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24 pages, 15145 KiB

Open AccessArticle

3D Pharmacophore-Based Discovery of Novel K_V10.1 Inhibitors with Antiproliferative Activity

by Žan Toplak, Louise Antonia Hendrickx, Špela Gubič, Štefan Možina, Bojana Žegura, Alja Štern, Matjaž Novak, Xiaoyi Shi, Steve Peigneur, Jan Tytgat, Tihomir Tomašič, Luis A. Pardo and Lucija Peterlin Mašič

Cancers 2021, 13(6), 1244; https://doi.org/10.3390/cancers13061244 - 12 Mar 2021

Cited by 9 | Viewed by 3199

Abstract

(1) Background: The voltage-gated potassium channel K_V10.1 (Eag1) is considered a near- universal tumour marker and represents a promising new target for the discovery of novel anticancer drugs. (2) Methods: We utilized the ligand-based drug discovery methodology using 3D pharmacophore modelling [...] Read more.

(1) Background: The voltage-gated potassium channel K_V10.1 (Eag1) is considered a near- universal tumour marker and represents a promising new target for the discovery of novel anticancer drugs. (2) Methods: We utilized the ligand-based drug discovery methodology using 3D pharmacophore modelling and medicinal chemistry approaches to prepare a novel structural class of K_V10.1 inhibitors. Whole-cell patch clamp experiments were used to investigate potency, selectivity, kinetics and mode of inhibition. Anticancer activity was determined using 2D and 3D cell-based models. (3) Results: The virtual screening hit compound ZVS-08 discovered by 3D pharmacophore modelling exhibited an IC₅₀ value of 3.70 µM against K_V10.1 and inhibited the channel in a voltage-dependent manner consistent with the action of a gating modifier. Structural optimization resulted in the most potent K_V10.1 inhibitor of the series with an IC₅₀ value of 740 nM, which was potent on the MCF-7 cell line expressing high K_V10.1 levels and low hERG levels, induced significant apoptosis in tumour spheroids of Colo-357 cells and was not mutagenic. (4) Conclusions: Computational ligand-based drug design methods can be successful in the discovery of new potent K_V10.1 inhibitors. The main problem in the field of K_V10.1 inhibitors remains selectivity against the hERG channel, which needs to be addressed in the future also with target-based drug design methods. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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18 pages, 819 KiB

Open AccessArticle

Transitioning the Molecular Tumor Board from Proof of Concept to Clinical Routine: A German Single-Center Analysis

by Rouven Hoefflin, Adriana Lazarou, Maria Elena Hess, Meike Reiser, Julius Wehrle, Patrick Metzger, Anna Verena Frey, Heiko Becker, Konrad Aumann, Kai Berner, Martin Boeker, Nico Buettner, Christine Dierks, Jesus Duque-Afonso, Michel Eisenblaetter, Thalia Erbes, Ralph Fritsch, Isabell Xiang Ge, Anna-Lena Geißler, Markus Grabbert, Steffen Heeg, Dieter Henrik Heiland, Simone Hettmer, Gian Kayser, Alexander Keller, Anita Kleiber, Alexandra Kutilina, Leman Mehmed, Frank Meiss, Philipp Poxleitner, Justyna Rawluk, Juri Ruf, Henning Schäfer, Florian Scherer, Khalid Shoumariyeh, Andreas Tzschach, Christoph Peters, Tilman Brummer, Martin Werner, Justus Duyster, Silke Lassmann, Cornelius Miething, Melanie Boerries, Anna L. Illert and Nikolas von Bubnoff Show full author list Hide full author list

Cancers 2021, 13(5), 1151; https://doi.org/10.3390/cancers13051151 - 08 Mar 2021

Cited by 23 | Viewed by 3830

Abstract

Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of [...] Read more.

Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of the Comprehensive Cancer Center Freiburg (Germany) including workflows and process optimizations. This retrospective single-center study includes data on 488 patients enrolled in the MTB from February 2015 through December 2018. Recommendations include individual molecular diagnostics, molecular stratified therapies, assessment of treatment adherence and patient outcomes including overall survival. The majority of MTB patients presented with stage IV oncologic malignancies (90.6%) and underwent an average of 2.1 previous lines of therapy. Individual diagnostic recommendations were given to 487 patients (99.8%). A treatment recommendation was given in 264 of all cases (54.1%) which included a molecularly matched treatment in 212 patients (43.4%). The 264 treatment recommendations were implemented in 76 patients (28.8%). Stable disease was observed in 19 patients (25.0%), 17 had partial response (22.4%) and five showed a complete remission (6.6%). An objective response was achieved in 28.9% of cases with implemented recommendations and for 4.5% of the total population (22 of 488 patients). By optimizing the MTB workflow, case-discussions per session increased significantly while treatment adherence and outcome remained stable over time. Our data demonstrate the feasibility and effectiveness of molecular-guided personalized therapy for cancer patients in a clinical routine setting showing a low but robust and durable disease control rate over time. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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17 pages, 2856 KiB

Open AccessArticle

Prognostic Value and Function of KLF5 in Papillary Thyroid Cancer

by Poyil Pratheeshkumar, Abdul K. Siraj, Sasidharan Padmaja Divya, Sandeep Kumar Parvathareddy, Sarah Siraj, Roxanne Diaz, Rafia Begum, Saif S. Al-Sobhi, Fouad Al-Dayel and Khawla S. Al-Kuraya

Cancers 2021, 13(2), 185; https://doi.org/10.3390/cancers13020185 - 07 Jan 2021

Cited by 5 | Viewed by 2010

Abstract

The Krüppel-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in several solid tumors, but its role in PTC remains unclear. We investigated the expression of KLF5 protein in a large cohort of PTC patient samples and explored its functional role [...] Read more.

The Krüppel-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in several solid tumors, but its role in PTC remains unclear. We investigated the expression of KLF5 protein in a large cohort of PTC patient samples and explored its functional role and mechanism in PTC cell lines in vitro and in vivo. KLF5 overexpression was observed in 65.1% of all PTC cases and it was significantly associated with aggressive clinico-pathological parameters and poor outcome. Given the significant association between KLF5 and HIF-1α overexpression in PTC patients, we investigated the functional correlation between KLF5 and HIF-1α in PTC cells. Indeed, the analysis revealed the co-immunoprecipitation of KLF5 with HIF-1α in PTC cells. We also identified KLF5-binding sites in the HIF-1α promoter that specifically bound to KLF5 protein. Mechanistically, KLF5 promoted PTC cell growth, invasion, migration, and angiogenesis, while KLF5 downregulation via specific inhibitor or siRNA reverses its action in vitro. Importantly, the silencing of KLF5 decreases the self-renewal ability of spheroids generated from PTC cells. In addition, the depletion of KLF5 reduces PTC xenograft growth in vivo. These findings suggest KLF5 can be a possible new molecular therapeutic target for a subset of PTC. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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13 pages, 2371 KiB

Open AccessArticle

The Expression of CD74-Regulated Inflammatory Markers in Stage IV Melanoma: Risk of CNS Metastasis and Patient Survival

by Dai Ogata, Jason Roszik, Junna Oba, Sun-Hee Kim, Roland L. Bassett, Jr., Lauren E. Haydu, Keiji Tanese, Elizabeth A. Grimm and Suhendan Ekmekcioglu

Cancers 2020, 12(12), 3754; https://doi.org/10.3390/cancers12123754 - 14 Dec 2020

Cited by 3 | Viewed by 2332

Abstract

Innate inflammatory features have been found in melanoma tumors from patients at all stages, and molecular analysis has identified definitive inflammatory proteins expressed by tumors cells in patients who presents the worst prognosis. We have previously observed weakened outcomes in patients with constitutive [...] Read more.

Innate inflammatory features have been found in melanoma tumors from patients at all stages, and molecular analysis has identified definitive inflammatory proteins expressed by tumors cells in patients who presents the worst prognosis. We have previously observed weakened outcomes in patients with constitutive expression of inducible nitric oxide synthase (iNOS), macrophage migration inhibitory factor (MIF) and improved outcomes with CD74 expression in stage III melanoma. In our current study, we tested our hypothesis on CD74-regulated inflammatory markers’ expression in stage IV melanoma tumors whether the signature is associated with survival outcome and/or risk of developing CNS metastasis. We retrospectively identified 315 patients with stage IV melanoma. In a tissue microarray (TMA), we examined the expression of cells with CD74, its receptor MIF, and downstream inflammatory markers iNOS, nitrotyrosine (NT), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES1). We analyzed the association of those inflammatory markers with overall survival time (OS) and time to CNS metastasis using Kaplan–Meier survival analyses. Our data validates CD74 as a useful prognostic tumor cell protein marker associated with favorable OS as in stage III melanomas, while the tumor NT expression strongly predicts an increased risk of developing CNS metastasis (p = 0.0008) in those patients. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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11 pages, 2021 KiB

Open AccessArticle

Non-Invasive Measurement of Drug and 2-HG Signals Using ¹⁹F and ¹H MR Spectroscopy in Brain Tumors Treated with the Mutant IDH1 Inhibitor BAY1436032

by Katharina J. Wenger, Christian Richter, Michael C. Burger, Hans Urban, Stefan Kaulfuss, Patrick N. Harter, Sridhar Sreeramulu, Harald Schwalbe, Joachim P. Steinbach, Elke Hattingen, Oliver Bähr and Ulrich Pilatus

Cancers 2020, 12(11), 3175; https://doi.org/10.3390/cancers12113175 - 29 Oct 2020

Cited by 8 | Viewed by 2192

Abstract

Background: BAY1436032 is a fluorine-containing inhibitor of the R132X-mutant isocitrate dehydrogenase (mIDH1). It inhibits the mIDH1-mediated production of 2-hydroxyglutarate (2-HG) in glioma cells. We investigated brain penetration of BAY1436032 and its effects using ¹H/¹⁹F-Magnetic Resonance Spectroscopy (MRS). Methods: ¹⁹F-Nuclear [...] Read more.

Background: BAY1436032 is a fluorine-containing inhibitor of the R132X-mutant isocitrate dehydrogenase (mIDH1). It inhibits the mIDH1-mediated production of 2-hydroxyglutarate (2-HG) in glioma cells. We investigated brain penetration of BAY1436032 and its effects using ¹H/¹⁹F-Magnetic Resonance Spectroscopy (MRS). Methods: ¹⁹F-Nuclear Magnetic Resonance (NMR) Spectroscopy was conducted on serum samples from patients treated with BAY1436032 (NCT02746081 trial) in order to analyze ¹⁹F spectroscopic signal patterns and concentration-time dynamics of protein-bound inhibitor to facilitate their identification in vivo MRS experiments. Hereafter, 30 mice were implanted with three glioma cell lines (LNT-229, LNT-229 IDH1-R132H, GL261). Mice bearing the IDH-mutated glioma cells received 5 days of treatment with BAY1436032 between baseline and follow-up ¹H/¹⁹F-MRS scan. All other animals underwent a single scan after BAY1436032 administration. Mouse brains were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Results: Evaluation of ¹H-MRS data showed a decrease in 2-HG/total creatinine (tCr) ratios from the baseline to post-treatment scans in the mIDH1 murine model. Whole brain concentration of BAY1436032, as determined by ¹⁹F-MRS, was similar to total brain tissue concentration determined by Liquid Chromatography with tandem mass spectrometry (LC-MS/MS), with a signal loss due to protein binding. Intratumoral drug concentration, as determined by LC-MS/MS, was not statistically different in models with or without R132X-mutant IDH1 expression. Conclusions: Non-invasive monitoring of mIDH1 inhibition by BAY1436032 in mIDH1 gliomas is feasible. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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17 pages, 5810 KiB

Open AccessArticle

rhEGF Treatment Improves EGFR Inhibitor-Induced Skin Barrier and Immune Defects

by Ji Min Kim, Jun Ho Ji, Young Saing Kim, Suee Lee, Sung Yong Oh, Seok Jae Huh, Choon Hee Son, Jung Hun Kang, So Yun Ahn, Jung Eun Choo, Ki-Hoon Song and Mee Sook Roh

Cancers 2020, 12(11), 3120; https://doi.org/10.3390/cancers12113120 - 25 Oct 2020

Cited by 7 | Viewed by 2362

Abstract

The mechanisms of epidermal growth factor (EGF) affecting EGF receptor inhibitor (EGFRI)-related skin toxicities are as yet unknown. We investigated which mechanisms are involved in EGF’s positive effects. Two types of EGFRIs, cetuximab and gefitinib, were used to treat the cells or 3d-cultured [...] Read more.

The mechanisms of epidermal growth factor (EGF) affecting EGF receptor inhibitor (EGFRI)-related skin toxicities are as yet unknown. We investigated which mechanisms are involved in EGF’s positive effects. Two types of EGFRIs, cetuximab and gefitinib, were used to treat the cells or 3d-cultured human skin tissue with recombinant human EGF (rhEGF). As a result, rhEGF increased EGFR and pEGFR expression. Furthermore, rhEGF induces EGFR signaling by pAKT and pPI3K expression in gefitinib and rhEGF co-treated cells. In addition, rhEGF bound to EGFR after than cetuximab, but cetuximab bound to EGFR more strongly than rhEGF. Moreover, expressions of proliferation and differentiation proteins, both ki-67 and filaggrin, were decreased in EGFRI-treated tissue. However, in rhEGF and EGFRI co-treated tissue, those expressions were increased. Expression of IL-1α, IL-8, and TNF-α was increased by EGFRIs and down-regulated by rhEGF. Furthermore, hBD-2 and hBD-3 protein expressions were inhibited by cetuximab or gefitinib treatment, and those decrements were increased by rhEGF treatment. In patients’ tissue evaluation, compared with controls, patients’ Ki-67 and EGFR expression were decreased (p = 0.015, p = 0.001). Patients’ IL-17 and TNF-α expression intensity was higher than that of the control group (p = 0.038, p = 0.037). After treatment with EGF ointment, average values of Ki-67, EGFR, and Melan-A were changed to normal values. Oppositely, patients’ proportions of IL-17 and TNF-α were decreased to low stain level. In conclusion, treatment of rhEGF improved EGFRI-induced skin eruption via normalizing the proliferation and differentiation of keratinocytes, reducing inflammatory cytokines by the affected EGFRIs. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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18 pages, 3132 KiB

Open AccessArticle

AXL Inactivation Inhibits Mesothelioma Growth and Migration via Regulation of p53 Expression

by Wei Song, Hao Wang, Minmin Lu, Xinxin Ni, Nacef Bahri, Shuihao Zhu, Limin Chen, Yuehong Wu, Jieqiong Qiu, Jonathan A. Fletcher and Wen-Bin Ou

Cancers 2020, 12(10), 2757; https://doi.org/10.3390/cancers12102757 - 25 Sep 2020

Cited by 13 | Viewed by 3285

Abstract

Malignant mesothelioma is a locally aggressive and highly lethal neoplasm. Dysregulation and activation of Gas6/AXL tyrosine kinase signaling are associated with mesothelioma progression, but the mechanisms of these AXL tumorigenic roles are poorly understood. p53 mutants in lung carcinoma upregulate AXL expression by [...] Read more.

Malignant mesothelioma is a locally aggressive and highly lethal neoplasm. Dysregulation and activation of Gas6/AXL tyrosine kinase signaling are associated with mesothelioma progression, but the mechanisms of these AXL tumorigenic roles are poorly understood. p53 mutants in lung carcinoma upregulate AXL expression by binding and acetylating the AXL promoter. Although TP53 mutations are uncommon in mesothelioma, we hypothesized that these tumors might have alternative feedback mechanisms between AXL and p53. In the current report, we investigated AXL regulation of TP53 transcription, expression, and biological function in mesothelioma. AXL expression was stronger in mesothelioma than most of the other tumor types from the TCGA gene expression profile dataset. AXL knockdown by shRNA induced wild-type and mutant p53 expression in mesothelioma cell lines, suggesting that AXL pro-tumorigenic roles result in part from the suppression of p53 function. Likewise, induced AXL inhibited expression of wild type p53 in COS-7 cells and 293T cells. Immunofluorescence staining showed nuclear colocalization of AXL and p53; however, association of AXL and p53 was not demonstrated in immunoprecipitation complexes. The AXL effects on p53 expression resulted from the inhibition of TP53 transcription, as demonstrated by qRT-PCR after AXL silencing and TP53 promotor dual luciferase activity assays. Chromatin immunoprecipitation-qPCR and sequencing showed that AXL bound to the initial 600 bp sequence at the 5′ end of the TP53 promoter. AXL inhibition (shRNA or R428) reduced mesothelioma cell viability, migration, and invasion, whereas TP53 shRNA knockdown attenuated antiproliferative, migration, and invasive effects of AXL silencing or AXL inactivation in these cells. These studies demonstrate a novel feedback regulation loop between AXL and p53, and provide a rationale for mesothelioma therapies targeting AXL/p53 signaling. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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24 pages, 3716 KiB

Open AccessArticle

Leukaemia Inhibitory Factor (LIF) Inhibits Cancer Stem Cells Tumorigenic Properties through Hippo Kinases Activation in Gastric Cancer

by Lornella Seeneevassen, Julie Giraud, Silvia Molina-Castro, Elodie Sifré, Camille Tiffon, Clémentine Beauvoit, Cathy Staedel, Francis Mégraud, Philippe Lehours, Océane C.B. Martin, Hélène Boeuf, Pierre Dubus and Christine Varon

Cancers 2020, 12(8), 2011; https://doi.org/10.3390/cancers12082011 - 22 Jul 2020

Cited by 29 | Viewed by 4320

Abstract

Cancer stem cells (CSCs) present chemo-resistance mechanisms contributing to tumour maintenance and recurrence, making their targeting of utmost importance in gastric cancer (GC) therapy. The Hippo pathway has been implicated in gastric CSC properties and was shown to be regulated by leukaemia inhibitory [...] Read more.

Cancer stem cells (CSCs) present chemo-resistance mechanisms contributing to tumour maintenance and recurrence, making their targeting of utmost importance in gastric cancer (GC) therapy. The Hippo pathway has been implicated in gastric CSC properties and was shown to be regulated by leukaemia inhibitory factor receptor (LIFR) and its ligand LIF in breast cancer. This study aimed to determine LIF’s effect on CSC properties in GC cell lines and patient-derived xenograft (PDX) cells, which remains unexplored. LIF’s treatment effect on CSC markers expression and tumoursphere formation was evaluated. The Hippo kinase inhibitor XMU-MP-1 and/or the JAK1 inhibitor Ruxolitinib were used to determine Hippo and canonical JAK/STAT pathway involvement in gastric CSCs’ response to LIF. Results indicate that LIF decreased tumorigenic and chemo-resistant CSCs, in both GC cell lines and PDX cells. In addition, LIF increased activation of LATS1/2 Hippo kinases, thereby decreasing downstream YAP/TAZ nuclear accumulation and TEAD transcriptional activity. LIF’s anti-CSC effect was reversed by XMU-MP-1 but not by Ruxolitinib treatment, highlighting the opposite effects of these two pathways downstream LIFR. In conclusion, LIF displays anti-CSC properties in GC, through Hippo kinases activation, and could in fine constitute a new CSCs-targeting strategy to help decrease relapse cases and bad prognosis in GC. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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18 pages, 2240 KiB

Open AccessArticle

Rapid and Sensitive Quantification of Osimertinib in Human Plasma Using a Fully Validated MALDI–IM–MS/MS Assay

by Margaux Fresnais, André Roth, Kathrin I. Foerster, Dirk Jäger, Stefan M. Pfister, Walter E. Haefeli, Jürgen Burhenne and Rémi Longuespée

Cancers 2020, 12(7), 1897; https://doi.org/10.3390/cancers12071897 - 14 Jul 2020

Cited by 15 | Viewed by 3098

Abstract

The third-generation tyrosine kinase inhibitor (TKI), osimertinib, has revolutionized the treatment of patients with non-small cell lung carcinoma with epidermal growth factor receptor (EGFR)-activating mutation, and resistant to first- and second-generation TKIs. Osimertinib is now also proposed as a first-line therapy, thus extending [...] Read more.

The third-generation tyrosine kinase inhibitor (TKI), osimertinib, has revolutionized the treatment of patients with non-small cell lung carcinoma with epidermal growth factor receptor (EGFR)-activating mutation, and resistant to first- and second-generation TKIs. Osimertinib is now also proposed as a first-line therapy, thus extending the scope of applications in lung oncology. Personalized medicine approaches are still necessary to monitor if patients are exposed to adequate concentrations of osimertinib during their treatment. It would also help to understand the appearance of new resistances in patients after several months of dosing with osimertinib. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) is currently the gold standard for the quantification of drugs in plasma enabling pharmacokinetic analyses and patient monitoring. In the present study, we propose an alternative to LC–MS/MS methods for the rapid and sensitive quantification of osimertinib in plasma using matrix-assisted laser desorption/ionization (MALDI) –MS. The presented assay requires only 3 min per sample for their preparation, analysis, and data extraction, and less than 3 h for quantification. A lower limit of quantification (LLOQ) of 5 ng/mL in plasma was retrieved. The method was fully validated, following the guidelines of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for bioanalytical method validation. The present developments prove the importance to consider alternative MS assays for time-efficient quantification of small molecule inhibitors in plasma in the context of personalized medicine for targeted therapies. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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16 pages, 2502 KiB

Open AccessArticle

Dendrogenin A Synergizes with Cytarabine to Kill Acute Myeloid Leukemia Cells In Vitro and In Vivo

by Nizar Serhan, Pierre-Luc Mouchel, Philippe de Medina, Gregory Segala, Aurélie Mougel, Estelle Saland, Arnaud Rives, Antonin Lamaziere, Gaëtan Despres, Jean-Emmanuel Sarry, Clément Larrue, François Vergez, Laetitia Largeaud, Michel Record, Christian Récher, Sandrine Silvente-Poirot and Marc Poirot

Cancers 2020, 12(7), 1725; https://doi.org/10.3390/cancers12071725 - 29 Jun 2020

Cited by 13 | Viewed by 3582

Abstract

Dendrogenin A (DDA) is a mammalian cholesterol metabolite that displays potent antitumor properties on acute myeloid leukemia (AML). DDA triggers lethal autophagy in cancer cells through a biased activation of the oxysterol receptor LXRβ, and the inhibition of a sterol isomerase. We hypothesize [...] Read more.

Dendrogenin A (DDA) is a mammalian cholesterol metabolite that displays potent antitumor properties on acute myeloid leukemia (AML). DDA triggers lethal autophagy in cancer cells through a biased activation of the oxysterol receptor LXRβ, and the inhibition of a sterol isomerase. We hypothesize that DDA could potentiate the activity of an anticancer drug acting through a different molecular mechanism, and conducted in vitro and in vivo combination tests on AML cell lines and patient primary tumors. We report here results from tests combining DDA with antimetabolite cytarabine (Ara-C), one of the main drugs used for AML treatment worldwide. We demonstrated that DDA potentiated and sensitized AML cells, including primary patient samples, to Ara-C in vitro and in vivo. Mechanistic studies revealed that this sensitization was LXRβ-dependent and was due to the activation of lethal autophagy. This study demonstrates a positive in vitro and in vivo interaction between DDA and Ara-C, and supports the clinical evaluation of DDA in combination with Ara-C for the treatment of AML. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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11 pages, 984 KiB

Open AccessArticle

Effectiveness and Healthcare Cost of Adding Trastuzumab to Standard Chemotherapy for First-Line Treatment of Metastatic Gastric Cancer: A Population-Based Cohort Study

by Matteo Franchi, Roberta Tritto, Lorena Torroni, Chiara Reno, Carlo La Vecchia and Giovanni Corrao

Cancers 2020, 12(6), 1691; https://doi.org/10.3390/cancers12061691 - 25 Jun 2020

Cited by 10 | Viewed by 2589

Abstract

A randomized clinical trial showed that trastuzumab, added to traditional chemotherapy, significantly improved overall survival in human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic gastric cancer patients. This population-based study aimed at evaluating both the clinical and economic impact of trastuzumab in a [...] Read more.

A randomized clinical trial showed that trastuzumab, added to traditional chemotherapy, significantly improved overall survival in human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic gastric cancer patients. This population-based study aimed at evaluating both the clinical and economic impact of trastuzumab in a real-world setting. By using the healthcare utilization databases of Lombardy, Italy, a cohort of patients newly diagnosed with metastatic gastric cancer during the period 2011–2016 was selected. Among these, patients initially treated with either trastuzumab-based chemotherapy or standard chemotherapy alone were followed up until death, migration in other regions or June 2018. Overall survival and average cumulative costs were estimated and compared between the two treatment arms. Among the 1198 metastatic gastric cancer patients who started therapy within six months after metastasis detection, 87 were initially treated with trastuzumab-based chemotherapy and 1111 with standard chemotherapy. Median overall survival and restricted mean survival were 10.2 and 7.4 months, and 14.9 and 11.4 months, respectively, in the two treatment arms. The adjusted hazard ratio of death was 0.73 (95% CI 0.57–0.93). The average per capita cumulative healthcare costs were, respectively, EUR 39,337 and 26,504, corresponding to an incremental cost-effectiveness ratio of EUR 43,998 for each year of survival gained. Our study shows that adding trastuzumab to conventional chemotherapy is effective and cost-effective. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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15 pages, 2266 KiB

Open AccessArticle

An Anti-PSMA Immunotoxin Reduces Mcl-1 and Bcl2A1 and Specifically Induces in Combination with the BAD-Like BH3 Mimetic ABT-737 Apoptosis in Prostate Cancer Cells

by Anie P. Masilamani, Viviane Dettmer-Monaco, Gianni Monaco, Toni Cathomen, Irina Kuckuck, Susanne Schultze-Seemann, Nathalie Huber and Philipp Wolf

Cancers 2020, 12(6), 1648; https://doi.org/10.3390/cancers12061648 - 22 Jun 2020

Cited by 11 | Viewed by 3744

Abstract

Background: Upregulation of anti-apoptotic Bcl-2 proteins in advanced prostate cancer leads to therapeutic resistance by prevention of cell death. New therapeutic approaches aim to target the Bcl-2 proteins for the restoration of apoptosis. Methods: The immunotoxin hD7-1(VL-VH)-PE40 specifically binds to the prostate specific [...] Read more.

Background: Upregulation of anti-apoptotic Bcl-2 proteins in advanced prostate cancer leads to therapeutic resistance by prevention of cell death. New therapeutic approaches aim to target the Bcl-2 proteins for the restoration of apoptosis. Methods: The immunotoxin hD7-1(VL-VH)-PE40 specifically binds to the prostate specific membrane antigen (PSMA) on prostate cancer cells and inhibits protein biosynthesis. It was tested with respect to its effects on the expression of anti-apoptotic Bcl-2 proteins. Combination with the BAD-like mimetic ABT-737 was examined on prostate cancer cells and 3D spheroids and in view of tumor growth and survival in the prostate cancer SCID mouse xenograft model. Results: The immunotoxin led to a specific inhibition of Mcl-1 and Bcl2A1 expression in PSMA expressing target cells. Its combination with ABT-737, which inhibits Bcl-2, Bcl-xl, and Bcl-w, led to an induction of the intrinsic apoptotic pathway and to a synergistic cytotoxicity in prostate cancer cells and 3D spheroids. Furthermore, combination therapy led to a significantly prolonged survival of mice bearing prostate cancer xenografts based on an inhibition of tumor growth. Conclusion: The combination therapy of anti-PSMA immunotoxin plus ABT-737 represents the first tumor-specific therapeutic approach on the level of Bcl-2 proteins for the induction of apoptosis in prostate cancer. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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21 pages, 3208 KiB

Open AccessArticle

Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression

by Olaia Martinez-Iglesias, Alba Casas-Pais, Raquel Castosa, Andrea Díaz-Díaz, Daniel Roca-Lema, Ángel Concha, Álvaro Cortés, Federico Gago and Angélica Figueroa

Cancers 2020, 12(5), 1340; https://doi.org/10.3390/cancers12051340 - 23 May 2020

Cited by 15 | Viewed by 5470

Abstract

The requirement of the E3 ubiquitin-ligase Hakai for the ubiquitination and subsequent degradation of E-cadherin has been associated with enhanced epithelial-to-mesenchymal transition (EMT), tumour progression and carcinoma metastasis. To date, most of the reported EMT-related inhibitors were not developed for anti-EMT purposes, but [...] Read more.

The requirement of the E3 ubiquitin-ligase Hakai for the ubiquitination and subsequent degradation of E-cadherin has been associated with enhanced epithelial-to-mesenchymal transition (EMT), tumour progression and carcinoma metastasis. To date, most of the reported EMT-related inhibitors were not developed for anti-EMT purposes, but indirectly affect EMT. On the other hand, E3 ubiquitin-ligase enzymes have recently emerged as promising therapeutic targets, as their specific inhibition would prevent wider side effects. Given this background, a virtual screening was performed to identify novel specific inhibitors of Hakai, targeted against its phosphotyrosine-binding pocket, where phosphorylated-E-cadherin specifically binds. We selected a candidate inhibitor, Hakin-1, which showed an important effect on Hakai-induced ubiquitination. Hakin-1 also inhibited carcinoma growth and tumour progression both in vitro, in colorectal cancer cell lines, and in vivo, in a tumour xenograft mouse model, without apparent systemic toxicity in mice. Our results show for the first time that a small molecule putatively targeting the E3 ubiquitin-ligase Hakai inhibits Hakai-dependent ubiquitination of E-cadherin, having an impact on the EMT process. This represents an important step forward in a future development of an effective therapeutic drug to prevent or inhibit carcinoma tumour progression. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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23 pages, 3610 KiB

Open AccessArticle

All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells

by Marco Bolis, Gabriela Paroni, Maddalena Fratelli, Arianna Vallerga, Luca Guarrera, Adriana Zanetti, Mami Kurosaki, Silvio Ken Garattini, Maurizio Gianni’, Monica Lupi, Linda Pattini, Maria Monica Barzago, Mineko Terao and Enrico Garattini

Cancers 2020, 12(5), 1169; https://doi.org/10.3390/cancers12051169 - 06 May 2020

Cited by 15 | Viewed by 3604

Abstract

All-trans retinoic acid (ATRA), a recognized differentiating agent, has significant potential in the personalized/stratified treatment of breast cancer. The present study reports on the molecular mechanisms underlying the anti-tumor activity of ATRA in breast cancer. The work is based on transcriptomic experiments performed [...] Read more.

All-trans retinoic acid (ATRA), a recognized differentiating agent, has significant potential in the personalized/stratified treatment of breast cancer. The present study reports on the molecular mechanisms underlying the anti-tumor activity of ATRA in breast cancer. The work is based on transcriptomic experiments performed on ATRA-treated breast cancer cell-lines, short-term tissue cultures of patient-derived mammary-tumors and a xenograft model. ATRA upregulates gene networks involved in interferon-responses, immune-modulation and antigen-presentation in retinoid-sensitive cells and tumors characterized by poor immunogenicity. ATRA-dependent upregulation of these gene networks is caused by a viral mimicry process, involving the activation of endogenous retroviruses. ATRA induces a non-canonical type of viral mimicry, which results in increased expression of the IRF1 (Interferon Responsive Factor 1) transcription factor and the DTX3L (Deltex-E3-Ubiquitin-Ligase-3L) downstream effector. Functional knockdown studies indicate that IRF1 and DTX3L are part of a negative feedback loop controlling ATRA-dependent growth inhibition of breast cancer cells. The study is of relevance from a clinical/therapeutic perspective. In fact, ATRA stimulates processes controlling the sensitivity to immuno-modulatory drugs, such as immune-checkpoint-inhibitors. This suggests that ATRA and immunotherapeutic agents represent rational combinations for the personalized treatment of breast cancer. Remarkably, ATRA-sensitivity seems to be relatively high in immune-cold mammary tumors, which are generally resistant to immunotherapy. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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20 pages, 2620 KiB

Open AccessArticle

Preclinical Targeted α- and β⁻-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies

by Janik Puttemans, Yana Dekempeneer, Jos L. Eersels, Heleen Hanssens, Pieterjan Debie, Marleen Keyaerts, Albert D. Windhorst, Frank van der Aa, Quentin Lecocq, Karine Breckpot, Alfred Morgenstern, Frank Bruchertseifer, Tony Lahoutte, Nick Devoogdt and Matthias D’Huyvetter

Cancers 2020, 12(4), 1017; https://doi.org/10.3390/cancers12041017 - 21 Apr 2020

Cited by 44 | Viewed by 4662

Abstract

HER2-targeted therapies have drastically improved the outcome for breast cancer patients. However, when metastasis to the brain is involved, current strategies fail to hold up to the same promise. Camelid single-domain antibody-fragments (sdAbs) have been demonstrated to possess favorable properties for detecting and [...] Read more.

HER2-targeted therapies have drastically improved the outcome for breast cancer patients. However, when metastasis to the brain is involved, current strategies fail to hold up to the same promise. Camelid single-domain antibody-fragments (sdAbs) have been demonstrated to possess favorable properties for detecting and treating cancerous lesions in vivo using different radiolabeling methods. Here we evaluate the anti-HER2 sdAb 2Rs15d, coupled to diagnostic γ- and therapeutic α- and β⁻-emitting radionuclides for the detection and treatment of HER2^pos brain lesions in a preclinical setting. 2Rs15d was radiolabeled with ¹¹¹In, ²²⁵Ac and ¹³¹I using DTPA- and DOTA-based bifunctional chelators and Sn-precursor of SGMIB respectively and evaluated in orthotopic tumor-bearing athymic nude mice. Therapeutic efficacy as well as systemic toxicity were determined for ¹³¹I- and ²²⁵Ac-labeled sdAbs and compared to anti-HER2 monoclonal antibody (mAb) trastuzumab in two different HER2^pos tumor models. Radiolabeled 2Rs15d showed high and specific tumor uptake in both HER2^pos SK-OV-3-Luc-IP1 and HER2^pos MDA-MB-231Br brain lesions, whereas radiolabeled trastuzumab was unable to accumulate in intracranial SK-OV-3-Luc-IP1 tumors. Administration of [¹³¹I]-2Rs15d and [²²⁵Ac]-2Rs15d alone and in combination with trastuzumab showed a significant increase in median survival in 2 tumor models that remained largely unresponsive to trastuzumab treatment alone. Histopathological analysis revealed no significant early toxicity. Radiolabeled sdAbs prove to be promising vehicles for molecular imaging and targeted radionuclide therapy of metastatic lesions in the brain. These data demonstrate the potential of radiolabeled sdAbs as a valuable add-on treatment option for patients with difficult-to-treat HER2^pos metastatic cancer. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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27 pages, 5545 KiB

Open AccessArticle

Downstream Effectors of ILK in Cisplatin-Resistant Ovarian Cancer

by Jeyshka M. Reyes-González, Blanca I. Quiñones-Díaz, Yasmarie Santana, Perla M. Báez-Vega, Daniel Soto, Fatima Valiyeva, María J. Marcos-Martínez, Ricardo J. Fernández-de Thomas and Pablo E. Vivas-Mejía

Cancers 2020, 12(4), 880; https://doi.org/10.3390/cancers12040880 - 04 Apr 2020

Cited by 15 | Viewed by 5359

Abstract

Despite good responses to first-line treatment with platinum-based combination chemotherapy, most ovarian cancer patients will relapse and eventually develop platinum-resistant disease with poor prognosis. Although reports suggest that integrin-linked kinase (ILK) is a potential target for ovarian cancer treatment, identification of ILK downstream [...] Read more.

Despite good responses to first-line treatment with platinum-based combination chemotherapy, most ovarian cancer patients will relapse and eventually develop platinum-resistant disease with poor prognosis. Although reports suggest that integrin-linked kinase (ILK) is a potential target for ovarian cancer treatment, identification of ILK downstream effectors has not been fully explored. The purpose of this study was to investigate the molecular and biological effects of targeting ILK in cisplatin-resistant ovarian cancer. Western blot analysis showed that phosphorylation levels of ILK were higher in cisplatin-resistant compared with cisplatin-sensitive ovarian cancer cells. Further immunohistochemical analysis of ovarian cancer patient samples showed a significant increase in phosphorylated ILK levels in the tumor tissue when compared to normal ovarian epithelium. Targeting ILK by small-interfering RNA (siRNA) treatment reduced cisplatin-resistant cell growth and invasion ability, and increased apoptosis. Differential gene expression analysis by RNA sequencing (RNA-Seq) upon ILK-siRNA transfection followed by Ingenuity Pathway Analysis (IPA) and survival analysis using the Kaplan–Meier plotter database identified multiple target genes involved in cell growth, apoptosis, invasion, and metastasis, including several non-coding RNAs. Taken together, results from this study support ILK as an attractive target for ovarian cancer and provide potential ILK downstream effectors with prognostic and therapeutic value. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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Review

Jump to: Research, Other

21 pages, 1278 KiB

Open AccessReview

Targeted Therapy in Follicular Lymphoma: Towards a Chemotherapy-Free Approach

by Chung-Jiah J. Chen, Michael Y. Choi and Benjamin M. Heyman

Cancers 2023, 15(18), 4483; https://doi.org/10.3390/cancers15184483 - 08 Sep 2023

Viewed by 1946

Abstract

Background: The treatment of follicular lymphoma (FL) has previously centered on chemoimmunotherapy, which can be disadvantageous due to patient intolerance, cumulative toxicities, and disease refractoriness. Targeted therapies can produce deep responses and improve progression-free and overall survival with more tolerable adverse event profiles. [...] Read more.

Background: The treatment of follicular lymphoma (FL) has previously centered on chemoimmunotherapy, which can be disadvantageous due to patient intolerance, cumulative toxicities, and disease refractoriness. Targeted therapies can produce deep responses and improve progression-free and overall survival with more tolerable adverse event profiles. Methods: We summarize the current literature and key clinical trials regarding targeted therapies in follicular lymphoma both in the front-line and in the relapsed-refractory setting. Results: Targeted therapies studied in FL include immune modulators, anti-CD20 antibodies, Bruton’s tyrosine kinase (BTK) inhibitors, enhancers of zeste homolog 2 (EZH2) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, and B-cell lymphoma 2 (BCL-2) inhibitors. Chimeric antigen receptor (CAR-T) therapy and bispecific T-cell engager (BiTE) therapies also show promise in monotherapy and in combination with targeted therapies. These therapies exhibit high overall response rates and substantial progression-free survival and overall survival, even in high-risk patients or patients previously refractory to chemotherapy or rituximab. Adverse events vary substantially but are generally manageable and compare favorably to the cumulative toxicities of chemotherapy. Conclusion: Targeted therapies represent a paradigm shift in the treatment of FL. Further studies are needed to directly compare these targeted therapies and their combinations, as well as to investigate biomarkers predictive of response. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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15 pages, 529 KiB

Open AccessEditor’s ChoiceReview

Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives

by Shirin Hafezi and Mohamed Rahmani

Cancers 2021, 13(6), 1292; https://doi.org/10.3390/cancers13061292 - 14 Mar 2021

Cited by 94 | Viewed by 9295

Abstract

The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, [...] Read more.

The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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14 pages, 597 KiB

Open AccessReview

Targeting KRAS in Cancer: Promising Therapeutic Strategies

by Lisa Maria Mustachio, Anca Chelariu-Raicu, Lorant Szekvolgyi and Jason Roszik

Cancers 2021, 13(6), 1204; https://doi.org/10.3390/cancers13061204 - 10 Mar 2021

Cited by 37 | Viewed by 5239

Abstract

The Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in approximately 25% of all human cancers and is known to be a major player promoting and maintaining tumorigenesis through the RAS/MAPK pathway. Over the years, a large number of studies [...] Read more.

The Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in approximately 25% of all human cancers and is known to be a major player promoting and maintaining tumorigenesis through the RAS/MAPK pathway. Over the years, a large number of studies have identified strategies at different regulatory levels to tackle this ‘difficult-to-target’ oncoprotein. Yet, the most ideal strategy to overcome KRAS and its downstream effects has yet to be uncovered. This review summarizes the role of KRAS activating mutations in multiple cancer types as well as the key findings for potential strategies inhibiting its oncogenic behavior. A comprehensive analysis of the different pathways and mechanisms associated with KRAS activity in tumors will ultimately pave the way for promising future work that will identify optimum therapeutic strategies. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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29 pages, 990 KiB

Open AccessReview

Targeted Therapies for Pancreatic Cancer: Overview of Current Treatments and New Opportunities for Personalized Oncology

by Cédric Leroux and Georgia Konstantinidou

Cancers 2021, 13(4), 799; https://doi.org/10.3390/cancers13040799 - 14 Feb 2021

Cited by 29 | Viewed by 8061

Abstract

Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers [...] Read more.

Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers intratumoral and intertumoral heterogeneity with distinct proliferative and metastatic propensity. This heterogeneity can explain why tumors do not behave uniformly and are able to escape therapy. The advance in technology of whole-genome sequencing has now provided the possibility of identifying every somatic mutation, copy-number change, and structural variant in a given cancer, giving rise to personalized targeted therapies. In this review, we provide an overview of the current and emerging treatment strategies in pancreatic cancer. By highlighting new paradigms in pancreatic ductal adenocarcinoma treatment, we hope to stimulate new thoughts for clinical trials aimed at improving patient outcomes. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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37 pages, 4888 KiB

Open AccessReview

Perspectives on the Role of Isoliquiritigenin in Cancer

by Kai-Lee Wang, Ying-Chun Yu and Shih-Min Hsia

Cancers 2021, 13(1), 115; https://doi.org/10.3390/cancers13010115 - 01 Jan 2021

Cited by 64 | Viewed by 5422

Abstract

Isoliquiritigenin (2′,4′,4-trihydroxychalcone, ISL), one of the most important bioactive compounds with a chalcone structure, is derived from licorice root. Licorice is commonly known as Glycyrrhiza, including Glycyrrhiza uralensis, Glycyrrhiza radix, and Glycyrrhiza glabra, which are generally available in common [...] Read more.

Isoliquiritigenin (2′,4′,4-trihydroxychalcone, ISL), one of the most important bioactive compounds with a chalcone structure, is derived from licorice root. Licorice is commonly known as Glycyrrhiza, including Glycyrrhiza uralensis, Glycyrrhiza radix, and Glycyrrhiza glabra, which are generally available in common foods and Chinese herbal medicines based on a wide variety of biological functions and pharmacological effects, and its derivative (ISL) is utilized as a food additive and adjunct disease treatment. In this review, we summarized the progress over the last 10 years in the targeted pathways and molecular mechanisms of ISL that are involved in the regulation of the onset and progression of different types of cancers. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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22 pages, 1143 KiB

Open AccessReview

Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update

by Luigi Sapio, Alessia Salzillo, Angela Ragone, Michela Illiano, Annamaria Spina and Silvio Naviglio

Cancers 2020, 12(11), 3166; https://doi.org/10.3390/cancers12113166 - 28 Oct 2020

Cited by 39 | Viewed by 4665

Abstract

Intratumor heterogeneity (ITH) is considered the major disorienting factor in cancer treatment. As a result of stochastic genetic and epigenetic alterations, the appearance of a branched evolutionary shape confers tumor plasticity, causing relapse and unfavorable clinical prognosis. The growing evidence in cancer discovery [...] Read more.

Intratumor heterogeneity (ITH) is considered the major disorienting factor in cancer treatment. As a result of stochastic genetic and epigenetic alterations, the appearance of a branched evolutionary shape confers tumor plasticity, causing relapse and unfavorable clinical prognosis. The growing evidence in cancer discovery presents to us “the great paradox” consisting of countless potential targets constantly discovered and a small number of candidates being effective in human patients. Among these, cyclic-AMP response element-binding protein (CREB) has been proposed as proto-oncogene supporting tumor initiation, progression and metastasis. Overexpression and hyperactivation of CREB are frequently observed in cancer, whereas genetic and pharmacological CREB downregulation affects proliferation and apoptosis. Notably, the present review is designed to investigate the feasibility of targeting CREB in cancer therapy. In particular, starting with the latest CREB evidence in cancer pathophysiology, we evaluate the advancement state of CREB inhibitor design, including the histone lysine demethylases JMJD3/UTX inhibitor GSKJ4 that we newly identified as a promising CREB modulator in leukemia cells. Moreover, an accurate analysis of strengths and weaknesses is also conducted to figure out whether CREB can actually represent a therapeutic candidate or just one of the innumerable preclinical cancer targets. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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40 pages, 1835 KiB

Open AccessReview

Connecting the Missing Dots: ncRNAs as Critical Regulators of Therapeutic Susceptibility in Breast Cancer

by Elena-Georgiana Dobre, Sorina Dinescu and Marieta Costache

Cancers 2020, 12(9), 2698; https://doi.org/10.3390/cancers12092698 - 21 Sep 2020

Cited by 9 | Viewed by 3836

Abstract

Whether acquired or de novo, drug resistance remains a significant hurdle in achieving therapeutic success in breast cancer (BC). Thus, there is an urge to find reliable biomarkers that will help in predicting the therapeutic response. Stable and easily accessible molecules such as [...] Read more.

Whether acquired or de novo, drug resistance remains a significant hurdle in achieving therapeutic success in breast cancer (BC). Thus, there is an urge to find reliable biomarkers that will help in predicting the therapeutic response. Stable and easily accessible molecules such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are regarded as valuable prognostic biomarkers and therapeutic targets since they act as crucial regulators of the various mechanisms involved in BC drug resistance. Here, we reviewed the current literature on ncRNAs as mediators of resistance to systemic therapies in BC. Interestingly, upon integrating data results from individual studies, we concluded that miR-221, miR-222, miR-451, Urothelial Carcinoma Associated 1 (UCA1), and Growth arrest-specific 5 (GAS5) are strong candidates as prognostic biomarkers and therapeutic targets since they are regulating multiple drug resistance phenotypes in BC. However, further research around their clinical implications is needed to validate and integrate them into therapeutic applications. Therefore, we believe that our review may provide relevant evidence for the selection of novel therapeutic targets and prognostic biomarkers for BC and will serve as a foundation for future translational research in the field. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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22 pages, 767 KiB

Open AccessReview

The Neurokinin-1 Receptor Antagonist Aprepitant: An Intelligent Bullet against Cancer?

by Miguel Muñoz and Rafael Coveñas

Cancers 2020, 12(9), 2682; https://doi.org/10.3390/cancers12092682 - 20 Sep 2020

Cited by 50 | Viewed by 8845

Abstract

Neurokinin-1 receptor (NK-1R) antagonists exert antitumor action, are safe and do not cause serious side-effects. These antagonists (via the NK-1R) exert multiple actions against cancer: antiproliferative and anti-Warburg effects and apoptotic, anti-angiogenic and antimetastatic effects. These multiple effects have been shown for a [...] Read more.

Neurokinin-1 receptor (NK-1R) antagonists exert antitumor action, are safe and do not cause serious side-effects. These antagonists (via the NK-1R) exert multiple actions against cancer: antiproliferative and anti-Warburg effects and apoptotic, anti-angiogenic and antimetastatic effects. These multiple effects have been shown for a broad spectrum of cancers. The drug aprepitant (an NK-1R antagonist) is currently used in clinical practice as an antiemetic. In in vivo and in vitro studies, aprepitant also showed the aforementioned multiple antitumor actions against many types of cancer. A successful combination therapy (aprepitant and radiotherapy) has recently been reported in a patient suffering from lung carcinoma: the tumor mass disappeared and side-effects were not observed. Aprepitant could be considered as an intelligent bullet against cancer. The administration of aprepitant in cancer patients to prevent recurrence and metastasis after surgical procedures, thrombosis and thromboembolism is discussed, as is the possible link, through the substance P (SP)/NK-1R system, between cancer and depression. Our main aim is to review the multiple antitumor actions exerted by aprepitant, and the use of this drug is suggested in cancer patients. Altogether, the data support the reprofiling of aprepitant for a new therapeutic use as an antitumor agent. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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18 pages, 857 KiB

Open AccessReview

Molecular Targets for the Treatment of Metastatic Colorectal Cancer

by Romain Cohen, Thomas Pudlarz, Jean-François Delattre, Raphaël Colle and Thierry André

Cancers 2020, 12(9), 2350; https://doi.org/10.3390/cancers12092350 - 20 Aug 2020

Cited by 30 | Viewed by 5411

Abstract

Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major [...] Read more.

Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major tools for personalized therapeutic strategies. Moreover, the routine implementation of molecular predictive tests provides new perspectives and challenges for the therapeutic management of CRC patients, such as liquid biopsies and the reintroduction of anti-EGFR monoclonal antibodies. In this review, we summarize the current landscape of targeted therapies for metastatic CRC patients, with a focus on new developments for EGFR blockade and emerging biomarkers (MSI, HER2, NTRK). Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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23 pages, 1150 KiB

Open AccessReview

Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma

by Yoshiaki Yura, Atsushi Masui and Masakazu Hamada

Cancers 2020, 12(8), 2062; https://doi.org/10.3390/cancers12082062 - 26 Jul 2020

Cited by 14 | Viewed by 3508

Abstract

In the treatment of advanced head and neck squamous cell carcinoma (HNSCC), including oral SCC, radiotherapy is a commonly performed therapeutic modality. The combined use of radiotherapy with chemotherapy improves therapeutic effects, but it also increases adverse events. Ceramide, a central molecule in [...] Read more.

In the treatment of advanced head and neck squamous cell carcinoma (HNSCC), including oral SCC, radiotherapy is a commonly performed therapeutic modality. The combined use of radiotherapy with chemotherapy improves therapeutic effects, but it also increases adverse events. Ceramide, a central molecule in sphingolipid metabolism and signaling pathways, mediates antiproliferative responses, and its level increases in response to radiotherapy and chemotherapy. However, when ceramide is metabolized, prosurvival factors, such as sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glucosylceramide, are produced, reducing the antitumor effects of ceramide. The activities of ceramide- and sphingosine-metabolizing enzymes are also associated with radio- and chemo-resistance. Ceramide analogs and low molecular-weight compounds targeting these enzymes exert anticancer effects. Synthetic ceramides and a therapeutic approach using ultrasound have also been developed. Inhibitors of ceramide- and sphingosine-metabolizing enzymes and synthetic ceramides can function as sensitizers of radiotherapy and chemotherapy for HNSCC. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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13 pages, 265 KiB

Open AccessReview

Recent Advances in Targeted Therapies for Advanced Gastrointestinal Malignancies

by Jasmine C. Huynh, Erin Schwab, Jingran Ji, Edward Kim, Anjali Joseph, Andrew Hendifar, May Cho and Jun Gong

Cancers 2020, 12(5), 1168; https://doi.org/10.3390/cancers12051168 - 06 May 2020

Cited by 10 | Viewed by 3649

Abstract

The treatment of advanced gastrointestinal (GI) cancers has become increasingly molecularly driven. Molecular profiling for HER2 and PD-L1 status is standard for metastatic gastroesophageal (GEJ) cancers to predict benefits from trastuzumab (HER2-targeted therapy) and pembrolizumab (anti-PD-1 therapy), while extended RAS and BRAF testing [...] Read more.

The treatment of advanced gastrointestinal (GI) cancers has become increasingly molecularly driven. Molecular profiling for HER2 and PD-L1 status is standard for metastatic gastroesophageal (GEJ) cancers to predict benefits from trastuzumab (HER2-targeted therapy) and pembrolizumab (anti-PD-1 therapy), while extended RAS and BRAF testing is standard in metastatic colorectal cancer to predict benefits from epidermal growth factor receptor (EGFR)-targeted therapies. Mismatch repair (MMR) or microsatellite instability (MSI) testing is standard for all advanced GI cancers to predict benefits from pembrolizumab and in metastatic colorectal cancer, nivolumab with or without ipilimumab. Here we review recent seminal trials that have further advanced targeted therapies in these cancers including Poly (adenosine diphosphate–ribose) polymerases (PARP) inhibition in pancreas cancer, BRAF inhibition in colon cancer, and isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) inhibition in biliary tract cancer. Targeted therapies in GI malignancies constitute an integral component of the treatment paradigm in these advanced cancers and have widely established the need for standard molecular profiling to identify candidates. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

29 pages, 2138 KiB

Open AccessReview

Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma: A Review of the Current Status of Literature

by Ashleigh Hull, Yanrui Li, Dylan Bartholomeusz, William Hsieh, Barry Allen and Eva Bezak

Cancers 2020, 12(2), 481; https://doi.org/10.3390/cancers12020481 - 19 Feb 2020

Cited by 10 | Viewed by 3335

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has long been associated with low survival rates. A lack of accurate diagnostic tests and limited treatment options contribute to the poor prognosis of PDAC. Radioimmunotherapy using α- or β-emitting radionuclides has been identified as a potential treatment for [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) has long been associated with low survival rates. A lack of accurate diagnostic tests and limited treatment options contribute to the poor prognosis of PDAC. Radioimmunotherapy using α- or β-emitting radionuclides has been identified as a potential treatment for PDAC. By harnessing the cytotoxicity of α or β particles, radioimmunotherapy may overcome the anatomic and physiological factors which traditionally make PDAC resistant to most conventional treatments. Appropriate selection of target receptors and the development of selective and cytotoxic radioimmunoconjugates are needed to achieve the desired results of radioimmunotherapy. The aim of this review is to examine the growing preclinical and clinical trial evidence regarding the application of α and β radioimmunotherapy for the treatment of PDAC. A systematic search of MEDLINE^® and Scopus databases was performed to identify 34 relevant studies conducted on α or β radioimmunotherapy of PDAC. Preclinical results demonstrated α and β radioimmunotherapy provided effective tumour control. Clinical studies were limited to investigating β radioimmunotherapy only. Phase I and II trials observed disease control rates of 11.2%–57.9%, with synergistic effects noted for combination therapies. Further developments and optimisation of treatment regimens are needed to improve the clinical relevance of α and β radioimmunotherapy in PDAC. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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24 pages, 1487 KiB

Open AccessReview

Cytoskeletal Proteins in Cancer and Intracellular Stress: A Therapeutic Perspective

by Mei Shan Ong, Shuo Deng, Clarissa Esmeralda Halim, Wanpei Cai, Tuan Zea Tan, Ruby Yun-Ju Huang, Gautam Sethi, Shing Chuan Hooi, Alan Prem Kumar and Celestial T. Yap

Cancers 2020, 12(1), 238; https://doi.org/10.3390/cancers12010238 - 18 Jan 2020

Cited by 63 | Viewed by 9569

Abstract

Cytoskeletal proteins, which consist of different sub-families of proteins including microtubules, actin and intermediate filaments, are essential for survival and cellular processes in both normal as well as cancer cells. However, in cancer cells, these mechanisms can be altered to promote tumour development [...] Read more.

Cytoskeletal proteins, which consist of different sub-families of proteins including microtubules, actin and intermediate filaments, are essential for survival and cellular processes in both normal as well as cancer cells. However, in cancer cells, these mechanisms can be altered to promote tumour development and progression, whereby the functions of cytoskeletal proteins are co-opted to facilitate increased migrative and invasive capabilities, proliferation, as well as resistance to cellular and environmental stresses. Herein, we discuss the cytoskeletal responses to important intracellular stresses (such as mitochondrial, endoplasmic reticulum and oxidative stresses), and delineate the consequences of these responses, including effects on oncogenic signalling. In addition, we elaborate how the cytoskeleton and its associated molecules present themselves as therapeutic targets. The potential and limitations of targeting new classes of cytoskeletal proteins are also explored, in the context of developing novel strategies that impact cancer progression. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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31 pages, 2009 KiB

Open AccessReview

Clinical Limitations of Photon, Proton and Carbon Ion Therapy for Pancreatic Cancer

by Mikaela Dell’Oro, Michala Short, Puthenparampil Wilson and Eva Bezak

Cancers 2020, 12(1), 163; https://doi.org/10.3390/cancers12010163 - 09 Jan 2020

Cited by 11 | Viewed by 4423

Abstract

Introduction: Despite improvements in radiation therapy, chemotherapy and surgical procedures over the last 30 years, pancreatic cancer 5-year survival rate remains at 9%. Reduced stroma permeability and heterogeneous blood supply to the tumour prevent chemoradiation from making a meaningful impact on overall survival. [...] Read more.

Introduction: Despite improvements in radiation therapy, chemotherapy and surgical procedures over the last 30 years, pancreatic cancer 5-year survival rate remains at 9%. Reduced stroma permeability and heterogeneous blood supply to the tumour prevent chemoradiation from making a meaningful impact on overall survival. Hypoxia-activated prodrugs are the latest strategy to reintroduce oxygenation to radioresistant cells harbouring in pancreatic cancer. This paper reviews the current status of photon and particle radiation therapy for pancreatic cancer in combination with systemic therapies and hypoxia activators. Methods: The current effectiveness of management of pancreatic cancer was systematically evaluated from MEDLINE^® database search in April 2019. Results: Limited published data suggest pancreatic cancer patients undergoing carbon ion therapy and proton therapy achieve a comparable median survival time (25.1 months and 25.6 months, respectively) and 1-year overall survival rate (84% and 77.8%). Inconsistencies in methodology, recording parameters and protocols have prevented the safety and technical aspects of particle therapy to be fully defined yet. Conclusion: There is an increasing requirement to tackle unmet clinical demands of pancreatic cancer, particularly the lack of synergistic therapies in the advancing space of radiation oncology. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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Other

Jump to: Research, Review

10 pages, 2507 KiB

Open AccessBrief Report

Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer

by Roberto Benelli, Delfina Costa, Luca Mastracci, Federica Grillo, Mark Jon Olsen, Paola Barboro, Alessandro Poggi and Nicoletta Ferrari

Cancers 2020, 12(4), 971; https://doi.org/10.3390/cancers12040971 - 14 Apr 2020

Cited by 9 | Viewed by 3051

Abstract

Colorectal cancer’s (CRC) ability to invade local tissues and lymph nodes and generate distant metastases is the key for TNM classification. Aspartate-β-hydroxylase (ASPH), a transmembrane protein that catalyzes Notch receptors and ligand activation, is involved in tumor invasion. Because Notch is involved in [...] Read more.

Colorectal cancer’s (CRC) ability to invade local tissues and lymph nodes and generate distant metastases is the key for TNM classification. Aspartate-β-hydroxylase (ASPH), a transmembrane protein that catalyzes Notch receptors and ligand activation, is involved in tumor invasion. Because Notch is involved in gut homeostasis, it could be a target for CRC therapy. ASPH mRNA and protein expression, promoter methylation and gene copy numbers were evaluated using the TCGA and CPTAC human CRC datasets. Using digital pathology, ASPH was scored in the luminal area (LM), center tumor (CT) and invasive margin (IM) of 100 human CRCs. The effect of ASPH targeting on invasiveness and viability was tested by siRNA knockdown and small molecule inhibitors (SMI). Bioinformatics analysis showed increased expression of ASPH mRNA and protein in CRC, paired with a decreased methylation profile. ASPH genetic gain or amplification was frequent (56%), while deletion was rare (0.03%). Digital pathology analysis showed that ASPH exerted its pathological activity in the invasive margin of the tumor, affecting invasive front morphology, tumor budding and patients’ overall survival. In vitro, ASPH targeting by siRNA or SMI reduced cell invasion and growth and caused Notch-1 downregulation. This study demonstrates that ASPH targeting by specific inhibitors could improve CRC treatment strategies. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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