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Pharmaceutics
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Combination Therapy Approaches for Cancer Treatment
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Combination Therapy Approaches for Cancer Treatment

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: 31 July 2025 | Viewed by 6737

Special Issue Editors

Dr. Ravi P. Sahu

E-Mail Website
Guest Editor
Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Fairborn, OH 45324, USA
Interests: oxidative stressors and lipid mediators; cancer pharmacology and chemoprevention; anticancer therapeutics and immunomodulation; photobiology and environmental factors; cellular signaling pathways in tumor resistance mechanisms; antitumor immune responses
Special Issues, Collections and Topics in MDPI journals
Dr. Anita Thyagarajan

E-Mail Website
Guest Editor
Boonshoft School of Medicine, Wright State University, Dayton, OH, USA
Interests: cancer therapy

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to a Special Issue on “Combination therapy approaches for cancer treatment”. The treatment of human malignancies invites ongoing challenges, including the development of tumor resistance mechanisms to conventional therapeutic agents. Thus, combination therapy approaches are being explored to target tumor resistance mechanisms and counter-regulatory pathways involved in impeding the efficacy of cancer therapies to improve the overall responses of therapeutic agents, including survival benefits.

This Special Issue aims to publish original research articles or reviews on combination therapy approaches for cancer treatment, which fits with the journal’s scope regarding drug targeting and interdisciplinary research, involving, but not limited to, biomedical sciences and cell biology.

In this Special Issue, research areas may include (but are not limited to) the following: a combination of chemotherapeutic agents, repurposed drugs, dietary phytochemicals, targeted therapy, and immunotherapy approaches on any cancer models.

We look forward to receiving your contributions

Dr. Ravi P. Sahu
Dr. Anita Thyagarajan
Guest 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 special issue website. Research articles, review articles as well as short 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. Pharmaceutics is an international peer-reviewed open access monthly 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

  • combination therapy approaches
  • cancer chemoprevention
  • chemotherapeutic agents
  • cell signaling pathways
  • dietary phytochemicals
  • tumor resistance mechanisms
  • repurposed drugs
  • targeted therapy
  • immunotherapy

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Published Papers (6 papers)

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Research

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26 pages, 13470 KiB  
Article
Drug Combinations Targeting FAK and MEK Overcomes Tumor Heterogeneity in Glioblastoma
by Muhammad Furqan, Richard J. R. Elliott, Peter W. K. Nagle, John C. Dawson, Roza Masalmeh, Virginia Alvarez Garcia, Alison F. Munro, Camilla Drake, Gillian M. Morrison, Steven M. Pollard, Daniel Ebner, Valerie G. Brunton, Margaret C. Frame and Neil O. Carragher
Pharmaceutics 2025, 17(5), 549; https://doi.org/10.3390/pharmaceutics17050549 - 23 Apr 2025
Viewed by 438
Abstract
Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis, largely owing to its heterogeneity and the involvement of multiple intracellular signaling pathways that contribute to drug resistance. While recent advancements in targeted drug combination therapies, such [...] Read more.
Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis, largely owing to its heterogeneity and the involvement of multiple intracellular signaling pathways that contribute to drug resistance. While recent advancements in targeted drug combination therapies, such as dabrafenib and trametinib, show promise for certain GBM subgroups, identifying effective drug combinations across the broader GBM population remains a challenge. Integrin-mediated signaling, particularly through Focal Adhesion Kinase (FAK), plays a pivotal role in GBM pathogenesis and invasion, making it a potential therapeutic target and component of future drug combination strategies. Methods: In this study, we utilized a chemogenomic screening approach to identify synergistic drug combinations that target FAK in glioblastoma. We initially employed a CRISPR-engineered GBM model to assess the effects of FAK depletion and subsequently discovered that combining FAK inhibitors such as VS4718 with MEK inhibitors, particularly trametinib, demonstrated synergistic effects. This potent combination was validated using various 2D and 3D assays, including cell viability/apoptosis assessment, synergistic analysis, cellular imaging, and target engagement assays. This combination also effectively inhibited spheroid growth and invasion across a diverse panel of patient-derived GBM stem cells. Molecular mechanisms underlying these effects include suppression of multiple kinase signaling pathways and enhanced apoptosis, elucidated using Reverse-Phase Protein Array (RPPA) profiling and Western blot validation. Result: In vivo, combination therapy significantly reduced the tumor volume in orthotopic transplantation models. Conclusions: These findings suggest that the combination of FAK and MEK inhibitors represents a promising therapeutic strategy to overcome the challenges of GBM treatment. Full article
(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)
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21 pages, 2096 KiB  
Article
The Impact of Doxycycline as an Adjunctive Therapy on Prostate-Specific Antigen, Quality of Life, and Cognitive Function in Metastatic Prostate Cancer Patients: A Phase II Randomized Controlled Trial
by José Guzmán-Esquivel, Hossana S. Garcia-Garcia, Gustavo A. Hernández-Fuentes, Jesús Venegas-Ramírez, Carlos D. Barajas-Mejía, Idalia Garza-Veloz, Margarita L. Martinez-Fierro, Nancy E. Magaña-Vergara, José A. Guzmán-Solórzano, Patricia Calvo-Soto, Oscar N. Avila-Zamora, Mercedes Fuentes-Murguia, Gabriel Ceja-Espíritu and Iván Delgado-Enciso
Pharmaceutics 2025, 17(4), 404; https://doi.org/10.3390/pharmaceutics17040404 - 24 Mar 2025
Viewed by 740
Abstract
Background/Objectives: Metastatic prostate cancer remains a major clinical challenge, with limited therapeutic options. Doxycycline, a tetracycline antibiotic with anti-inflammatory properties, has shown potential as an adjunctive therapy. This study aimed to evaluate its efficacy in reducing prostate-specific antigen (PSA) levels and improving quality [...] Read more.
Background/Objectives: Metastatic prostate cancer remains a major clinical challenge, with limited therapeutic options. Doxycycline, a tetracycline antibiotic with anti-inflammatory properties, has shown potential as an adjunctive therapy. This study aimed to evaluate its efficacy in reducing prostate-specific antigen (PSA) levels and improving quality of life in patients receiving standard treatment for metastatic prostate cancer. Methods: This phase II, double-blind, randomized controlled trial included 45 participants (aged 57–81 years) assigned to doxycycline (100 mg daily) or a placebo for six months. The primary outcome was the percentage change in PSA levels at 3 and 6 months. Secondary outcomes included quality of life (EQ-5D-5L), cognitive function (Mini-Mental State Examination), and glucose levels. Additionally, a structure–activity relationship (SAR) analysis was performed through an extensive bibliographic review to identify pharmacophores responsible for doxycycline’s biological activity, particularly its tetracyclic core. The SAR analysis included tetracyclines and derivatives, androgen-targeting agents, and other pharmacologically relevant molecules used in prostate cancer therapy. Statistical analysis was conducted using multivariate logistic regression. Results: At six months, the doxycycline group showed a median PSA reduction of 60% compared to 10% in the placebo group (p = 0.043). A ≥50% reduction in PSA levels was observed in 71.4% of patients receiving doxycycline versus 20.8% in the placebo group (p = 0.001), with an adjusted relative risk of 10.309 (95% CI: 2.359–45.055, p = 0.002). Quality of life improved, with 7.1% of doxycycline-treated patients reporting poor quality of life compared to 42.9% in the placebo group (p = 0.028). A slight improvement in cognitive function was also noted (p = 0.037). SAR analysis suggested that the tetracyclic ring of doxycycline may play a crucial role in its observed biological effects. Conclusions: Doxycycline demonstrates potential as an adjunctive therapy in metastatic prostate cancer by reducing PSA levels and improving quality of life. The SAR analysis supports the hypothesis that its tetracyclic structure may be responsible for its therapeutic effects. Further large-scale trials are warranted to confirm these findings. Full article
(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)
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18 pages, 2199 KiB  
Article
The Co-Administration of Paclitaxel with Novel Pyridine and Benzofuran Derivatives that Inhibit Tubulin Polymerisation: A Promising Anticancer Strategy
by Magdalena Perużyńska, Radosław Birger, Patrycja Kłos, Halina Kwiecień, Łukasz Struk, Jacek G. Sośnicki, Laurence Lafanechère and Marek Droździk
Pharmaceutics 2025, 17(2), 223; https://doi.org/10.3390/pharmaceutics17020223 - 9 Feb 2025
Viewed by 812
Abstract
Background: Paclitaxel (PTX), a crucial microtubule-stabilising agent in cancer treatment, is limited by its adverse effects and hydrophobic nature, which necessitate the use of toxic solvents. This study proposes a novel approach combining PTX with new microtubule-destabilising compounds at low, safe doses [...] Read more.
Background: Paclitaxel (PTX), a crucial microtubule-stabilising agent in cancer treatment, is limited by its adverse effects and hydrophobic nature, which necessitate the use of toxic solvents. This study proposes a novel approach combining PTX with new microtubule-destabilising compounds at low, safe doses that are ineffective when used individually. Objective: The aim was to evaluate the therapeutic efficacy of combining PTX with previously described pyridine (S1, S22) and benzofuran derivatives (13b, 14), which have demonstrated promising anticancer properties by inhibiting microtubule polymerisation. Methods: The PrestoBlue assay was used to determine the optimal concentrations of each compound, enabling synergistic interactions with a low dose of PTX in HeLa cervical cancer cells. The combined effects of the compounds and PTX on apoptosis, cell cycle distribution, and mitotic spindle formation were then evaluated. Results: The results showed that compounds 13b (1 µM), 14 (0.1 µM), S1 (2 µM), and S22 (2 µM) enhanced the proapoptotic and antimitotic effects of 1 nM PTX, which was ineffective alone. Notably, live-cell imaging revealed that the concurrent use of S1 and PTX produced effects similar to those of a higher PTX concentration (5 nM). Conclusions: These findings suggest that these compounds enhance the anticancer efficacy of low-dose PTX, potentially paving the way for more effective and safer cancer therapies. Full article
(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)
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14 pages, 2617 KiB  
Article
ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer
by Andrés Barba, Laura López-Vilaró, Malena Ferre, Margarita Majem, Sergio Martinez-Recio, Olga Bell, María J. Arranz, Juliana Salazar and Ivana Sullivan
Pharmaceutics 2024, 16(9), 1121; https://doi.org/10.3390/pharmaceutics16091121 - 25 Aug 2024
Cited by 1 | Viewed by 2066
Abstract
Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and [...] Read more.
Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and in etoposide metabolization could predict treatment efficacy and safety and help personalize platinum-based chemotherapy. Germline polymorphisms in XRCC1, ERCC1, ERCC2, ABCB1, ABCC3, UGT1A1 and GSTP1 genes were investigated in 145 patients with SCLC. The tumor expression of ERCC1 was determined using immunohistochemistry, and the tumor expression of ERCC1-XPF was determined via a proximity ligation assay. Survival analyses showed a statistically significant association between the ERCC1 rs11615 variant and median progression-free survival (PFS) in patients with limited-stage (LS) SCLC (multivariate: hazard ratio 3.25, [95% CI 1.38–7.70]; p = 0.007). Furthermore, we observed differences between the ERCC1-XPF complex and median PFS in LS-SCLC, although statistical significance was not reached (univariate: positive expression 10.8 [95% CI 4.09–17.55] months versus negative expression 13.3 [95% CI 7.32–19.31] months; p = 0.06). Safety analyses showed that the ERCC2 rs1799793 variant was significantly associated with the risk of grade ≥ 3 thrombocytopenia in the total cohort (multivariate: odds ratio 3.15, [95% CI 1.08–9.17]; p = 0.04). Our results provide evidence that ERCC1 and ERCC2 variants may predict the efficacy and safety of platinum-based chemotherapy in SCLC patients. LS-SCLC patients may benefit most from ERCC1 determination, but prospective studies are needed. Full article
(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)
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Review

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28 pages, 626 KiB  
Review
Metformin-Based Combination Approaches for Triple-Negative Breast Cancer
by Zaid Sirhan, Aya Abu Nada, Nadeen Anabtawi, Anita Thyagarajan and Ravi P. Sahu
Pharmaceutics 2025, 17(5), 558; https://doi.org/10.3390/pharmaceutics17050558 - 24 Apr 2025
Viewed by 343
Abstract
Numerous anti-diabetic medications, including metformin, have been explored for their anticancer effects because of the substantial correlation between diabetes and cancer incidence. Metformin has recently gained interest for its anticancer effects against malignancies such as breast cancer, one of the leading causes of [...] Read more.
Numerous anti-diabetic medications, including metformin, have been explored for their anticancer effects because of the substantial correlation between diabetes and cancer incidence. Metformin has recently gained interest for its anticancer effects against malignancies such as breast cancer, one of the leading causes of death among women worldwide. The cancer-related characteristics of cell proliferation, invasion, migration, and apoptosis are all targeted by metformin. Among breast cancer patients, triple-negative breast cancer (TNBC) is linked to an increased risk of early recurrence and metastases and has poor prognosis. In addition, TNBC has fewer treatment options compared to other breast cancer subtypes because it lacks hormone receptors and human epidermal growth factor receptor 2 (HER2), and it often develops resistance to available treatment options. The current review highlights the recent updates on the mechanistic insights and the efficacy of metformin and metformin-based approaches for the treatment of TNBC. We logically discuss the experimental evidence from the in vitro and in vivo studies exploring metformin’s effects on metabolic pathways, and then its combination with other therapeutic agents, targeting cell signaling pathways, and approaches to enhance metformin’s effects. We also present clinical studies that underscore the beneficial outcomes of metformin or its combination with other agents in TNBC patients. Full article
(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)
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17 pages, 2217 KiB  
Review
Targeting DLL3: Innovative Strategies for Tumor Treatment
by Hui Wang, Tong Zheng, Dan Xu, Chao Sun, Daqing Huang and Xiongxiong Liu
Pharmaceutics 2025, 17(4), 520; https://doi.org/10.3390/pharmaceutics17040520 - 16 Apr 2025
Viewed by 522
Abstract
Delta-like 3 (DLL3) is an oncogenic protein aberrantly expressed in several tumors, particularly in small-cell lung cancer. DLL3-targeted therapies have recently made significant progress, demonstrating promising preclinical and clinical efficacy. This review aims to explore the mechanisms, challenges, and future opportunities associated with [...] Read more.
Delta-like 3 (DLL3) is an oncogenic protein aberrantly expressed in several tumors, particularly in small-cell lung cancer. DLL3-targeted therapies have recently made significant progress, demonstrating promising preclinical and clinical efficacy. This review aims to explore the mechanisms, challenges, and future opportunities associated with therapies targeting DLL3 for cancer treatment. The biological characteristics of DLL3 and its role in the Notch signaling pathway are introduced first, delving into the role of DLL3 in tumorigenesis and cancer progression. Next, current therapeutic approaches targeting DLL3 are described, including antibody–drug conjugates, T cell engagers, chimeric antigen receptor T cells, and radiopharmaceutical therapy, highlighting their effectiveness and safety in clinical trials. Despite the promising prospects, difficulties remain in the use of DLL3 as a therapeutic target due to tumor heterogeneity, the development of resistance, potential adverse effects, and barriers to patient stratification. Therefore, the potential of combination therapies, the use of innovative drug delivery systems, and ongoing clinical trial advancements are also discussed. Finally, the potential of DLL3-targeted therapies is summarized, highlighting the importance of multidisciplinary research to guide the clinical application and optimization of this emerging treatment strategy. These approaches might provide new therapeutic options, potentially starting a new era in cancer treatment. Full article
(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)
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