Review
Biochemistry & Molecular Biology
Young-Hwa Soung, Jun Chung
Summary: This review summarizes the molecular mechanism of therapeutic action and resistance to PARPis, in addition to emerging combination treatment options involving PARPis.
Article
Chemistry, Medicinal
Nur Aininie Yusoh, Paul R. Tiley, Steffan D. James, Siti Norain Harun, Jim A. Thomas, Norazalina Saad, Ling-Wei Hii, Suet Lin Chia, Martin R. Gill, Haslina Ahmad
Summary: Through screening, three effective drug combinations were identified for Olaparib in BRCA-proficient triple-negative breast cancer cells, including curcumin and two ruthenium-polypyridyl metallomacrocycles. These combinations were shown to enhance DNA damage and induce apoptosis in cell and model experiments, with low cytotoxicity and toxicity effects.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Oncology
Shannon N. Westin, Marilyne Labrie, Jennifer K. Litton, Aurora Blucher, Yong Fang, Christopher P. Vellano, Joseph R. Marszalek, Ningping Feng, XiaoYan Ma, Allison Creason, Bryan Fellman, Ying Yuan, Sanghoon Lee, Tae-Beom Kim, Jinsong Liu, Anca Chelariu-Raicu, Tsun Hsuan Chen, Nashwa Kabil, Pamela T. Soliman, Michael Frumovitz, Katheleen M. Schmeler, Amir Jazaeri, Karen H. Lu, Rashmi Murthy, Larissa A. Meyer, Charlotte C. Sun, Anil K. Sood, Robert L. Coleman, Gordon B. Mills
Summary: This study aimed to confirm the recommended phase II dose for the combination of olaparib and capivasertib in multiple cancers, and evaluate molecular markers of response and resistance. Promising responses, especially in endometrial cancer, were observed among the 38 enrolled patients. Therapy resistance was associated with specific signaling pathways and metabolic factors.
CLINICAL CANCER RESEARCH
(2021)
Article
Cell Biology
Gamze Guney Eskiler, Melek Ozturk
Summary: The combination of PARP inhibitor Talazoparib (TAL) and PI3K inhibitor LY294002 was found to synergistically inhibit proliferation of BRCA1 mutant TNBC cells by inducing apoptosis, G0/G1 arrest, oxidative stress and increased DNA damage compared to treatment with either drug alone. This combination therapy also showed potential for overcoming TAL resistance.
CELLULAR SIGNALLING
(2022)
Review
Biochemistry & Molecular Biology
Abdullah Alhusaini, Aoife Cannon, Stephen G. Maher, John Reynolds, Niamh Lynam-Lennon
Summary: Gastrointestinal malignancies are a significant global health burden with high mortality rates. Novel therapeutic strategies involving PARP enzymes and PARPi are crucial for improving treatment and survival. The role of DDR PARP enzymes and HR status as predictive biomarkers in GI cancers, as well as combination strategies with PARPi and cytotoxic therapy, are important areas of research and clinical interest.
Review
Oncology
Yi Zhang, Lijie Liang, Zheng Li, Ying Huang, Ming Jiang, Bingwen Zou, Yong Xu
Summary: This article reviews the advances and implications of PARP inhibitors in tumor radiotherapy sensitization. The multiple functions of PARP and the mechanisms by which its inhibitors exert antitumor effects are summarized. The immunomodulatory effects of PARP and its inhibitors in tumors are discussed, as well as the theoretical basis of using PARP inhibitors in combination with radiotherapy and their importance in oncological radiotherapy.
FRONTIERS IN ONCOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Jennifer K. Matsui, Haley K. Perlow, Rohit K. Raj, Ansel P. Nalin, Eric J. Lehrer, Rupesh Kotecha, Daniel M. Trifiletti, Shearwood McClelland, Kari Kendra, Nicole Williams, Dwight H. Owen, Carolyn J. Presley, Evan M. Thomas, Sasha J. Beyer, Dukagjin M. Blakaj, Manmeet S. Ahluwalia, Raju R. Raval, Joshua D. Palmer
Summary: Brain metastases are a devastating consequence of common primary cancers, with limited treatment options. While systemic chemotherapy has shown little benefit, targeted therapies and immune checkpoint inhibitors have shown promise in recent years. Studies suggest a synergistic effect between radiotherapy and ICIs, with ongoing clinical trials assessing the benefits of combination therapy for patients with brain metastases.
Article
Biochemical Research Methods
Maruan Hijazi, Pedro Casado, Nosheen Akhtar, Saul Alvarez-Teijeiro, Vinothini Rajeeve, Pedro R. Cutillas
Summary: PI3K-mammalian target of rapamycin and MAPK/ERK kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways are frequently dysregulated in cancer. In this study, the researchers found that eEF2K, a key convergence point downstream of MAPK and PI3K pathways, mediates synergism to cotreatment with trametinib plus pictilisib. The activity of eEF2K may serve as a potential biomarker to predict synergy to cotreatment in cancer cells.
MOLECULAR & CELLULAR PROTEOMICS
(2022)
Article
Oncology
Maarten C. C. M. Hulshof, Elisabeth D. Geijsen, Tom Rozema, Vera Oppedijk, Jeroen Buijsen, Karen J. Neelis, Joost J. M. E. Nuyttens, Maurice J. C. van der Sangen, Paul M. Jeene, Jannie G. Reinders, Mark I. van Berge Henegouwen, Adriana Thano, Jeanin E. van Hooft, Hanneke W. M. van Laarhoven, Ate van der Gaast
Summary: In definitive chemoradiation for esophageal cancer, escalating radiation dose up to 61.6 Gy to the primary tumor did not significantly improve local tumor control compared to 50.4 Gy. The absence of a dose-effect was observed in both adenocarcinoma and squamous cell carcinoma.
JOURNAL OF CLINICAL ONCOLOGY
(2021)
Article
Pharmacology & Pharmacy
Wen Zhang, Peng Zhang, Xiaopeng Xu, Minghui Li, Shasha Wang, Hongjie Mu, Kaoxiang Sun
Summary: Doxorubicin is a commonly used chemotherapeutic agent, but its severe side effects limit its clinical application. It has been found that the DOX-metal chelate has lower cytotoxicity compared to DOX alone, as the anthracyclines of DOX can interact with transition metal ions. Additionally, the transition metal ions can produce hydroxyl radicals via Fenton/Fenton-like reactions, achieving antitumor chemodynamic therapy. This study utilized copper ions to create a DOX/Cu(II) prodrug and used a liposomal formulation to optimize its biodistribution. In vitro and in vivo results showed that this pH sensitive Cu-chelating prodrug could reduce adverse effects of DOX while improving the antitumor efficiency by combining chemotherapy and chemodynamic therapy. This study provides a facile and effective approach for combination cancer therapy using metal-chelating prodrugs.
Review
Oncology
Daniel An, Susana Banerjee, Jung-Min Lee
Summary: Ovarian cancer has a variety of treatment options, but achieving sustained benefit in the clinic remains challenging. Biomarker and genetic analysis can identify resistance and sensitivity pathways, providing potential for unique drug combinations.
CANCER TREATMENT REVIEWS
(2021)
Review
Pharmacology & Pharmacy
Nannan Wang, Yan Yang, Dongdong Jin, Zhenan Zhang, Ke Shen, Jing Yang, Huanhuan Chen, Xinyue Zhao, Li Yang, Huaiwu Lu
Summary: Breast cancer and gynecological tumors pose significant risks to women's physical and mental health, fertility, and quality of life. While the prognosis and overall survival of cancer patients have improved due to standardized treatments, advanced disease management remains challenging. The clinical approval of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) has significantly improved the quality of life for breast and gynecological cancer patients, particularly those with BRCA1/2 mutations. However, drug resistance to PARPi therapy hinders its widespread use, necessitating the development of new drug strategies. This article reviews the mechanisms of PARPi resistance and current combination therapies that can enhance its effectiveness.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Virology
Ourania N. Kostopoulou, Mark Zupancic, Mariona Pont, Emma Papin, Monika Lukoseviciute, Borja Agirre Mikelarena, Stefan Holzhauser, Tina Dalianis
Summary: This study found that combining CDK4/6 with PI3K or FGFR inhibitors can have a synergistic effect and significantly decrease the viability of cancer cells. The combination of CDK4/6 with PD-0332991 showed the best results, while synergy with PARP and WEE1 inhibitors was less common.
Article
Oncology
Karin Byskata, Monika Lukoseviciute, Filippo Tuti, Mark Zupancic, Ourania N. Kostopoulou, Stefan Holzhauser, Tina Dalianis
Summary: Combined gene therapy with radiotherapy can effectively treat human papillomavirus positive tonsillar and base of tongue cancers, but the synergistic effects of radiotherapy and targeted therapy are limited.
Article
Biochemical Research Methods
David J. Wooten, Reka Albert
Summary: Combining multiple pharmacological agents can provide significant benefits over single agent treatment, with synergistic combinations exceeding the sum of their parts. The Synergy Python library offers a wide range of synergy models, tools for evaluating confidence intervals and conducting power analysis, as well as standardized tools for analyzing and visualizing drug combinations and their synergies and antagonisms.
Review
Cell & Tissue Engineering
Siddharth Patel, Avathamsa Athirasala, Paula P. Menezes, N. Ashwanikumar, Ting Zou, Gaurav Sahay, Luiz E. Bertassoni
TISSUE ENGINEERING PART A
(2019)
Article
Chemistry, Multidisciplinary
Yulia Eygeris, Siddharth Patel, Antony Jozic, Gaurav Sahay
Editorial Material
Pharmacology & Pharmacy
Marco Herrera-Barrera, Gaurav Sahay
Summary: The study has identified an endogenous delivery system that can encapsulate and transport mRNA effectively, providing a potential strategy for gene delivery in disease treatment.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2022)
Review
Pharmacology & Pharmacy
Sakib Haque, Kiri Cook, Gaurav Sahay, Conroy Sun
Summary: Triple-negative breast cancer is a highly heterogeneous and aggressive cancer subtype with the highest mortality rate. Conventional treatments have been unsuccessful, leading to research efforts in developing new strategies. Targeted molecular therapy and RNA-based therapeutics are key areas of investigation for treating TNBC.
Article
Chemistry, Multidisciplinary
Jeonghwan Kim, Antony Jozic, Yuxin Lin, Yulia Eygeris, Elissa Bloom, Xiaochen Tan, Christopher Acosta, Kelvin D. MacDonald, Kevin D. Welsher, Gaurav Sahay
Summary: By incorporating PEG lipid and beta-sitosterol, the stability and endosomal escape of lipid nanoparticles (LNPs) for lung mRNA therapy could be enhanced, leading to effective treatment.
Article
Medicine, Research & Experimental
Michael I. Henderson, Yulia Eygeris, Antony Jozic, Marco Herrera, Gaurav Sahay
Summary: This study investigates the impact of commonly used biological buffers on the performance and durability of mRNA-LNPs and finds that Tris or HEPES buffers contribute to better stability and transfection efficiency compared to PBS.
MOLECULAR PHARMACEUTICS
(2022)
Review
Nanoscience & Nanotechnology
Allison N. DuRoss, Jack Phan, Alexander J. Lazar, Joshua M. Walker, Alexander R. Guimaraes, Carole Baas, Sunil Krishnan, Charles R. Thomas, Conroy Sun, Alexander F. Bagley
Summary: Radioenhancing nanoparticles are being evaluated in clinical trials for various cancers. Supported by preclinical research and recent trial data, these agents have the potential to influence future multimodality treatment paradigms. While the physical interactions between nanoparticles and radiation are well understood, their impact on the tumor microenvironment, particularly tumor immunogenicity, is still not fully known. This review discusses the multidisciplinary considerations for designing clinical trials involving radioenhancing nanoparticles.
WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Jeonghwan Kim, Antony Jozic, Anindit Mukherjee, Dylan Nelson, Kevin Chiem, Md Siddiqur Rahman Khan, Jordi B. Torrelles, Luis Martinez-Sobrido, Gaurav Sahay
Summary: This study demonstrates that engineered mRNA encoding soluble hACE2 can be delivered to cells using lipid nanoparticles, leading to the production of hsACE2 proteins. The hsACE2 proteins bind to the viral spike protein, preventing viral entry and effectively inhibiting SARS-CoV-2 and its pseudoviruses from infecting host cells. This proof of principle study suggests that mRNA-based nanotherapeutics could be a potential treatment for COVID-19.
Article
Engineering, Biomedical
Eunseo Choi, Madeleine Landry, Nathan Pennock, Megan Neufeld, Katherine Weinfurter, Andrea Goforth, Joshua Walker, Conroy Sun
Summary: Recent studies have shown that combination radiotherapy and immunotherapy can improve outcomes. This study explores the use of folate-modified hafnium-based metal-organic frameworks as enhancers for radiotherapy and immune activation. The combination of HfMOF-PEG-FA with imiquimod effectively stimulates the immune response and enhances the antitumor effects of radiotherapy.
ADVANCED HEALTHCARE MATERIALS
(2023)
Review
Chemistry, Medicinal
Tetiana Korzun, Abraham S. Moses, Parham Diba, Ariana L. Sattler, Olena R. Taratula, Gaurav Sahay, Oleh Taratula, Daniel L. Marks
Summary: This article provides a comprehensive review on the reactogenicity of empty lipid nanoparticles used as delivery vehicles, with a focus on their application in mRNA-based therapies. The key components of lipid nanoparticles, including ionizable lipids and PEG-lipids, have been identified as significant contributors to their reactogenicity. Understanding the relationship between lipid nanoparticles, their structural constituents, cytokine production, and resultant reactogenic outcomes is essential for safe and effective application in mRNA-based therapies.
Article
Materials Science, Biomaterials
Marco Herrera, Jeonghwan Kim, Yulia Eygeris, Antony Jozic, Gaurav Sahay
Summary: The study utilized a Galectin 8-GFP cell reporter system to visualize the endosomal escape capabilities of lipid-based nanoparticles (LNPs) encapsulating mRNA. LNPs containing beta-sitosterol showed superior ability to escape from endosomal entrapment compared to standard cholesterol LNPs. Live-cell imaging demonstrated a 10-fold increase in detectable endosomal perturbation events with LNPs containing beta-sitosterol.
BIOMATERIALS SCIENCE
(2021)
Article
Multidisciplinary Sciences
Renee C. Ryals, Siddharth Patel, Chris Acosta, Madison McKinney, Mark E. Pennesi, Gaurav Sahay
Article
Multidisciplinary Sciences
Anindit Mukherjee, Kelvin D. MacDonald, Jeonghwan Kim, Michael Henderson, Yulia Eygeris, Gaurav Sahay
Article
Chemistry, Multidisciplinary
Justin G. Rosch, Madeleine R. Landry, Charles R. Thomas, Conroy Sun