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Cancers
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Combination Therapies in Cancers
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Combination Therapies in Cancers

A topical collection in Cancers (ISSN 2072-6694). This collection belongs to the section "Cancer Therapy".

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Editors

Prof. Dr. Patrycja Nowak-Sliwinska

E-Mail Website
Collection Editor
1. Molecular Pharmacology Group, School of Pharmaceutical Sciences, Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland
2. Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland
3. Translational Research Center in Oncohaematology, 1211 Geneva, Switzerland
Interests: combination therapy; tumor microenvirontment; targeted therapy; angiogenesis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Arjan W. Griffioen

E-Mail Website
Collection Editor
Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam UMC, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
Interests: angiogenesis; immunology; cancer vaccines; immunotherapy

Topical Collection Information

Dear Colleagues,

This Topical Collection on “Combination Therapies in Cancers” will address the current efforts and advances in preclinical and clinical studies for the development of combinatorial approaches for effective cancer treatment. Special attention will be on the translation of these findings towards the clinic. The Topical Collection will show different perspectives of improving the activity of cancer treatment through the design of combination therapies and the development of combinatorial strategies with other treatment options. Although many questions might remain unanswered, general interest in combination strategies seems to drive the whole field of cancer research. We hope that this Topical Collection facilitates recognition and understanding of the power of carefully designed combination treatments.

Prof. Dr. Patrycja Nowak-Sliwinska
Prof. Dr. Arjan W. Griffioen
Collection Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • angiogenesis
  • combination therapy
  • drug–drug interactions
  • drug synergy
  • immunology

Published Papers (8 papers)

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2024

Jump to: 2023, 2022, 2021

16 pages, 1469 KiB  
Review
The Promise of Combination Therapies with FOXM1 Inhibitors for Cancer Treatment
by Nawal Merjaneh, Mona Hajjar, Ying-Wei Lan, Vladimir V. Kalinichenko and Tanya V. Kalin
Cancers 2024, 16(4), 756; https://doi.org/10.3390/cancers16040756 - 12 Feb 2024
Cited by 3 | Viewed by 2568
Abstract
Forkhead box M1 (FOXM1) is a transcription factor in the forkhead (FOX) family, which is required for cellular proliferation in normal and neoplastic cells. FOXM1 is highly expressed in many different cancers, and its expression is associated with a higher tumor stage and [...] Read more.
Forkhead box M1 (FOXM1) is a transcription factor in the forkhead (FOX) family, which is required for cellular proliferation in normal and neoplastic cells. FOXM1 is highly expressed in many different cancers, and its expression is associated with a higher tumor stage and worse patient-related outcomes. Abnormally high expression of FOXM1 in cancers compared to normal tissue makes FOXM1 an attractive target for pharmacological inhibition. FOXM1-inhibiting agents and specific FOXM1-targeted small-molecule inhibitors have been developed in the lab and some of them have shown promising efficacy and safety profiles in mouse models. While the future goal is to translate FOXM1 inhibitors to clinical trials, potential synergistic drug combinations can maximize anti-tumor efficacy while minimizing off-target side effects. Hence, we discuss the rationale and efficacy of all previously studied drug combinations with FOXM1 inhibitors for cancer therapies. Full article
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2023

Jump to: 2024, 2022, 2021

22 pages, 5924 KiB  
Article
Discovering Synergistic Compounds with BYL-719 in PI3K Overactivated Basal-like PDXs
by David C. Boyd, Emily K. Zboril, Amy L. Olex, Tess J. Leftwich, Nicole S. Hairr, Holly A. Byers, Aaron D. Valentine, Julia E. Altman, Mohammad A. Alzubi, Jacqueline M. Grible, Scott A. Turner, Andrea Ferreira-Gonzalez, Mikhail G. Dozmorov and J. Chuck Harrell
Cancers 2023, 15(5), 1582; https://doi.org/10.3390/cancers15051582 - 3 Mar 2023
Cited by 8 | Viewed by 2810
Abstract
Basal-like triple-negative breast cancer (TNBC) tumor cells are difficult to eliminate due to resistance mechanisms that promote survival. While this breast cancer subtype has low PIK3CA mutation rates when compared to estrogen receptor-positive (ER+) breast cancers, most basal-like TNBCs have an overactive PI3K [...] Read more.
Basal-like triple-negative breast cancer (TNBC) tumor cells are difficult to eliminate due to resistance mechanisms that promote survival. While this breast cancer subtype has low PIK3CA mutation rates when compared to estrogen receptor-positive (ER+) breast cancers, most basal-like TNBCs have an overactive PI3K pathway due to gene amplification or high gene expression. BYL-719 is a PIK3CA inhibitor that has been found to have low drug-drug interactions, which increases the likelihood that it could be useful for combinatorial therapy. Alpelisib (BYL-719) with fulvestrant was recently approved for treating ER+ breast cancer patients whose cancer had developed resistance to ER-targeting therapy. In these studies, a set of basal-like patient-derived xenograft (PDX) models was transcriptionally defined with bulk and single-cell RNA-sequencing and clinically actionable mutation profiles defined with Oncomine mutational profiling. This information was overlaid onto therapeutic drug screening results. BYL-719-based, synergistic two-drug combinations were identified with 20 different compounds, including everolimus, afatinib, and dronedarone, which were also found to be effective at minimizing tumor growth. These data support the use of these drug combinations towards cancers with activating PIK3CA mutations/gene amplifications or PTEN deficient/PI3K overactive pathways. Full article
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19 pages, 3667 KiB  
Article
SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling
by Yusuke Shibuya, Kei Kudo, Kristen P. Zeligs, David Anderson, Lidia Hernandez, Franklin Ning, Christopher B. Cole, Maria Fergusson, Noemi Kedei, John Lyons, Jason Taylor, Soumya Korrapati and Christina M. Annunziata
Cancers 2023, 15(4), 1315; https://doi.org/10.3390/cancers15041315 - 18 Feb 2023
Cited by 2 | Viewed by 2818
Abstract
The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of [...] Read more.
The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity. Accordingly, we performed a high-throughput screening matrix to identify synergistic drug combinations with birinapant. SMAC mimetics in combination with an HDAC inhibitor showed remarkable synergy and was, therefore, selected for further evaluation. We show here that this synergy observed both in vitro and in vivo results from multiple convergent pathways to include increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling. These findings provide a rationale for the integration of SMAC mimetics and HDAC inhibitors in clinical trials for recurrent ovarian cancer where treatment options are still limited. Full article
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11 pages, 1924 KiB  
Article
In Vivo Efficacy Testing of Peptide Receptor Radionuclide Therapy Radiosensitization Using Olaparib
by Danny Feijtel, Thom G. A. Reuvers, Christine van Tuyll-van Serooskerken, Corrina M. A. de Ridder, Debra C. Stuurman, Erik de Blois, Nicole S. Verkaik, Peter de Bruijn, Stijn L. W. Koolen, Marion de Jong and Julie Nonnekens
Cancers 2023, 15(3), 915; https://doi.org/10.3390/cancers15030915 - 1 Feb 2023
Cited by 8 | Viewed by 2229
Abstract
Peptide receptor radionuclide therapy (PRRT), a form of internal targeted radiation treatment using [177Lu]Lu [DOTA0-Tyr3]octreotate, is used to treat patients with metastasized neuroendocrine tumors (NETs). Even though PRRT is now the second line of treatment for patients [...] Read more.
Peptide receptor radionuclide therapy (PRRT), a form of internal targeted radiation treatment using [177Lu]Lu [DOTA0-Tyr3]octreotate, is used to treat patients with metastasized neuroendocrine tumors (NETs). Even though PRRT is now the second line of treatment for patients with metastasized NETs, the majority of patients will not be cured by the treatment. PRRT functions by inducing DNA damage upon radioactive decay and inhibition of DNA damage repair proteins could therefore be used as a strategy to potentiate PRRT. Previous work has shown promising results on the combination of PRRT with the PARP inhibitor olaparib in cell lines and mice and we have been taken the next step for further in vivo validation using two different xenografted mouse models. We observed that this combination therapy resulted in increased therapeutic efficacy only in one model and not the other. Overall, our findings indicate a tumor-type dependent anti-tumor response to the combination of PRRT and olaparib. These data emphasize the unmet need for the molecular stratification of tumors to predetermine the potential clinical value of combining PARP inhibition with PRRT. Full article
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19 pages, 2673 KiB  
Review
Tumor Treating Fields (TTFields) Therapy Concomitant with Taxanes for Cancer Treatment
by Ignace Vergote, Teresa Macarulla, Fred R. Hirsch, Carsten Hagemann and David Scott Miller
Cancers 2023, 15(3), 636; https://doi.org/10.3390/cancers15030636 - 19 Jan 2023
Cited by 9 | Viewed by 5974
Abstract
Non-small cell lung cancer, ovarian cancer, and pancreatic cancer all present with high morbidity and mortality. Systemic chemotherapies have historically been the cornerstone of standard of care (SOC) regimens for many cancers, but are associated with systemic toxicity. Multimodal treatment combinations can help [...] Read more.
Non-small cell lung cancer, ovarian cancer, and pancreatic cancer all present with high morbidity and mortality. Systemic chemotherapies have historically been the cornerstone of standard of care (SOC) regimens for many cancers, but are associated with systemic toxicity. Multimodal treatment combinations can help improve patient outcomes; however, implementation is limited by additive toxicities and potential drug–drug interactions. As such, there is a high unmet need to develop additional therapies to enhance the efficacy of SOC treatments without increasing toxicity. Tumor Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. The therapy is locoregional and is delivered noninvasively to the tumor site via a portable medical device that consists of field generator and arrays that are placed on the patient’s skin. As a noninvasive treatment modality, TTFields therapy-related adverse events mainly consist of localized skin reactions, which are manageable with effective acute and prophylactic treatments. TTFields selectively target cancer cells through a multi-mechanistic approach without affecting healthy cells and tissues. Therefore, the application of TTFields therapy concomitant with other cancer treatments may lead to enhanced efficacy, with low risk of further systemic toxicity. In this review, we explore TTFields therapy concomitant with taxanes in both preclinical and clinical settings. The summarized data suggest that TTFields therapy concomitant with taxanes may be beneficial in the treatment of certain cancers. Full article
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2022

Jump to: 2024, 2023, 2021

12 pages, 2794 KiB  
Article
Phase II Trial of the Combination of Alectinib with Bevacizumab in Alectinib Refractory ALK-Positive Nonsquamous Non-Small-Cell Lung Cancer (NLCTG1501)
by Satoshi Watanabe, Kazuko Sakai, Naoya Matsumoto, Jun Koshio, Akira Ishida, Tetsuya Abe, Daisuke Ishikawa, Tomohiro Tanaka, Ami Aoki, Tomosue Kajiwara, Kenichi Koyama, Satoru Miura, Yuka Goto, Tomoki Sekiya, Ryo Suzuki, Kohei Kushiro, Toshiya Fujisaki, Naohiro Yanagimura, Aya Ohtsubo, Satoshi Shoji, Koichiro Nozaki, Yu Saida, Hirohisa Yoshizawa, Kazuto Nishio and Toshiaki Kikuchiadd Show full author list remove Hide full author list
Cancers 2023, 15(1), 204; https://doi.org/10.3390/cancers15010204 - 29 Dec 2022
Cited by 9 | Viewed by 2447
Abstract
Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase [...] Read more.
Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2–16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients. Full article
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13 pages, 2119 KiB  
Article
Histology Classification Highlights Differences in Efficacy of S-1 versus Capecitabine, in Combination with Cisplatin, for HER2-Negative Unresectable Advanced or Recurrent Gastric Cancer with Measurable Disease
by Hisato Kawakami, Kazuhiro Nishikawa, Toshio Shimokawa, Kazumasa Fujitani, Shigeyuki Tamura, Shunji Endo, Michiya Kobayashi, Junji Kawada, Yukinori Kurokawa, Akira Tsuburaya, Takaki Yoshikawa, Junichi Sakamoto, Taroh Satoh and on behalf of the HERBIS-2, HERBIS-4A and XParTS II Study Investigators
Cancers 2022, 14(22), 5673; https://doi.org/10.3390/cancers14225673 - 18 Nov 2022
Cited by 2 | Viewed by 1768
Abstract
It has been suggested that the therapeutic efficacy of S-1 + cisplatin (SP) and capecitabine + cisplatin (XP) may differ depending on the histology of the tumor, but no clear evidence exists. Individual participant data were obtained from three randomized phase II trials [...] Read more.
It has been suggested that the therapeutic efficacy of S-1 + cisplatin (SP) and capecitabine + cisplatin (XP) may differ depending on the histology of the tumor, but no clear evidence exists. Individual participant data were obtained from three randomized phase II trials in which such patients received either SP (S-1 [40–60 mg twice daily for 21 days] plus cisplatin [60 mg/m2 on day 8], every 5 weeks) or XP (capecitabine [1000 mg/m2 twice daily for 14 days] plus cisplatin [80 mg/m2 on day 1], every 3 weeks). A total of 162 patients were included, with 79 patients in the SP arm and 83 patients in the XP arm. Although there was also no difference between arms in ORR according to histological classification, differentiated tumors showed a significantly better OS (but not PFS) for SP versus XP that was associated with a deeper tumor shrinkage. Undifferentiated tumors showed a consistently better OS, and PFS for SP versus XP, likely because cases without tumor shrinkage tended to be fewer for SP. Our data thus showed that SP was superior to XP in this setting, but there were qualitative differences in therapeutic efficacy dependent on tumor histology. Full article
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2021

Jump to: 2024, 2023, 2022

18 pages, 2532 KiB  
Article
Semi-Mechanistic Model for the Antitumor Response of a Combination Cocktail of Immuno-Modulators in Non-Inflamed (Cold) Tumors
by Aymara Sancho-Araiz, Sara Zalba, María J. Garrido, Pedro Berraondo, Brian Topp, Dinesh de Alwis, Zinnia P. Parra-Guillen, Víctor Mangas-Sanjuan and Iñaki F. Trocóniz
Cancers 2021, 13(20), 5049; https://doi.org/10.3390/cancers13205049 - 9 Oct 2021
Cited by 4 | Viewed by 2128
Abstract
Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors. Tumor size of mice [...] Read more.
Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors. Tumor size of mice treated with TC-1/A9 non-inflamed tumors and the drug effects of an antigen, a toll-like receptor-3 agonist (PIC), and an immune checkpoint inhibitor (anti-programmed cell death 1 antibody) were modeled using Monolix and following a middle-out strategy. Tumor growth was best characterized by an exponential model with an estimated initial tumor size of 19.5 mm3 and a doubling time of 3.6 days. In the treatment groups, contrary to the lack of response observed in monotherapy, combinations including the antigen were able to induce an antitumor response. The final model successfully captured the 23% increase in the probability of cure from bi-therapy to triple-therapy. Moreover, our work supports that CD8+ T lymphocytes and resistance mechanisms are strongly related to the clinical outcome. The activation of antigen-presenting cells might be needed to achieve an antitumor response in reduced immunogenic tumors when combined with other immunotherapies. These models can be used as a platform to evaluate different immuno-oncology combinations in preclinical and clinical scenarios. Full article
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