serve as promising markers for the early detection and treatment of tumors. Besides, the glycolytic process of tumors is reversible and could represent a therapeutic target. So-called mono-target therapies are often unsafe and ineffective, and have a high prevalence of recurrence. Their success is hindered by the ability of tumor cells to simultaneously develop multiple chemoresistance pathways. Therefore, agents that modify several cellular targets, such as energy restriction to target tumor cells specifically, have therapeutic potential. Resveratrol, a natural active polyphenol found in grapes and red wine and used in many traditional medicines, is known for its ability to target multiple components of signaling pathways in tumors, leading to the suppression of cell proliferation, activation of apoptosis, and regression in tumor growth. Here, we describe current knowledge on the various mechanisms by which resveratrol modulates glucose metabolism, its potential as an imitator of caloric restriction, and its therapeutic capacity in tumors. Full article

(This article belongs to the Special Issue Significance of Altered (Glucose) Metabolism in Cancers)

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29 pages, 3481 KiB

Open AccessEditor’s ChoiceReview

Cancer and Stress: Does It Make a Difference to the Patient When These Two Challenges Collide?

by Anem Iftikhar, Mohammad Islam, Simon Shepherd, Sarah Jones and Ian Ellis

Cancers 2021, 13(2), 163; https://doi.org/10.3390/cancers13020163 - 06 Jan 2021

Cited by 20 | Viewed by 5765

Abstract

A single head and neck Cancer (HNC) is a globally growing challenge associated with significant morbidity and mortality. The diagnosis itself can affect the patients profoundly let alone the complex and disfiguring treatment. The highly important functions of structures of the head and [...] Read more.

A single head and neck Cancer (HNC) is a globally growing challenge associated with significant morbidity and mortality. The diagnosis itself can affect the patients profoundly let alone the complex and disfiguring treatment. The highly important functions of structures of the head and neck such as mastication, speech, aesthetics, identity and social interactions make a cancer diagnosis in this region even more psychologically traumatic. The emotional distress engendered as a result of functional and social disruption is certain to negatively affect health-related quality of life (HRQoL). The key biological responses to stressful events are moderated through the combined action of two systems, the hypothalamus–pituitary–adrenal axis (HPA) which releases glucocorticoids and the sympathetic nervous system (SNS) which releases catecholamines. In acute stress, these hormones help the body to regain homeostasis; however, in chronic stress their increased levels and activation of their receptors may aid in the progression of cancer. Despite ample evidence on the existence of stress in patients diagnosed with HNC, studies looking at the effect of stress on the progression of disease are scarce, compared to other cancers. This review summarises the challenges associated with HNC that make it stressful and describes how stress signalling aids in the progression of cancer. Growing evidence on the relationship between stress and HNC makes it paramount to focus future research towards a better understanding of stress and its effect on head and neck cancer. Full article

(This article belongs to the Special Issue Head and Neck Cancers)

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14 pages, 532 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Resistance to KRAS^G12C Inhibitors

by Victoria Dunnett-Kane, Pantelis Nicola, Fiona Blackhall and Colin Lindsay

Cancers 2021, 13(1), 151; https://doi.org/10.3390/cancers13010151 - 05 Jan 2021

Cited by 74 | Viewed by 11463

Abstract

KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of “undruggable”. Recent efforts to produce subtype specific inhibitors have been more successful, and several KRAS^G12C inhibitors have reached [...] Read more.

KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of “undruggable”. Recent efforts to produce subtype specific inhibitors have been more successful, and several KRAS^G12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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17 pages, 715 KiB

Open AccessEditor’s ChoiceReview

The Network of Cytokines in Brain Metastases

by Jawad Fares, Alex Cordero, Deepak Kanojia and Maciej S. Lesniak

Cancers 2021, 13(1), 142; https://doi.org/10.3390/cancers13010142 - 05 Jan 2021

Cited by 21 | Viewed by 4069

Abstract

Brain metastases are the most common of all intracranial tumors and a major cause of death in patients with cancer. Cytokines, including chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors are key regulators in the formation of brain metastases. They regulate the infiltration [...] Read more.

Brain metastases are the most common of all intracranial tumors and a major cause of death in patients with cancer. Cytokines, including chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors are key regulators in the formation of brain metastases. They regulate the infiltration of different cellular subsets into the tumor microenvironment and affect the therapeutic outcomes in patients. Elucidating the cancer cell-cytokine interactions in the setting of brain metastases is crucial for the development of more accurate diagnostics and efficacious therapies. In this review, we focus on cytokines that are found in the tumor microenvironment of brain metastases and elaborate on their trends of expression, regulation, and roles in cellular recruitment and tumorigenesis. We also explore how cytokines can alter the anti-tumor response in the context of brain metastases and discuss ways through which cytokine networks can be manipulated for diagnosis and treatment. Full article

(This article belongs to the Special Issue Cytokines in Cancer Immunotherapy)

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16 pages, 1752 KiB

Open AccessEditor’s ChoiceReview

Ways into Understanding HIF Inhibition

by Tina Schönberger, Joachim Fandrey and Katrin Prost-Fingerle

Cancers 2021, 13(1), 159; https://doi.org/10.3390/cancers13010159 - 05 Jan 2021

Cited by 24 | Viewed by 7518

Abstract

Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging [...] Read more.

Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds. Full article

(This article belongs to the Special Issue Inhibition of HIFs as an Anti-Cancer Strategy)

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12 pages, 1691 KiB

Open AccessEditor’s ChoiceArticle

Molecular Changes in Retinoblastoma beyond RB1: Findings from Next-Generation Sequencing

by Jasmine H. Francis, Allison L. Richards, Diana L. Mandelker, Michael F. Berger, Michael F. Walsh, Ira J. Dunkel, Mark T. A. Donoghue and David H. Abramson

Cancers 2021, 13(1), 149; https://doi.org/10.3390/cancers13010149 - 05 Jan 2021

Cited by 26 | Viewed by 4356

Abstract

This investigation uses hybridization capture-based next-generation sequencing to deepen our understanding of genetics that underlie retinoblastoma. Eighty-three enucleated retinoblastoma specimens were evaluated using a MSK-IMPACT clinical next-generation sequencing panel to evaluate both somatic and germline alterations. Somatic copy number variations (CNVs) were also [...] Read more.

This investigation uses hybridization capture-based next-generation sequencing to deepen our understanding of genetics that underlie retinoblastoma. Eighty-three enucleated retinoblastoma specimens were evaluated using a MSK-IMPACT clinical next-generation sequencing panel to evaluate both somatic and germline alterations. Somatic copy number variations (CNVs) were also identified. Genetic profiles were correlated to clinicopathologic characteristics. RB1 inactivation was found in 79 (97.5%) patients. All specimens had additional molecular alterations. The most common non-RB1 gene alteration was BCOR in 19 (22.9%). Five (11.0%) had pathogenic germline mutations in other non-RB1 cancer predisposition genes. Significant clinicopathologic correlations included: vitreous seeds associated with 1q gains and 16q loss of heterozygosity (BH-corrected p-value = 0.008, 0.004; OR = 12.6, 26.7, respectively). BCOR mutations were associated with poor prognosis, specifically metastases-free survival (MFS) (nominal p-value 0.03). Furthermore, retinoblastoma patients can have non-RB1 germline mutations in other cancer-associated genes. No two specimens had the identical genetic profile, emphasizing the individuality of tumors with the same clinical diagnosis. Full article

(This article belongs to the Section Methods and Technologies Development)

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30 pages, 2929 KiB

Open AccessEditor’s ChoiceReview

The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy

by Anastasia Mpakali and Efstratios Stratikos

Cancers 2021, 13(1), 134; https://doi.org/10.3390/cancers13010134 - 04 Jan 2021

Cited by 65 | Viewed by 7015

Abstract

Recent clinical successes of cancer immunotherapy using immune checkpoint inhibitors (ICIs) are rapidly changing the landscape of cancer treatment. Regardless of initial impressive clinical results though, the therapeutic benefit of ICIs appears to be limited to a subset of patients and tumor types. [...] Read more.

Recent clinical successes of cancer immunotherapy using immune checkpoint inhibitors (ICIs) are rapidly changing the landscape of cancer treatment. Regardless of initial impressive clinical results though, the therapeutic benefit of ICIs appears to be limited to a subset of patients and tumor types. Recent analyses have revealed that the potency of ICI therapies depends on the efficient presentation of tumor-specific antigens by cancer cells and professional antigen presenting cells. Here, we review current knowledge on the role of antigen presentation in cancer. We focus on intracellular antigen processing and presentation by Major Histocompatibility class I (MHCI) molecules and how it can affect cancer immune evasion. Finally, we discuss the pharmacological tractability of manipulating intracellular antigen processing as a complementary approach to enhance tumor immunogenicity and the effectiveness of ICI immunotherapy. Full article

(This article belongs to the Special Issue The Portrait of Cancer Immunotherapy: Tumor Microenvironment, Biomarkers and Immune Resistance)

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15 pages, 1701 KiB

Open AccessEditor’s ChoiceReview

The Evolutionary Landscape of Treatment for BRAF^V600E Mutant Metastatic Colorectal Cancer

by Gianluca Mauri, Erica Bonazzina, Alessio Amatu, Federica Tosi, Katia Bencardino, Viviana Gori, Daniela Massihnia, Tiziana Cipani, Francesco Spina, Silvia Ghezzi, Salvatore Siena and Andrea Sartore-Bianchi

Cancers 2021, 13(1), 137; https://doi.org/10.3390/cancers13010137 - 04 Jan 2021

Cited by 41 | Viewed by 6724

Abstract

The BRAF^V600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with [...] Read more.

The BRAF^V600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAF^V600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer: Biological Features, Old and New Treatments)

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13 pages, 590 KiB

Open AccessEditor’s ChoicePerspective

Sex Hormones and Hormone Therapy during COVID-19 Pandemic: Implications for Patients with Cancer

by Carlo Cattrini, Melissa Bersanelli, Maria Maddalena Latocca, Benedetta Conte, Giacomo Vallome and Francesco Boccardo

Cancers 2020, 12(8), 2325; https://doi.org/10.3390/cancers12082325 - 18 Aug 2020

Cited by 59 | Viewed by 7449

Abstract

The novel coronavirus disease 2019 (COVID-19) shows a wide spectrum of clinical presentations, severity, and fatality rates. The reason older patients and males show increased risk of severe disease and death remains uncertain. Sex hormones, such as estradiol, progesterone, and testosterone, might be [...] Read more.

The novel coronavirus disease 2019 (COVID-19) shows a wide spectrum of clinical presentations, severity, and fatality rates. The reason older patients and males show increased risk of severe disease and death remains uncertain. Sex hormones, such as estradiol, progesterone, and testosterone, might be implicated in the age-dependent and sex-specific severity of COVID-19. High testosterone levels could upregulate transmembrane serine protease 2 (TMPRSS2), facilitating the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells via angiotensin-converting enzyme 2 (ACE2). Data from patients with prostate cancer treated with androgen-deprivation therapy seem to confirm this hypothesis. Clinical studies on TMPRSS2 inhibitors, such as camostat, nafamostat, and bromhexine, are ongoing. Antiandrogens, such as bicalutamide and enzalutamide, are also under investigation. Conversely, other studies suggest that the immune modulating properties of androgens could protect from the unfavorable cytokine storm, and that low testosterone levels might be associated with a worse prognosis in patients with COVID-19. Some evidence also supports the notion that estrogens and progesterone might exert a protective effect on females, through direct antiviral activity or immune-mediated mechanisms, thus explaining the higher COVID-19 severity in post-menopausal women. In this perspective, we discuss the available evidence on sex hormones and hormone therapy in patients infected with SARS-CoV-2, and we highlight the possible implications for cancer patients, who can receive hormonal therapies during their treatment plans. Full article

(This article belongs to the Collection The Impact of COVID-19 Infection in Cancer)

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31 pages, 1324 KiB

Open AccessEditor’s ChoiceReview

Evolution of the Experimental Models of Cholangiocarcinoma

by Annamaria Massa, Chiara Varamo, Francesca Vita, Simona Tavolari, Caterina Peraldo-Neia, Giovanni Brandi, Alessandro Rizzo, Giuliana Cavalloni and Massimo Aglietta

Cancers 2020, 12(8), 2308; https://doi.org/10.3390/cancers12082308 - 17 Aug 2020

Cited by 75 | Viewed by 8901

Abstract

Cholangiocarcinoma (CCA) is a rare, aggressive disease with poor overall survival. In advanced cases, surgery is often not possible or fails; in addition, there is a lack of effective and specific therapies. Multidisciplinary approaches and advanced technologies have improved the knowledge of CCA [...] Read more.

Cholangiocarcinoma (CCA) is a rare, aggressive disease with poor overall survival. In advanced cases, surgery is often not possible or fails; in addition, there is a lack of effective and specific therapies. Multidisciplinary approaches and advanced technologies have improved the knowledge of CCA molecular pathogenesis, highlighting its extreme heterogeneity and high frequency of genetic and molecular aberrations. Effective preclinical models, therefore, should be based on a comparable level of complexity. In the past years, there has been a consistent increase in the number of available CCA models. The exploitation of even more complex CCA models is rising. Examples are the use of CRISPR/Cas9 or stabilized organoids for in vitro studies, as well as patient-derived xenografts or transgenic mouse models for in vivo applications. Here, we examine the available preclinical CCA models exploited to investigate: (i) carcinogenesis processes from initiation to progression; and (ii) tools for personalized therapy and innovative therapeutic approaches, including chemotherapy and immune/targeted therapies. For each model, we describe the potential applications, highlighting both its advantages and limits. Full article

(This article belongs to the Special Issue Immunotherapy and Targeted Agents for Biliary Tract Cancer)

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20 pages, 853 KiB

Open AccessEditor’s ChoiceReview

Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

by Lynda Wyld, Ilaria Bellantuono, Tamara Tchkonia, Jenna Morgan, Olivia Turner, Fiona Foss, Jayan George, Sarah Danson and James L. Kirkland

Cancers 2020, 12(8), 2134; https://doi.org/10.3390/cancers12082134 - 31 Jul 2020

Cited by 128 | Viewed by 11147

Abstract

Cellular senescence is a key component of human aging that can be induced by a range of stimuli, including DNA damage, cellular stress, telomere shortening, and the activation of oncogenes. Senescence is generally regarded as a tumour suppressive process, both by preventing cancer [...] Read more.

Cellular senescence is a key component of human aging that can be induced by a range of stimuli, including DNA damage, cellular stress, telomere shortening, and the activation of oncogenes. Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease. It may also be a key effector mechanism of many types of anticancer therapies, such as chemotherapy, radiotherapy, and endocrine therapies, both directly and via bioactive molecules released by senescent cells that may stimulate an immune response. However, senescence may contribute to reduced patient resilience to cancer therapies and may provide a pathway for disease recurrence after cancer therapy. A new group of drugs, senotherapies, (drugs which interact with senescent cells to interfere with their pro-aging impacts by either selectively destroying senescent cells (senolytic drugs) or inhibiting their function (senostatic drugs)) are under active investigation to determine whether they can enhance the efficacy of cancer therapies and improve resilience to cancer treatments. Senolytic drugs include quercetin, navitoclax, and fisetin and preclinical and early phase clinical data are emerging of their potential role in cancer treatments, although none are yet in routine use clinically. This article provides a review of these issues. Full article

(This article belongs to the Special Issue Senescence and Cancer)

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21 pages, 585 KiB

Open AccessEditor’s ChoiceReview

Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm

by Sakti Chakrabarti, Mandana Kamgar and Amit Mahipal

Cancers 2020, 12(8), 2039; https://doi.org/10.3390/cancers12082039 - 24 Jul 2020

Cited by 51 | Viewed by 4620

Abstract

Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of [...] Read more.

Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC. Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

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36 pages, 2920 KiB

Open AccessEditor’s ChoiceReview

Gold Nanoparticles as a Potent Radiosensitizer: A Transdisciplinary Approach from Physics to Patient

by Sébastien Penninckx, Anne-Catherine Heuskin, Carine Michiels and Stéphane Lucas

Cancers 2020, 12(8), 2021; https://doi.org/10.3390/cancers12082021 - 23 Jul 2020

Cited by 100 | Viewed by 5733

Abstract

Over the last decade, a growing interest in the improvement of radiation therapies has led to the development of gold-based nanomaterials as radiosensitizer. Although the radiosensitization effect was initially attributed to a dose enhancement mechanism, an increasing number of studies challenge this mechanistic [...] Read more.

Over the last decade, a growing interest in the improvement of radiation therapies has led to the development of gold-based nanomaterials as radiosensitizer. Although the radiosensitization effect was initially attributed to a dose enhancement mechanism, an increasing number of studies challenge this mechanistic hypothesis and evidence the importance of chemical and biological contributions. Despite extensive experimental validation, the debate regarding the mechanism(s) of gold nanoparticle radiosensitization is limiting its clinical translation. This article reviews the current state of knowledge by addressing how gold nanoparticles exert their radiosensitizing effects from a transdisciplinary perspective. We also discuss the current and future challenges to go towards a successful clinical translation of this promising therapeutic approach. Full article

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21 pages, 1306 KiB

Open AccessEditor’s ChoiceReview

A Comprehensive Review of Cancer MicroRNA Therapeutic Delivery Strategies

by Alexis Forterre, Hiroaki Komuro, Shakhlo Aminova and Masako Harada

Cancers 2020, 12(7), 1852; https://doi.org/10.3390/cancers12071852 - 09 Jul 2020

Cited by 138 | Viewed by 6709

Abstract

In the field of molecular oncology, microRNAs (miRNAs) and their role in regulating physiological processes and cancer pathogenesis have been a revolutionary discovery over the last decade. It is now considered that miRNA dysregulation influences critical molecular pathways involved in tumor progression, invasion, [...] Read more.

In the field of molecular oncology, microRNAs (miRNAs) and their role in regulating physiological processes and cancer pathogenesis have been a revolutionary discovery over the last decade. It is now considered that miRNA dysregulation influences critical molecular pathways involved in tumor progression, invasion, angiogenesis and metastasis in a wide range of cancer types. Hence, altering miRNA levels in cancer cells has promising potential as a therapeutic intervention, which is discussed in many other articles in this Special Issue. Some of the most significant hurdles in therapeutic miRNA usage are the stability and the delivery system. In this review, we cover a comprehensive update on the challenges and strategies for the development of therapeutic miRNA delivery systems that includes virus-based delivery, non-viral delivery (artificial lipid-based vesicles, polymer-based or chemical structures), and recently emerged extracellular vesicle (EV)-based delivery systems. Full article

(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)

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13 pages, 503 KiB

Open AccessEditor’s ChoiceArticle

Presenting Features and Early Mortality from SARS-CoV-2 Infection in Cancer Patients during the Initial Stage of the COVID-19 Pandemic in Europe

by David J. Pinato, Alvin J. X. Lee, Federica Biello, Elia Seguí, Juan Aguilar-Company, Anna Carbó, Riccardo Bruna, Mark Bower, Gianpiero Rizzo, Sarah Benafif, Carme Carmona, Neha Chopra, Claudia Andrea Cruz, Francesca D’Avanzo, Joanne S. Evans, Myria Galazi, Isabel Garcia-Fructuoso, Alessia Dalla Pria, Thomas Newsom-Davis, Diego Ottaviani, Andrea Patriarca, Roxana Reyes, Rachel Sharkey, Christopher C. T. Sng, Yien Ning Sophia Wong, Daniela Ferrante, Lorenza Scotti, Gian Carlo Avanzi, Mattia Bellan, Luigi Mario Castello, Javier Marco-Hernández, Meritxell Mollà, Mario Pirisi, Isabel Ruiz-Camps, Pier Paolo Sainaghi, Gianluca Gaidano, Joan Brunet, Josep Tabernero, Aleix Prat and Alessandra Gennari Show full author list Hide full author list

Cancers 2020, 12(7), 1841; https://doi.org/10.3390/cancers12071841 - 08 Jul 2020

Cited by 55 | Viewed by 6226

Abstract

We describe the outcomes in cancer patients during the initial outbreak of the COVID-19 in Europe from the retrospective, multi-center observational OnCovid study. We identified 204 cancer patients from eight centers in the United Kingdom, Italy, and Spain aged >18 (mean = 69) [...] Read more.

We describe the outcomes in cancer patients during the initial outbreak of the COVID-19 in Europe from the retrospective, multi-center observational OnCovid study. We identified 204 cancer patients from eight centers in the United Kingdom, Italy, and Spain aged >18 (mean = 69) and diagnosed with COVID-19 between 26 February and 1 April 2020. A total of 127 (62%) were male, 184 (91%) had a diagnosis of solid malignancy, and 103 (51%) had non-metastatic disease. A total of 161 (79%) had >1 co-morbidity. A total of 141 (69%) patients had >1 COVID-19 complication. A total of 36 (19%) were escalated to high-dependency or intensive care. A total of 59 (29%) died, 53 (26%) were discharged, and 92 (45%) were in-hospital survivors. Mortality was higher in patients aged >65 (36% vs. 16%), in those with >2 co-morbidities (40% vs. 18%) and developing >1 complication from COVID-19 (38% vs. 4%, p = 0.004). Multi-variable analyses confirmed age > 65 and >2 co-morbidities to predict for patient mortality independent of tumor stage, active malignancy, or anticancer therapy. During the early outbreak of SARS-CoV-2 infection in Europe co-morbid burden and advancing age predicted for adverse disease course in cancer patients. The ongoing OnCovid study will allow us to compare risks and outcomes in cancer patients between the initial and later stages of the COVID-19 pandemic. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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33 pages, 2255 KiB

Open AccessEditor’s ChoiceReview

MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy

by Annelisa M. Cornel, Iris L. Mimpen and Stefan Nierkens

Cancers 2020, 12(7), 1760; https://doi.org/10.3390/cancers12071760 - 02 Jul 2020

Cited by 189 | Viewed by 19272

Abstract

In recent years, major advances have been made in cancer immunotherapy. This has led to significant improvement in prognosis of cancer patients, especially in the hematological setting. Nonetheless, translation of these successes to solid tumors was found difficult. One major mechanism through which [...] Read more.

In recent years, major advances have been made in cancer immunotherapy. This has led to significant improvement in prognosis of cancer patients, especially in the hematological setting. Nonetheless, translation of these successes to solid tumors was found difficult. One major mechanism through which solid tumors can avoid anti-tumor immunity is the downregulation of major histocompatibility complex class I (MHC-I), which causes reduced recognition by- and cytotoxicity of CD8⁺ T-cells. Downregulation of MHC-I has been described in 40–90% of human tumors, often correlating with worse prognosis. Epigenetic and (post-)transcriptional dysregulations relevant in the stabilization of NFkB, IRFs, and NLRC5 are often responsible for MHC-I downregulation in cancer. The intrinsic reversible nature of these dysregulations provides an opportunity to restore MHC-I expression and facilitate adaptive anti-tumor immunity. In this review, we provide an overview of the mechanisms underlying reversible MHC-I downregulation and describe potential strategies to counteract this reduction in MHC-I antigen presentation in cancer. Full article

(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)

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28 pages, 2670 KiB

Open AccessEditor’s ChoiceReview

Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

by Flávia Alves Verza, Umashankar Das, Ana Lúcia Fachin, Jonathan R. Dimmock and Mozart Marins

Cancers 2020, 12(6), 1664; https://doi.org/10.3390/cancers12061664 - 23 Jun 2020

Cited by 74 | Viewed by 5377

Abstract

Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of [...] Read more.

Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of transcription factors which can induce or repress gene transcription. The HATs catalyze acetylation and the events related to gene transcription and are also responsible for transporting newly synthesized histones from the cytoplasm to the nucleus. The activity of HDACs is mainly involved in silencing gene expression and according to their specialized functions are divided into classes I, II, III and IV. The disturbance of the expression and mutations of HDAC genes causes the aberrant transcription of key genes regulating important cancer pathways such as cell proliferation, cell-cycle regulation and apoptosis. In view of their role in cancer pathways, HDACs are considered promising therapeutic targets and the development of HDAC inhibitors is a hot topic in the search for new anticancer drugs. The present review will focus on HDACs I, II and IV, the best known inhibitors and potential alternative inhibitors derived from natural and synthetic products which can be used to influence HDAC activity and the development of new cancer therapies. Full article

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38 pages, 1489 KiB

Open AccessEditor’s ChoiceReview

EMT-Associated Heterogeneity in Circulating Tumor Cells: Sticky Friends on the Road to Metastasis

by Anthony Genna, Aline M. Vanwynsberghe, Amélie V. Villard, Charles Pottier, Julien Ancel, Myriam Polette and Christine Gilles

Cancers 2020, 12(6), 1632; https://doi.org/10.3390/cancers12061632 - 19 Jun 2020

Cited by 70 | Viewed by 5228

Abstract

Epithelial–mesenchymal transitions (EMTs) generate hybrid phenotypes with an enhanced ability to adapt to diverse microenvironments encountered during the metastatic spread. Accordingly, EMTs play a crucial role in the biology of circulating tumor cells (CTCs) and contribute to their heterogeneity. Here, we review major [...] Read more.

Epithelial–mesenchymal transitions (EMTs) generate hybrid phenotypes with an enhanced ability to adapt to diverse microenvironments encountered during the metastatic spread. Accordingly, EMTs play a crucial role in the biology of circulating tumor cells (CTCs) and contribute to their heterogeneity. Here, we review major EMT-driven properties that may help hybrid Epithelial/Mesenchymal CTCs to survive in the bloodstream and accomplish early phases of metastatic colonization. We then discuss how interrogating EMT in CTCs as a companion biomarker could help refine cancer patient management, further supporting the relevance of CTCs in personalized medicine. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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28 pages, 1261 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Combined PARP Inhibition and Immune Checkpoint Therapy in Solid Tumors

by Florent Peyraud and Antoine Italiano

Cancers 2020, 12(6), 1502; https://doi.org/10.3390/cancers12061502 - 09 Jun 2020

Cited by 135 | Viewed by 8650

Abstract

Genomic instability is a hallmark of cancer related to DNA damage response (DDR) deficiencies, offering vulnerabilities for targeted treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) interfere with the efficient repair of DNA damage, particularly in tumors with existing defects in DNA repair, and [...] Read more.

Genomic instability is a hallmark of cancer related to DNA damage response (DDR) deficiencies, offering vulnerabilities for targeted treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) interfere with the efficient repair of DNA damage, particularly in tumors with existing defects in DNA repair, and induce synthetic lethality. PARPi are active across a range of tumor types harboring BRCA mutations and also BRCA-negative cancers, such as ovarian, breast or prostate cancers with homologous recombination deficiencies (HRD). Depending on immune contexture, immune checkpoint inhibitors (ICIs), such as anti-PD1/PD-L1 and anti-CTLA-4, elicit potent antitumor effects and have been approved in various cancers types. Although major breakthroughs have been performed with either PARPi or ICIs alone in multiple cancers, primary or acquired resistance often leads to tumor escape. PARPi-mediated unrepaired DNA damages modulate the tumor immune microenvironment by a range of molecular and cellular mechanisms, such as increasing genomic instability, immune pathway activation, and PD-L1 expression on cancer cells, which might promote responsiveness to ICIs. In this context, PARPi and ICIs represent a rational combination. In this review, we summarize the basic and translational biology supporting the combined strategy. We also detail preclinical results and early data of ongoing clinical trials indicating the synergistic effect of PARPi and ICIs. Moreover, we discuss the limitations and the future direction of the combination. Full article

(This article belongs to the Special Issue PARPs, PAR and NAD Metabolism and Their Inhibitors in Cancer)

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29 pages, 1234 KiB

Open AccessEditor’s ChoiceReview

BCMA-Targeting Therapy: Driving a New Era of Immunotherapy in Multiple Myeloma

by Shih-Feng Cho, Liang Lin, Lijie Xing, Yuyin Li, Tengteng Yu, Kenneth C Anderson and Yu-Tzu Tai

Cancers 2020, 12(6), 1473; https://doi.org/10.3390/cancers12061473 - 05 Jun 2020

Cited by 38 | Viewed by 7692

Abstract

The treatment of multiple myeloma (MM) has entered into a new era of immunotherapy. Novel immunotherapies will significantly improve patient outcome via simultaneously targeting malignant plasma cell (PC) and reversing immunocompromised bone marrow (BM) microenvironment. B-cell maturation antigen (BCMA), selectively expressed in PCs [...] Read more.

The treatment of multiple myeloma (MM) has entered into a new era of immunotherapy. Novel immunotherapies will significantly improve patient outcome via simultaneously targeting malignant plasma cell (PC) and reversing immunocompromised bone marrow (BM) microenvironment. B-cell maturation antigen (BCMA), selectively expressed in PCs and a key receptor for A proliferation-inducing ligand (APRIL), is highly expressed in MM cells from patients at all stages. The APRIL/BCMA signal cascades promote the survival and drug resistance of MM cells and further modulate immunosuppressive BM milieu. Impressively, anti-BCMA immunotherapeutic reagents, including chimeric antigen receptor (CAR), antibody-drug conjugate (ADC) and bispecific T cell engager (BiTE) have all shown high response rates in their first clinical trials in relapse and refractory patients with very limited treatment options. These results rapidly inspired numerous development of next-generation anti-BCMA biotherapeutics, i.e., bispecific molecule, bispecific or trispecific antibodies, a novel form of CAR T/NK cells and T Cell Antigen Coupler (TAC) receptors, antibody-coupled T cell receptor (ACTR) as well as a cancer vaccine. We here highlight seminal preclinical and clinical studies on novel BCMA-based immunotherapies as effective monotherapy and discuss their potential in combination with current anti-MM and novel checkpoint drugs in earlier disease stages to further achieve durable responses in patients. Full article

(This article belongs to the Special Issue Antigens and Cancer Therapy)

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29 pages, 1482 KiB

Open AccessEditor’s ChoiceReview

The Role of the Gut Microbiome in Colorectal Cancer Development and Therapy Response

by Lidia Sánchez-Alcoholado, Bruno Ramos-Molina, Ana Otero, Aurora Laborda-Illanes, Rafael Ordóñez, José Antonio Medina, Jaime Gómez-Millán and María Isabel Queipo-Ortuño

Cancers 2020, 12(6), 1406; https://doi.org/10.3390/cancers12061406 - 29 May 2020

Cited by 169 | Viewed by 13599

Abstract

Colorectal cancer (CRC) is the third most common cancer worldwide and the leading cause of cancer-related deaths. Recently, several studies have demonstrated that gut microbiota can alter CRC susceptibility and progression by modulating mechanisms such as inflammation and DNA damage, and by producing [...] Read more.

Colorectal cancer (CRC) is the third most common cancer worldwide and the leading cause of cancer-related deaths. Recently, several studies have demonstrated that gut microbiota can alter CRC susceptibility and progression by modulating mechanisms such as inflammation and DNA damage, and by producing metabolites involved in tumor progression or suppression. Dysbiosis of gut microbiota has been observed in patients with CRC, with a decrease in commensal bacterial species (butyrate-producing bacteria) and an enrichment of detrimental bacterial populations (pro-inflammatory opportunistic pathogens). CRC is characterized by altered production of bacterial metabolites directly involved in cancer metabolism including short-chain fatty acids and polyamines. Emerging evidence suggests that diet has an important impact on the risk of CRC development. The intake of high-fiber diets and the supplementation of diet with polyunsaturated fatty acids, polyphenols and probiotics, which are known to regulate gut microbiota, could be not only a potential mechanism for the reduction of CRC risk in a primary prevention setting, but may also be important to enhance the response to cancer therapy when used as adjuvant to conventional treatment for CRC. Therefore, a personalized modulation of the pattern of gut microbiome by diet may be a promising approach to prevent the development and progression of CRC and to improve the efficacy of antitumoral therapy. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

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14 pages, 285 KiB

Open AccessEditor’s ChoiceReview

PSMA Theranostics: Review of the Current Status of PSMA-Targeted Imaging and Radioligand Therapy

by Wallace Jones, Kelly Griffiths, Pedro C. Barata and Channing J. Paller

Cancers 2020, 12(6), 1367; https://doi.org/10.3390/cancers12061367 - 26 May 2020

Cited by 70 | Viewed by 6082

Abstract

Prostate-specific membrane antigen (PSMA) has been the subject of extensive investigation in the past two decades as a promising molecular target for prostate cancer (PCa). Its appealing molecular features have enabled the development of a novel diagnostic and therapeutic—thus “theranostic”—approach to PCa. There [...] Read more.

Prostate-specific membrane antigen (PSMA) has been the subject of extensive investigation in the past two decades as a promising molecular target for prostate cancer (PCa). Its appealing molecular features have enabled the development of a novel diagnostic and therapeutic—thus “theranostic”—approach to PCa. There is now substantial evidence of the high sensitivity of PSMA-targeted imaging for PCa lesions and growing evidence of the therapeutic efficacy of PSMA radioligand therapy for metastatic castration-resistant prostate cancer. This article presents a broad overview of the current status of PSMA theranostics, including current evidence, potential clinical impact, and active areas of research. Full article

(This article belongs to the Special Issue New Therapies for Prostate Cancer)

18 pages, 1731 KiB

Open AccessEditor’s ChoiceReview

Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

by Jeffrey Norton, Deshka Foster, Malini Chinta, Ashley Titan and Michael Longaker

Cancers 2020, 12(5), 1347; https://doi.org/10.3390/cancers12051347 - 25 May 2020

Cited by 77 | Viewed by 7796

Abstract

Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis [...] Read more.

Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer. Full article

(This article belongs to the Special Issue A Special Issue on Tumor Stroma )

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20 pages, 3732 KiB

Open AccessEditor’s ChoiceArticle

The Dynamic Relationship of Breast Cancer Cells and Fibroblasts in Fibronectin Accumulation at Primary and Metastatic Tumor Sites

by Sarah Libring, Aparna Shinde, Monica K. Chanda, Maryam Nuru, Heather George, Aya M. Saleh, Ammara Abdullah, Tamara L. Kinzer-Ursem, Sarah Calve, Michael K. Wendt and Luis Solorio

Cancers 2020, 12(5), 1270; https://doi.org/10.3390/cancers12051270 - 17 May 2020

Cited by 67 | Viewed by 8049

Abstract

In breast cancer (BC), tissue stiffening via fibronectin (FN) and collagen accumulation is associated with advanced disease progression at both the primary tumor and metastatic sites. Here, we evaluate FN production in 15 BC cell lines, representing a variety of subtypes, phenotypes, metastatic [...] Read more.

In breast cancer (BC), tissue stiffening via fibronectin (FN) and collagen accumulation is associated with advanced disease progression at both the primary tumor and metastatic sites. Here, we evaluate FN production in 15 BC cell lines, representing a variety of subtypes, phenotypes, metastatic potentials, and chemotherapeutic sensitivities. We demonstrate that intracellular and soluble FN is initially lost during tumorigenic transformation but is rescued in all lines with epithelial-mesenchymal plasticity (EMP). Importantly, we establish that no BC cell line was able to independently organize a robust FN matrix. Non-transformed mammary epithelial cells were also unable to deposit FN matrices unless transglutaminase 2, a FN crosslinking enzyme, was overexpressed. Instead, BC cells manipulated the FN matrix production of fibroblasts in a phenotypic-dependent manner. In addition, varied accumulation levels were seen depending if the fibroblasts were conditioned to model paracrine signaling or endocrine signaling of the metastatic niche. In the former, fibroblasts conditioned by BC cultures with high EMP resulted in the largest FN matrix accumulation. In contrast, mesenchymal BC cells produced extracellular vesicles (EV) that resulted in the highest levels of matrix formation by conditioned fibroblasts. Overall, we demonstrate a dynamic relationship between tumor and stromal cells within the tumor microenvironment, in which the levels and fibrillarization of FN in the extracellular matrix are modulated during the particular stages of disease progression. Full article

(This article belongs to the Special Issue A Special Issue on Tumor Stroma )

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14 pages, 880 KiB

Open AccessEditor’s ChoiceReview

The Effects of Obesity on Anti-Cancer Immunity and Cancer Immunotherapy

by Matthew J. Woodall, Silke Neumann, Katrin Campbell, Sharon T. Pattison and Sarah L. Young

Cancers 2020, 12(5), 1230; https://doi.org/10.3390/cancers12051230 - 14 May 2020

Cited by 67 | Viewed by 5831

Abstract

Cancer is one of the leading causes of morbidity and mortality worldwide. Traditional treatments include surgery, chemotherapy and radiation therapy, and more recently targeted therapies including immunotherapy are becoming routine care for some cancers. Immunotherapy aims to upregulate the patient’s own immune system, [...] Read more.

Cancer is one of the leading causes of morbidity and mortality worldwide. Traditional treatments include surgery, chemotherapy and radiation therapy, and more recently targeted therapies including immunotherapy are becoming routine care for some cancers. Immunotherapy aims to upregulate the patient’s own immune system, enabling it to destroy cancerous cells. Obesity is a metabolic disorder characterized by significant weight that is an important contributor to many different diseases, including cancers. Obesity impacts the immune system and causes, among other things, a state of chronic low-grade inflammation. This is hypothesized to impact the efficacy of the immunotherapies. This review discusses the effects of obesity on the immune system and cancer immunotherapy, including the current evidence on the effect of obesity on immune checkpoint blockade, something which currently published reviews on this topic have not delved into. Data from several studies show that even though obesity causes a state of chronic low-grade inflammation with reductions in effector immune populations, it has a beneficial effect on patient survival following anti-PD-1/PD-L1 and anti-CTLA-4 treatment. However, research in this field is just emerging and further work is needed to expand our understanding of which cancer patients are likely to benefit from immunotherapy. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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14 pages, 295 KiB

Open AccessEditor’s ChoiceReview

Biliary Tract Cancer: Current Medical Treatment Strategies

by Ester Oneda, Mohammed Abu Hilal and Alberto Zaniboni

Cancers 2020, 12(5), 1237; https://doi.org/10.3390/cancers12051237 - 14 May 2020

Cited by 41 | Viewed by 4531

Abstract

Background: Biliary tract cancers (BTCs) include cholangiocarcinomas and gallbladder cancers usually present at an advanced stage, which are considered resectable in less than 20% of cases and characterised by poor prognosis. Methods: In this review, we discussed the most recent therapeutic options on [...] Read more.

Background: Biliary tract cancers (BTCs) include cholangiocarcinomas and gallbladder cancers usually present at an advanced stage, which are considered resectable in less than 20% of cases and characterised by poor prognosis. Methods: In this review, we discussed the most recent therapeutic options on the basis of the most updated and complete reviews and recent prospective studies in selected BTC patients. Results: Due to the high recurrence rate of BTCs, we suggest the new recommendations that have been made on adjuvant chemotherapy and radiotherapy treatment after surgery. New chemotherapy combinations in advanced-stage patients allow a better survival benefit than the standard treatment. Furthermore, the revelation of complex molecular events and their interactions and relationships with some risk factors allowed the development of targeted/toxic agents alone or combination with chemotherapy that is really promising. In unresectable patients, hepatic arterial infusion of high-dose chemotherapy or selective internal radiotherapy could offer a primary mass volume reduction or its resection with the maintenance of liver function. Conclusions: The therapeutic landscape for BTCs is blooming again, the knowledge of their biology is still growing, but the available data on chemotherapy, radiotherapy, locoregional treatments, and target therapies have added hopes to improve patient survival. Full article

18 pages, 2429 KiB

Open AccessEditor’s ChoiceReview

Inducing Angiogenesis, a Key Step in Cancer Vascularization, and Treatment Approaches

by Harman Saman, Syed Shadab Raza, Shahab Uddin and Kakil Rasul

Cancers 2020, 12(5), 1172; https://doi.org/10.3390/cancers12051172 - 06 May 2020

Cited by 80 | Viewed by 7629

Abstract

Angiogenesis is a term that describes the formation of new blood and lymphatic vessels from a pre-existing vasculature. This allows tumour cells to acquire sustenance in the form of nutrients and oxygen and the ability to evacuate metabolic waste. As one of the [...] Read more.

Angiogenesis is a term that describes the formation of new blood and lymphatic vessels from a pre-existing vasculature. This allows tumour cells to acquire sustenance in the form of nutrients and oxygen and the ability to evacuate metabolic waste. As one of the hallmarks of cancer, angiogenesis has been studied extensively in animal and human models to enable better understanding of cancer biology and the development of new anti-cancer treatments. Angiogenesis plays a crucial role in the process of tumour genesis, because solid tumour need a blood supply if they are to grow beyond a few millimeters in size. On the other hand, there is growing evidence that some solid tumour exploit existing normal blood supply and do not require a new vessel formation to grow and to undergo metastasis. This review of the literature will present the current understanding of this intricate process and the latest advances in the use of angiogenesis-targeting therapies in the fight against cancer. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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20 pages, 4638 KiB

Open AccessEditor’s ChoiceArticle

A Novel 4-gene Score to Predict Survival, Distant Metastasis and Response to Neoadjuvant Therapy in Breast Cancer

by Masanori Oshi, Eriko Katsuta, Li Yan, John M.L. Ebos, Omar M. Rashid, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe

Cancers 2020, 12(5), 1148; https://doi.org/10.3390/cancers12051148 - 02 May 2020

Cited by 46 | Viewed by 5307

Abstract

We generated a 4-gene score with genes upregulated in LM2-4, a metastatic variant of MDA-MB-231 (DOK 4, HCCS, PGF, and SHCBP1) that was strongly associated with disease-free survival (DFS) in TCGA cohort (hazard ratio [HR]>1.2, p < 0.02). The 4-gene score correlated with [...] Read more.

We generated a 4-gene score with genes upregulated in LM2-4, a metastatic variant of MDA-MB-231 (DOK 4, HCCS, PGF, and SHCBP1) that was strongly associated with disease-free survival (DFS) in TCGA cohort (hazard ratio [HR]>1.2, p < 0.02). The 4-gene score correlated with overall survival of TCGA (HR = 1.44, p < 0.001), which was validated with DFS and disease-specific survival of METABRIC cohort. The 4-gene score was able to predict worse survival or clinically aggressive tumors, such as high Nottingham pathological grade and advanced cancer staging. High score was associated with worse survival in the hormonal receptor (HR)-positive/Her2-negative subtype. High score enriched cell proliferation-related gene sets in GSEA. The score was high in primary tumors that originated, in and metastasized to, brain and lung, and it predicted worse progression-free survival for metastatic tumors. Good tumor response to neoadjuvant chemotherapy or hormonal therapy was accompanied by score reduction. High scores were also predictive of response to neoadjuvant chemotherapy for HR-positive/Her2-negative subtype. High score tumors had increased expression of T cell exhaustion marker genes, suggesting that the score may also be a biomarker for immunotherapy response. Our novel 4-gene score with both prognostic and predictive values may, therefore, be clinically useful particularly in HR-positive breast cancer. Full article

(This article belongs to the Collection Novel Biomarkers and Molecular Targets in Cancer)

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22 pages, 1045 KiB

Open AccessEditor’s ChoiceReview

Warburg and Beyond: The Power of Mitochondrial Metabolism to Collaborate or Replace Fermentative Glycolysis in Cancer

by Shamir Cassim, Milica Vučetić, Maša Ždralević and Jacques Pouyssegur

Cancers 2020, 12(5), 1119; https://doi.org/10.3390/cancers12051119 - 30 Apr 2020

Cited by 110 | Viewed by 9899

Abstract

A defining hallmark of tumor phenotypes is uncontrolled cell proliferation, while fermentative glycolysis has long been considered as one of the major metabolic pathways that allows energy production and provides intermediates for the anabolic growth of cancer cells. Although such a vision has [...] Read more.

A defining hallmark of tumor phenotypes is uncontrolled cell proliferation, while fermentative glycolysis has long been considered as one of the major metabolic pathways that allows energy production and provides intermediates for the anabolic growth of cancer cells. Although such a vision has been crucial for the development of clinical imaging modalities, it has become now evident that in contrast to prior beliefs, mitochondria play a key role in tumorigenesis. Recent findings demonstrated that a full genetic disruption of the Warburg effect of aggressive cancers does not suppress but instead reduces tumor growth. Tumor growth then relies exclusively on functional mitochondria. Besides having fundamental bioenergetic functions, mitochondrial metabolism indeed provides appropriate building blocks for tumor anabolism, controls redox balance, and coordinates cell death. Hence, mitochondria represent promising targets for the development of novel anti-cancer agents. Here, after revisiting the long-standing Warburg effect from a historic and dynamic perspective, we review the role of mitochondria in cancer with particular attention to the cancer cell-intrinsic/extrinsic mechanisms through which mitochondria influence all steps of tumorigenesis, and briefly discuss the therapeutic potential of targeting mitochondrial metabolism for cancer therapy. Full article

(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)

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38 pages, 1760 KiB

Open AccessEditor’s ChoiceReview

Current Approaches for Combination Therapy of Cancer: The Role of Immunogenic Cell Death

by Zahra Asadzadeh, Elham Safarzadeh, Sahar Safaei, Ali Baradaran, Ali Mohammadi, Khalil Hajiasgharzadeh, Afshin Derakhshani, Antonella Argentiero, Nicola Silvestris and Behzad Baradaran

Cancers 2020, 12(4), 1047; https://doi.org/10.3390/cancers12041047 - 23 Apr 2020

Cited by 157 | Viewed by 8653

Abstract

Cell death resistance is a key feature of tumor cells. One of the main anticancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be [...] Read more.

Cell death resistance is a key feature of tumor cells. One of the main anticancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be suggested as an effective approach against cancer. Accumulating evidence proposes that several anticancer agents provoke the release of danger-associated molecular patterns (DAMPs) that are determinants of immunogenicity and stimulate immunogenic cell death (ICD). It has been suggested that ICD inducers are two different types according to their various activities. Here, we review the well-characterized DAMPs and focus on the different types of ICD inducers and recent combination therapies that can augment the immunogenicity of cancer cells. Full article

(This article belongs to the Special Issue Immunogenic Cell Death and Immunotherapy in Cancers)

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20 pages, 1530 KiB

Open AccessEditor’s ChoiceReview

Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies

by Vaishnavi Muralikrishnan, Thomas D. Hurley and Kenneth P. Nephew

Cancers 2020, 12(4), 961; https://doi.org/10.3390/cancers12040961 - 13 Apr 2020

Cited by 35 | Viewed by 7675

Abstract

Gynecologic cancers cause over 600,000 deaths annually in women worldwide. The development of chemoresistance after initial rounds of chemotherapy contributes to tumor relapse and death due to gynecologic malignancies. In this regard, cancer stem cells (CSCs), a subpopulation of stem cells with the [...] Read more.

Gynecologic cancers cause over 600,000 deaths annually in women worldwide. The development of chemoresistance after initial rounds of chemotherapy contributes to tumor relapse and death due to gynecologic malignancies. In this regard, cancer stem cells (CSCs), a subpopulation of stem cells with the ability to undergo self-renewal and clonal evolution, play a key role in tumor progression and drug resistance. Aldehyde dehydrogenases (ALDH) are a group of enzymes shown to be robust CSC markers in gynecologic and other malignancies. These enzymes also play functional roles in CSCs, including detoxification of aldehydes, scavenging of reactive oxygen species (ROS), and retinoic acid (RA) signaling, making ALDH an attractive therapeutic target in various clinical scenarios. In this review, we discuss the critical roles of the ALDH in driving stemness in different gynecologic malignancies. We review inhibitors of ALDH, both general and isoform-specific, which have been used to target CSCs in gynecologic cancers. Many of these inhibitors have been shown to be effective in preclinical models of gynecologic malignancies, supporting further development in the clinic. Furthermore, ALDH inhibitors, including 673A and CM037, synergize with chemotherapy to reduce tumor growth. Thus, ALDH-targeted therapies hold promise for improving patient outcomes in gynecologic malignancies. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)

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28 pages, 1355 KiB

Open AccessEditor’s ChoiceReview

Glioblastoma: Pathogenesis and Current Status of Chemotherapy and Other Novel Treatments

by Vilashini Rajaratnam, Mohammad Mohiminul Islam, Maixee Yang, Rachel Slaby, Hilda Martinez Ramirez and Shama Parveen Mirza

Cancers 2020, 12(4), 937; https://doi.org/10.3390/cancers12040937 - 10 Apr 2020

Cited by 80 | Viewed by 9871

Abstract

Glioblastoma is one of the most common and detrimental forms of solid brain tumor, with over 10,000 new cases reported every year in the United States. Despite aggressive multimodal treatment approaches, the overall survival period is reported to be less than 15 months [...] Read more.

Glioblastoma is one of the most common and detrimental forms of solid brain tumor, with over 10,000 new cases reported every year in the United States. Despite aggressive multimodal treatment approaches, the overall survival period is reported to be less than 15 months after diagnosis. A widely used approach for the treatment of glioblastoma is surgical removal of the tumor, followed by radiotherapy and chemotherapy. While there are several drugs available that are approved by the Food and Drug Administration (FDA), significant efforts have been made in recent years to develop new chemotherapeutic agents for the treatment of glioblastoma. This review describes the molecular targets and pathogenesis as well as the current progress in chemotherapeutic development and other novel therapies in the clinical setting for the treatment of glioblastoma. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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31 pages, 2085 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

by Nurbubu T. Moldogazieva, Innokenty M. Mokhosoev and Alexander A. Terentiev

Cancers 2020, 12(4), 862; https://doi.org/10.3390/cancers12040862 - 02 Apr 2020

Cited by 94 | Viewed by 15410

Abstract

It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over [...] Read more.

It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatidyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs. Full article

(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)

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38 pages, 550 KiB

Open AccessEditor’s ChoiceReview

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

by Tareq Saleh, Sarah Bloukh, Valerie J. Carpenter, Enas Alwohoush, Jomana Bakeer, Sarah Darwish, Belal Azab and David A. Gewirtz

Cancers 2020, 12(4), 822; https://doi.org/10.3390/cancers12040822 - 29 Mar 2020

Cited by 159 | Viewed by 13091

Abstract

For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. [...] Read more.

For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse. Full article

(This article belongs to the Special Issue Senescence and Cancer)

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25 pages, 358 KiB

Open AccessEditor’s ChoiceReview

Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes

by Anna Diana, Francesca Carlino, Elisena Franzese, Olga Oikonomidou, Carmen Criscitiello, Ferdinando De Vita, Fortunato Ciardiello and Michele Orditura

Cancers 2020, 12(4), 819; https://doi.org/10.3390/cancers12040819 - 29 Mar 2020

Cited by 53 | Viewed by 7263

Abstract

Triple negative breast cancers (TNBCs) are characterized by worse prognosis, higher propensity to earlier metastases, and shorter survival after recurrence compared with other breast cancer subtypes. Anthracycline- and taxane-based chemotherapy is still the mainstay of treatment in early stages, although several escalation approaches [...] Read more.

Triple negative breast cancers (TNBCs) are characterized by worse prognosis, higher propensity to earlier metastases, and shorter survival after recurrence compared with other breast cancer subtypes. Anthracycline- and taxane-based chemotherapy is still the mainstay of treatment in early stages, although several escalation approaches have been evaluated to improve survival outcomes. The addition of platinum salts to standard neoadjuvant chemotherapy (NACT) remains controversial due to the lack of clear survival advantage, and the use of adjuvant capecitabine represents a valid treatment option in TNBC patients with residual disease after NACT. Recently, several clinical trials showed promising results through the use of poly ADP-ribose polymerase (PARP) inhibitors and by incorporating immunotherapy with chemotherapy, enriching treatment options beyond conventional cytotoxic agents. In this review, we provided an overview on the current standard of care and a comprehensive update of the recent advances in the management of early stage TNBC and focused on the latest emerging biomarkers and their clinical application to select the best therapeutic strategy in this hard-to-treat population. Full article

(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)

15 pages, 293 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Immunotherapy for Hepatocellular Carcinoma

by Shigeharu Nakano, Yuji Eso, Hirokazu Okada, Atsushi Takai, Ken Takahashi and Hiroshi Seno

Cancers 2020, 12(4), 775; https://doi.org/10.3390/cancers12040775 - 25 Mar 2020

Cited by 60 | Viewed by 6249

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of [...] Read more.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of cancer therapy. Since HCC is characterized by metachronous multicentric occurrence, immunotherapies that induce systemic and durable responses could be an appealing treatment option. Despite the suppressive milieu of the liver and tumor immunosurveillance escape mechanisms, clinical studies of checkpoint inhibitors in patients with advanced HCC have yielded promising results. Here, we provide an update on recent advances in HCC immunotherapies. First, we describe the unique tolerogenic properties of hepatic immunity and its interaction with HCC and then review the status of already or nearly available immune checkpoint blockade-based therapies as well as other immunotherapy strategies at the preclinical or clinical trial stage. Full article

(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)

27 pages, 1353 KiB

Open AccessEditor’s ChoiceReview

The Emerging Roles of RNA Modifications in Glioblastoma

by Zhen Dong and Hongjuan Cui

Cancers 2020, 12(3), 736; https://doi.org/10.3390/cancers12030736 - 20 Mar 2020

Cited by 85 | Viewed by 8192

Abstract

Glioblastoma (GBM) is a grade IV glioma that is the most malignant brain tumor type. Currently, there are no effective and sufficient therapeutic strategies for its treatment because its pathological mechanism is not fully characterized. With the fast development of the Next Generation [...] Read more.

Glioblastoma (GBM) is a grade IV glioma that is the most malignant brain tumor type. Currently, there are no effective and sufficient therapeutic strategies for its treatment because its pathological mechanism is not fully characterized. With the fast development of the Next Generation Sequencing (NGS) technology, more than 170 kinds of covalent ribonucleic acid (RNA) modifications are found to be extensively present in almost all living organisms and all kinds of RNAs, including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and messenger RNAs (mRNAs). RNA modifications are also emerging as important modulators in the regulation of biological processes and pathological progression, and study of the epi-transcriptome has been a new area for researchers to explore their connections with the initiation and progression of cancers. Recently, RNA modifications, especially m⁶A, and their RNA-modifying proteins (RMPs) such as methyltransferase like 3 (METTL3) and α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5), have also emerged as important epigenetic mechanisms for the aggressiveness and malignancy of GBM, especially the pluripotency of glioma stem-like cells (GSCs). Although the current study is just the tip of an iceberg, these new evidences will provide new insights for possible GBM treatments. In this review, we summarize the recent studies about RNA modifications, such as N⁶-methyladenosine (m⁶A), N⁶,2′O-dimethyladenosine (m⁶A_m), 5-methylcytosine (m⁵C), N¹-methyladenosine (m¹A), inosine (I) and pseudouridine (ψ) as well as the corresponding RMPs including the writers, erasers and readers that participate in the tumorigenesis and development of GBM, so as to provide some clues for GBM treatment. Full article

(This article belongs to the Special Issue Brain Tumors)

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17 pages, 1030 KiB

Open AccessEditor’s ChoiceReview

Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy

by Charles Pottier, Margaux Fresnais, Marie Gilon, Guy Jérusalem, Rémi Longuespée and Nor Eddine Sounni

Cancers 2020, 12(3), 731; https://doi.org/10.3390/cancers12030731 - 20 Mar 2020

Cited by 257 | Viewed by 19241

Abstract

Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness [...] Read more.

Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness is limited by the appearance of resistance or adverse effects. In this review, we summarize the main features of RTKs and their inhibitors (RTKIs), their current use in oncology, and mechanisms of resistance. We also describe the technological advances of artificial intelligence, chemoproteomics, and microfluidics in elaborating powerful strategies that could be used in providing more efficient and selective small molecules inhibitors of RTKs. Finally, we discuss the interest of therapeutic combination of different RTKIs or with other molecules for personalized treatments, and the challenge for effective combination with less toxic and off-target effects. Full article

(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)

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