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14 pages, 28960 KiB

Open AccessArticle

HOPS/TMUB1 Enhances Apoptosis in TP53 Mutation-Independent Setting in Human Cancers

by Nicola Di-Iacovo, Simona Ferracchiato, Stefania Pieroni, Damiano Scopetti, Marilena Castelli, Danilo Piobbico, Luca Pierucci, Marco Gargaro, Davide Chiasserini, Giuseppe Servillo and Maria Agnese Della-Fazia

Int. J. Mol. Sci. 2024, 25(9), 4600; https://doi.org/10.3390/ijms25094600 - 23 Apr 2024

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Abstract

TP53 mutations are prevalent in various cancers, yet the complexity of apoptotic pathway deregulation suggests the involvement of additional factors. HOPS/TMUB1 is known to extend the half-life of p53 under normal and stress conditions, implying a regulatory function. This study investigates, for the [...] Read more.

TP53 mutations are prevalent in various cancers, yet the complexity of apoptotic pathway deregulation suggests the involvement of additional factors. HOPS/TMUB1 is known to extend the half-life of p53 under normal and stress conditions, implying a regulatory function. This study investigates, for the first time, the potential modulatory role of the ubiquitin-like-protein HOPS/TMUB1 in p53-mutants. A comprehensive analysis of apoptosis in the most frequent p53-mutants, R175, R248, and R273, in SKBR3, MIA PaCa2, and H1975 cells indicates that the overexpression of HOPS induces apoptosis at least equivalent to that caused by DNA damage. Immunoprecipitation assays confirm HOPS binding to p53-mutant forms. The interaction of HOPS/TMUB1 with p53-mutants strengthens its effect on the apoptotic cascade, showing a context-dependent gain or loss of function. Gene expression analysis of the MYC and TP63 genes shows that H1975 exhibit a gain-of-function profile, while SKBR3 promote apoptosis in a TP63-dependent manner. The TCGA data further corroborate HOPS/TMUB1’s positive correlation with apoptotic genes BAX, BBC3, and NOXA1, underscoring its relevance in patient samples. Notably, singular TP53 mutations inadequately explain pathway dysregulation, emphasizing the need to explore additional contributing factors. These findings illuminate the intricate interplay among TP53 mutations, HOPS/TMUB1, and apoptotic pathways, providing valuable insights for targeted cancer interventions. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

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14 pages, 2623 KiB

Open AccessArticle

Patterns of Chromosomal Instability and Clonal Heterogeneity in Luminal B Breast Cancer: A Pilot Study

by Valentina Camargo-Herrera, Giovanny Castellanos, Nelson Rangel, Guillermo Antonio Jiménez-Tobón, María Martínez-Agüero and Milena Rondón-Lagos

Int. J. Mol. Sci. 2024, 25(8), 4478; https://doi.org/10.3390/ijms25084478 - 19 Apr 2024

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Abstract

Chromosomal instability (CIN), defined by variations in the number or structure of chromosomes from cell to cell, is recognized as a distinctive characteristic of cancer associated with the ability of tumors to adapt to challenging environments. CIN has been recognized as a source [...] Read more.

Chromosomal instability (CIN), defined by variations in the number or structure of chromosomes from cell to cell, is recognized as a distinctive characteristic of cancer associated with the ability of tumors to adapt to challenging environments. CIN has been recognized as a source of genetic variation that leads to clonal heterogeneity (CH). Recent findings suggest a potential association between CIN and CH with the prognosis of BC patients, particularly in tumors expressing the epidermal growth factor receptor 2 (HER2+). In fact, information on the role of CIN in other BC subtypes, including luminal B BC, is limited. Additionally, it remains unknown whether CIN in luminal B BC tumors, above a specific threshold, could have a detrimental effect on the growth of human tumors or whether low or intermediate CIN levels could be linked to a more favorable BC patient prognosis when contrasted with elevated levels. Clarifying these relationships could have a substantial impact on risk stratification and the development of future therapeutic strategies aimed at targeting CIN in BC. This study aimed to assess CIN and CH in tumor tissue samples from ten patients with luminal B BC and compare them with established clinicopathological parameters. The results of this study reveal that luminal B BC patients exhibit intermediate CIN and stable aneuploidy, both of which correlate with lymphovascular invasion. Our results also provide valuable preliminary data that could contribute to the understanding of the implications of CIN and CH in risk stratification and the development of future therapeutic strategies in BC. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

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16 pages, 8465 KiB

Open AccessArticle

Exploiting Synthetic Lethality between Germline BRCA1 Haploinsufficiency and PARP Inhibition in JAK2V617F-Positive Myeloproliferative Neoplasms

by Max Bermes, Maria Jimena Rodriguez, Marcelo Augusto Szymanski de Toledo, Sabrina Ernst, Gerhard Müller-Newen, Tim Henrik Brümmendorf, Nicolas Chatain, Steffen Koschmieder and Julian Baumeister

Int. J. Mol. Sci. 2023, 24(24), 17560; https://doi.org/10.3390/ijms242417560 - 16 Dec 2023

Cited by 1 | Viewed by 1115

Abstract

Myeloproliferative neoplasms (MPN) are rare hematologic disorders characterized by clonal hematopoiesis. Familial clustering is observed in a subset of cases, with a notable proportion exhibiting heterozygous germline mutations in DNA double-strand break repair genes (e.g., BRCA1). We investigated the therapeutic potential of [...] Read more.

Myeloproliferative neoplasms (MPN) are rare hematologic disorders characterized by clonal hematopoiesis. Familial clustering is observed in a subset of cases, with a notable proportion exhibiting heterozygous germline mutations in DNA double-strand break repair genes (e.g., BRCA1). We investigated the therapeutic potential of targeting BRCA1 haploinsufficiency alongside the JAK2V617F driver mutation. We assessed the efficacy of combining the PARP inhibitor olaparib with interferon-alpha (IFNα) in CRISPR/Cas9-engineered Brca1^+/− Jak2V617F-positive 32D cells. Olaparib treatment induced a higher number of DNA double-strand breaks, as demonstrated by γH2AX analysis through Western blot (p = 0.024), flow cytometry (p = 0.013), and confocal microscopy (p = 0.071). RAD51 foci formation was impaired in Brca1^+/− cells compared to Brca1^+/+ cells, indicating impaired homologous recombination repair due to Brca1 haploinsufficiency. Importantly, olaparib enhanced apoptosis while diminishing cell proliferation and viability in Brca1^+/− cells compared to Brca1^+/+ cells. These effects were further potentiated by IFNα. Olaparib induced interferon-stimulated genes and increased endogenous production of IFNα in Brca1^+/− cells. These responses were abrogated by STING inhibition. In conclusion, our findings suggest that the combination of olaparib and IFNα presents a promising therapeutic strategy for MPN patients by exploiting the synthetic lethality between germline BRCA1 mutations and the JAK2V617F MPN driver mutation. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

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18 pages, 7739 KiB

Open AccessArticle

Unraveling Connective Tissue Growth Factor as a Therapeutic Target and Assessing Kahweol as a Potential Drug Candidate in Triple-Negative Breast Cancer Treatment

by Jeong Hee Lee, Jongsu Kim, Hong Sook Kim and Young Jin Kang

Int. J. Mol. Sci. 2023, 24(22), 16307; https://doi.org/10.3390/ijms242216307 - 14 Nov 2023

Cited by 1 | Viewed by 934

Abstract

Triple-negative breast cancer (TNBC) is characterized by aggressive behavior and limited treatment options, necessitating the identification of novel therapeutic targets. In this study, we investigated the clinical significance of connective tissue growth factor (CTGF) as a prognostic marker and explored the potential therapeutic [...] Read more.

Triple-negative breast cancer (TNBC) is characterized by aggressive behavior and limited treatment options, necessitating the identification of novel therapeutic targets. In this study, we investigated the clinical significance of connective tissue growth factor (CTGF) as a prognostic marker and explored the potential therapeutic effects of kahweol, a coffee diterpene molecule, in TNBC treatment. Initially, through a survival analysis on breast cancer patients from The Cancer Genome Atlas (TCGA) database, we found that CTGF exhibited significant prognostic effects exclusively in TNBC patients. To gain mechanistic insights, we performed the functional annotation and gene set enrichment analyses, revealing the involvement of CTGF in migratory pathways relevant to TNBC treatment. Subsequently, in vitro experiments using MDA-MB 231 cells, a representative TNBC cell line, demonstrated that recombinant CTGF (rCTGF) administration enhanced cell motility, whereas CTGF knockdown using CTGF siRNA resulted in reduced motility. Notably, rCTGF restored kahweol-reduced cell motility, providing compelling evidence for the role of CTGF in mediating kahweol’s effects. At the molecular level, kahweol downregulated the protein expression of CTGF as well as critical signaling molecules, such as p-ERK, p-P38, p-PI3K/AKT, and p-FAK, associated with cell motility. In summary, our findings propose CTGF as a potential prognostic marker for guiding TNBC treatment and suggest kahweol as a promising antitumor compound capable of regulating CTGF expression to suppress cell motility in TNBC. These insights hold promise for the development of targeted therapies and improved clinical outcomes for TNBC patients. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

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20 pages, 7795 KiB

Open AccessArticle

Uncovering NOTCH1 as a Promising Target in the Treatment of MLL-Rearranged Leukemia

by Jacqueline Fischer, Estelle Erkner, Rahel Fitzel, Pia Radszuweit, Hildegard Keppeler, Fulya Korkmaz, Giovanni Roti, Claudia Lengerke, Dominik Schneidawind and Corina Schneidawind

Int. J. Mol. Sci. 2023, 24(19), 14466; https://doi.org/10.3390/ijms241914466 - 23 Sep 2023

Cited by 1 | Viewed by 1085

Abstract

MLL rearrangement (MLLr) is responsible for the development of acute leukemias with poor outcomes. Therefore, new therapeutic approaches are urgently needed. The NOTCH1 pathway plays a critical role in the pathogenesis of many cancers including acute leukemia. Using a CRISPR/Cas9 MLL-AF4/-AF9 [...] Read more.

MLL rearrangement (MLLr) is responsible for the development of acute leukemias with poor outcomes. Therefore, new therapeutic approaches are urgently needed. The NOTCH1 pathway plays a critical role in the pathogenesis of many cancers including acute leukemia. Using a CRISPR/Cas9 MLL-AF4/-AF9 translocation model, the newly developed NOTCH1 inhibitor CAD204520 with less toxic side effects allowed us to unravel the impact of NOTCH1 as a pathogenic driver and potential therapeutic target in MLLr leukemia. RNA sequencing (RNA-seq) and RT-qPCR of our MLLr model and MLLr cell lines showed the NOTCH1 pathway was overexpressed and activated. Strikingly, we confirmed this elevated expression level in leukemia patients. We also demonstrated that CAD204520 treatment of MLLr cells significantly reduces NOTCH1 and its target genes as well as NOTCH1 receptor expression. This was not observed with a comparable cytarabine treatment, indicating the specificity of the small molecule. Accordingly, treatment with CAD204520 resulted in dose-dependent reduced proliferation and viability, increased apoptosis, and the induction of cell cycle arrest via the downregulation of MLL and NOTCH1 target genes. In conclusion, our findings uncover the oncogenic relevance of the NOTCH1 pathway in MLLr leukemia. Its inhibition leads to specific anti-leukemic effects and paves the way for further evaluation in clinical settings. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

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18 pages, 4314 KiB

Open AccessArticle

USP7 Inhibition Suppresses Neuroblastoma Growth via Induction of p53-Mediated Apoptosis and EZH2 and N-Myc Downregulation

by Christophe Le Clorennec, Karen Lee, Yuchen Huo and Peter E. Zage

Int. J. Mol. Sci. 2023, 24(18), 13780; https://doi.org/10.3390/ijms241813780 - 7 Sep 2023

Cited by 1 | Viewed by 1498

Abstract

Neuroblastoma (NB) is a pediatric malignancy originating from neural crest cells of the sympathetic nervous system that accounts for 15% of all pediatric cancer deaths. Despite advances in treatment, high-risk NB remains difficult to cure, highlighting the need for novel therapeutic approaches. Ubiquitin-specific [...] Read more.

Neuroblastoma (NB) is a pediatric malignancy originating from neural crest cells of the sympathetic nervous system that accounts for 15% of all pediatric cancer deaths. Despite advances in treatment, high-risk NB remains difficult to cure, highlighting the need for novel therapeutic approaches. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that plays a critical role in tumor suppression and DNA repair, and USP7 overexpression has been associated with tumor aggressiveness in a variety of tumors, including NB. Therefore, USP7 is a potential therapeutic target for NB. The tumor suppressor p53 is a known target of USP7, and therefore reactivation of the p53 pathway may be an effective therapeutic strategy for NB treatment. We hypothesized that inhibition of USP7 would be effective against NB tumor growth. Using a novel USP7 inhibitor, Almac4, we have demonstrated significant antitumor activity, with significant decreases in both cell proliferation and cell viability in TP53 wild-type NB cell lines. USP7 inhibition in NB cells activated the p53 pathway via USP7 and MDM2 degradation, leading to reduced p53 ubiquitination and increased p53 expression in all sensitive NB cells. In addition, USP7 inhibition led to decreased N-myc protein levels in both MYCN-amplified and -nonamplified NB cell lines, but no correlation was observed between MYCN amplification and treatment response. USP7 inhibition induced apoptosis in all TP53 wild-type NB cell lines. USP7 inhibition also induced EZH2 ubiquitination and degradation. Lastly, the combination of USP7 and MDM2 inhibition showed enhanced efficacy. Our data suggests that USP7 inhibition may be a promising therapeutic strategy for children with high-risk and relapsed NB. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

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14 pages, 12250 KiB

Open AccessArticle

Analysis of Under-Diagnosed Malignancy during Fine Needle Aspiration Cytology of Lymphadenopathies

by Jeeyong Lee, Hwa Jeong Ha, Da Yeon Kim, Jae Soo Koh and Eun Ju Kim

Int. J. Mol. Sci. 2023, 24(15), 12394; https://doi.org/10.3390/ijms241512394 - 3 Aug 2023

Viewed by 1001

Abstract

Fine needle aspiration cytology (FNAC) is a useful tool in the evaluation of lymphadenopathy. It is a safe and minimally invasive procedure that provides preoperative details for subsequent treatment. It can also diagnose the majority of malignant tumors. However, there are some instances [...] Read more.

Fine needle aspiration cytology (FNAC) is a useful tool in the evaluation of lymphadenopathy. It is a safe and minimally invasive procedure that provides preoperative details for subsequent treatment. It can also diagnose the majority of malignant tumors. However, there are some instances where the diagnosis of tumors remains obscure. To address this, we re-analyzed the misinterpreted patients’ samples using mRNA sequencing technology and then identified the characteristics of non-Hodgkin’s lymphoma that tend to be under-diagnosed. To decipher the involved genes and pathways, we used bioinformatic and biological analysis approaches, identifying the response to oxygen species, inositol phosphate metabolic processes, and peroxisome and PPAR pathways as possibly being involved with this type of tumor. Notably, these analyses identified FOS, ENDOG, and PRKAR2B as hub genes. cBioPortal, a multidimensional cancer genomics database, also confirmed that these genes were associated with lymphoma patients. These results thus point to candidate genes that could be used as biomarkers to minimize the false-negative rate of FNAC diagnosis. We are currently pursuing the development of a gene chip to improve the diagnosis of lymphadenopathy patients with the ultimate goal of improving their prognosis. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

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19 pages, 6999 KiB

Open AccessArticle

Synthesis and Evaluation of ¹⁷⁷Lu-DOTA-PD-L1-i and ²²⁵Ac-HEHA-PD-L1-i as Potential Radiopharmaceuticals for Tumor Microenvironment-Targeted Radiotherapy

by Myrna Luna-Gutiérrez, Pedro Cruz-Nova, Nallely Jiménez-Mancilla, Rigoberto Oros-Pantoja, Nancy Lara-Almazán, Clara Santos-Cuevas, Erika Azorín-Vega, Blanca Ocampo-García and Guillermina Ferro-Flores

Int. J. Mol. Sci. 2023, 24(15), 12382; https://doi.org/10.3390/ijms241512382 - 3 Aug 2023

Viewed by 1493

Abstract

Current cancer therapies focus on reducing immunosuppression and remodeling the tumor microenvironment to inhibit metastasis, cancer progression, and therapeutic resistance. Programmed death receptor 1 (PD-1) is expressed on immune T cells and is one of the so-called checkpoint proteins that can suppress or [...] Read more.

Current cancer therapies focus on reducing immunosuppression and remodeling the tumor microenvironment to inhibit metastasis, cancer progression, and therapeutic resistance. Programmed death receptor 1 (PD-1) is expressed on immune T cells and is one of the so-called checkpoint proteins that can suppress or stop the immune response. To evade the immune system, cancer cells overexpress a PD-1 inhibitor protein (PD-L1), which binds to the surface of T cells to activate signaling pathways that induce immune suppression. This research aimed to synthesize PD-L1 inhibitory peptides (PD-L1-i) labeled with lutetium-177 (¹⁷⁷Lu-DOTA-PD-L1-i) and actinium-225 (²²⁵Ac-HEHA-PD-L1-i) and to preclinically evaluate their potential as radiopharmaceuticals for targeted radiotherapy at the tumor microenvironment level. Using PD-L1-i peptide as starting material, conjugation with HEHA-benzene-SCN and DOTA-benzene-SCN was performed to yield DOTA-PD-L1-i and HEHA-PD-L1-I, which were characterized by FT-IR, UV-vis spectroscopy, and HPLC. After labeling the conjugates with ²²⁵Ac and ¹⁷⁷Lu, cellular uptake in HCC827 cancer cells (PD-L1 positive), conjugate specificity evaluation by immunofluorescence, radiotracer effect on cell viability, biodistribution, biokinetics, and assessment of radiation absorbed dose in mice with in duced lung micrometastases were performed. ²²⁵Ac-HEHA-PD-L1-i and ¹⁷⁷Lu-DOTA-PD-L1-i, obtained with radiochemical purities of 95 ± 3% and 98.5 ± 0.5%, respectively, showed in vitro and in vivo specific recognition for the PD-L1 protein in lung cancer cells and high uptake in HCC287 lung micrometastases (>30% ID). The biokinetic profiles of ¹⁷⁷Lu-DOTA-PD-L1-i and ²²⁵Ac-DOTA-PD-L1-i showed rapid blood clearance with renal and hepatobiliary elimination and no accumulation in normal tissues. ²²⁵Ac-DOTA-PD-L1-i produced a radiation dose of 5.15 mGy/MBq to lung micrometastases. In the case of ¹⁷⁷Lu-DOTA-PD-L1-i, the radiation dose delivered to the lung micrometastases was ten times (43 mGy/MBq) that delivered to the kidneys (4.20 mGy/MBq) and fifty times that delivered to the liver (0.85 mGy/MBq). Therefore, the radiotherapeutic PD-L1-i ligands of ²²⁵Ac and ¹⁷⁷Lu developed in this research could be combined with immunotherapy to enhance the therapeutic effect in various types of cancer. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

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Review

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21 pages, 1710 KiB

Open AccessReview

The Relevance, Predictability, and Utility of Annexin A5 for Human Physiopathology

by Jian Jing

Int. J. Mol. Sci. 2024, 25(5), 2865; https://doi.org/10.3390/ijms25052865 - 1 Mar 2024

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Abstract

As an important functional protein molecule in the human body, human annexin A5 (hAnxA5) is widely found in human cells and body fluids. hAnxA5, the smallest type of annexin, performs a variety of biological functions by reversibly and specifically binding phosphatidylserine (PS) in [...] Read more.

As an important functional protein molecule in the human body, human annexin A5 (hAnxA5) is widely found in human cells and body fluids. hAnxA5, the smallest type of annexin, performs a variety of biological functions by reversibly and specifically binding phosphatidylserine (PS) in a calcium-dependent manner and plays an important role in many human physiological and pathological processes. The free state hAnxA5 exists in the form of monomers and usually forms a polymer in a specific self-assembly manner when exerting biological activity. This review systematically discusses the current knowledge and understanding of hAnxA5 from three perspectives: physiopathological relevance, diagnostic value, and therapeutic utility. hAnxA5 affects the occurrence and development of many physiopathological processes. Moreover, hAnxA5 can be used independently or in combination as a biomarker of physiopathological phenomena for the diagnosis of certain diseases. Importantly, based on the properties of hAnxA5, many novel drug candidates have been designed and prepared for application in actual medical practice. However, there are also some gaps and shortcomings in hAnxA5 research. This in-depth study will not only expand the understanding of structural and functional relationships but also promote the application of hAnxA5 in the field of biomedicine. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

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27 pages, 383 KiB

Open AccessReview

Targeted Therapy for Cancers: From Ongoing Clinical Trials to FDA-Approved Drugs

by Ha Yeong Choi and Ji-Eun Chang

Int. J. Mol. Sci. 2023, 24(17), 13618; https://doi.org/10.3390/ijms241713618 - 3 Sep 2023

Cited by 9 | Viewed by 3050

Abstract

The development of targeted therapies has revolutionized cancer treatment, offering improved efficacy with reduced side effects compared with traditional chemotherapy. This review highlights the current landscape of targeted therapy in lung cancer, colorectal cancer, and prostate cancer, focusing on key molecular targets. Moreover, [...] Read more.

The development of targeted therapies has revolutionized cancer treatment, offering improved efficacy with reduced side effects compared with traditional chemotherapy. This review highlights the current landscape of targeted therapy in lung cancer, colorectal cancer, and prostate cancer, focusing on key molecular targets. Moreover, it aligns with US Food and Drug Administration (FDA)-approved drugs and drug candidates. In lung cancer, mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene rearrangements have emerged as significant targets. FDA-approved drugs like osimertinib and crizotinib specifically inhibit these aberrant pathways, providing remarkable benefits in patients with EGFR-mutated or ALK-positive lung cancer. Colorectal cancer treatment has been shaped by targeting the vascular endothelial growth factor (VEGF) and EGFR. Bevacizumab and cetuximab are prominent FDA-approved agents that hinder VEGF and EGFR signaling, significantly enhancing outcomes in metastatic colorectal cancer patients. In prostate cancer, androgen receptor (AR) targeting is pivotal. Drugs like enzalutamide, apalutamide, and darolutamide effectively inhibit AR signaling, demonstrating efficacy in castration-resistant prostate cancer. This review further highlights promising targets like mesenchymal-epithelial transition (MET), ROS1, BRAF, and poly(ADP-ribose) polymeras (PARP) in specific cancer subsets, along with ongoing clinical trials that continue to shape the future of targeted therapy. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

18 pages, 1514 KiB

Open AccessReview

FOXM1, MEK, and CDK4/6: New Targets for Malignant Peripheral Nerve Sheath Tumor Therapy

by Ellen Voigt and Dawn E. Quelle

Int. J. Mol. Sci. 2023, 24(17), 13596; https://doi.org/10.3390/ijms241713596 - 2 Sep 2023

Cited by 2 | Viewed by 1919

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas, which desperately need effective therapies. Half of all MPNSTs arise in patients with neurofibromatosis type I (NF1), a common inherited disease. NF1 patients can develop benign lesions called plexiform neurofibromas (PNFs), often in adolescence, [...] Read more.

Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas, which desperately need effective therapies. Half of all MPNSTs arise in patients with neurofibromatosis type I (NF1), a common inherited disease. NF1 patients can develop benign lesions called plexiform neurofibromas (PNFs), often in adolescence, and over time, some PNFs, but not all, will transform into MPNSTs. A deeper understanding of the molecular and genetic alterations driving PNF–MPNST transformation will guide development of more targeted and effective treatments for these patients. This review focuses on an oncogenic transcription factor, FOXM1, which is a powerful oncogene in other cancers but little studied in MPNSTs. Elevated expression of FOXM1 was seen in patient MPNSTs and correlated with poor survival, but otherwise, its role in the disease is unknown. We discuss what is known about FOXM1 in MPNSTs relative to other cancers and how FOXM1 may be regulated by and/or regulate the most commonly altered players in MPNSTs, particularly in the MEK and CDK4/6 kinase pathways. We conclude by considering FOXM1, MEK, and CDK4/6 as new, clinically relevant targets for MPNST therapy. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

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30 pages, 2929 KiB

Open AccessReview

BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets

by Francesco Claps, Nicola Pavan, Luca Ongaro, Domenico Tierno, Gabriele Grassi, Carlo Trombetta, Gabriele Tulone, Alchiede Simonato, Riccardo Bartoletti, Laura S. Mertens, Bas W. G. van Rhijn, Maria Carmen Mir and Bruna Scaggiante

Int. J. Mol. Sci. 2023, 24(16), 12596; https://doi.org/10.3390/ijms241612596 - 9 Aug 2023

Cited by 5 | Viewed by 3138

Abstract

Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most common cancers among UCs (90–95%). BC is the most common cancer and can be a highly heterogeneous disease, including [...] Read more.

Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most common cancers among UCs (90–95%). BC is the most common cancer and can be a highly heterogeneous disease, including both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) forms with different oncologic outcomes. Approximately 80% of new BC diagnoses are classified as NMIBC after the initial transurethral resection of the bladder tumor (TURBt). In this setting, intravesical instillation of Bacillus Calmette–Guerin (BCG) is the current standard treatment for intermediate- and high-risk patients. Unfortunately, recurrence occurs in 30% to 40% of patients despite adequate BCG treatment. Radical cystectomy (RC) is currently considered the standard treatment for NMIBC that does not respond to BCG. However, RC is a complex surgical procedure with a recognized high perioperative morbidity that is dependent on the patient, disease behaviors, and surgical factors and is associated with a significant impact on quality of life. Therefore, there is an unmet clinical need for alternative bladder-preserving treatments for patients who desire a bladder-sparing approach or are too frail for major surgery. In this review, we aim to present the strategies in BCG-unresponsive NMIBC, focusing on novel molecular therapeutic targets. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers 2.0)

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