Huddle with Dr. Eswar Shankar and Ph.D. candidate Xilal Y. Rima
Dr. Eswar Shankar and Ph.D. Candidate Xilal Y. Rima will discuss the following poster:
Simultaneous Inhibition of EZH2 and Activation of Dopamine D1 in an Isotropic Triple-Negative Breast Cancer Microgel Model.
Treatment of Triple Negative Breast Cancer (TNBC) is a challenge due to its aggressive behavior, poor clinical outcome and prone to relapse. Triple Negative Breast Cancer (TNBC) accounts for ~15% of the breast cancer cases with higher histological grades and poorly differentiated cell type exhibiting aggressive characteristics and poor prognosis. The heterogeneity and lack of actionable targets has been a major challenge in developing better therapies for TNBC. Though taxane chemotherapy remains the standard-of-care treatment option for advance-stage TNBC patients, however, the response to these treatment(s) is often short and associated with non-responsiveness and poor prognosis with median overall survival of 9-12 months. Therefore, new target-based approach is urgently needed for the effective management of this aggressive form of disease. Our proposal aims in the development of new combinatorial therapy for the treatment of TNBC by the use of existing Dopamine D1 Receptor (D1R) agonist and EZH2 inhibitors as a better efficacious treatment modality. The hypothesis proposed here in preclinical models not only to investigate the effect on the inhibition of tumor progression but also to establish that the combination would protect from degeneration of bone. Dopamine D1 agonists are FDA approved for the treatment of Parkinson’s disease hence there is no further approval formalities required. This also helps the clinicians to design doses along the use of EZH2 inhibitors that are available in the market. The time taken for the treatment would be lessened. Since a combination has been used here, the doses of each drug would be half thereby lessening the side effects of chemotherapy. Conventional in vitro models utilize monolayers to investigate the effect of drugs on cancer cells but do not accurately recapitulate the in vivo microenvironment as the cells are subjected to homogeneous growth conditions. Microgels are miniature compartmentalized hydrogels that yield isotropic cell culture conditions unbiased by gravitational or hydrodynamic forces. As such, microgels lend suitable microenvironments conducive to the growth of tumor spheroids, which impose radial-dependent growth conditions as observed in vivo. While non-transformed epithelial cells with reconstituted basement membrane form hollow, growth-arrested, polarized three-dimensional (3D) structures, tumorigenic cells form large, solid, proliferating, and invasive structures characteristic of in vivo tumor, which are recapitulated by tumor spheroids. As such, tumor spheroids become an ideal model to study the sensitivity of drugs combination, which led us to investigate the efficacy of EZH2 inhibitor and D1R agonist on TNBC tumor spheroids. Tumor spheroids were formed in monodisperse calcium-alginate microgels generated via droplet-based microfluidics, which mimic the viscoelastic properties of decellularized ECM and induce aggregation by removing integrin-binding sites. Here we have used invitro tumor models of TNBC to study the efficacy of the combination before we transition into in vivo or preclinical models. Therefore, the successful completion of this proposal will give insights on how this combination could be converted into a clinical trial so that it becomes readily available for TNBC patients. The impact of this study is in consonance with the mission of BCRP/GRASP in finding a cure, increase survival, provide a better quality of life, and lessen the financial burden of patients.
Eswar ShankarAssistant Research Professor, Ohio State University Comprehensive Cancer Center
Assistant Research Professor. The Ohio State University Comprehensive Cancer Center, Columbus, OH. Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.
The research focus of Dr. Shankar is on breast and prostate cancer studying the molecular mechanism attributing to initiation and metastasis identifying targets associated with cancer progression and drug resistance. Over the last 14 years Dr. Shankar’s research has evolved in elucidating the mechanisms of oncogenes that orchestrate tumor promotion. In the recent years Dr. Shankar has been involved research to repurpose drugs and come out with combinatorial treatments that synergistically inhibit the growth of metastatic breast cancer. In the current position Dr. Shankar in collaboration with Dr. Bhuvaneswari Ramaswamy, MD, Breast Oncologist, Ohio State University’s Wexner Medical Center and Dr. Vish Subramaniam, Ph.D. Academy Professor, Department of Mechanical & Aerospace Engineering, and OSU Emeritus Academy is developing combinational treatments to inhibit metastasis with minimal or no toxicity to normal cells. He is also involved in applying induced electric field (iEF) technology as a non-pharmacological means of treating metastatic cancer. As evident from his research publications Dr. Shankar has made significant contribution in understanding the molecular signatures altered during this devastating disease. He is funded by the department of defense (DoD)to evaluate the combinatorial effect of dopamine D1 agonist and EZH2 inhibitor GSK126 in arresting triple negative breast cancer progression.
Most recently Dr. Shankar presented how the combinatorial treatment of Dopamine Receptor D1 agonist and EZH2 inhibitor could attenuate Triple Negative Breast cancer progression at a poster session at the San Antonio Breast Cancer Symposium in December of 2022. This work was selected by GRASP advocates and discussed in the advocacy session in December 2022.
Dr. Shankar received is MS from Annamalai University, Tamil Nadu India and completed his Ph.D. from Cochin University of Science and Technology, Kerala, India in Neuroscience.
Xilal Y. RimaPh.D. Candidate
Xilal is a Ph.D. candidate working under Distinguished Associate Professor of Engineering Inclusive Excellence, Eduardo Reátegui, Ph.D., in the Department of Chemical and Biomolecular Engineering and is co-advised by Breast Oncologist, Professor Bhuvaneswari Ramaswamy, M.D. He works on engineering novel in vitro methods to facilitate therapeutic screenings and the profiling of cells in physically relevant model systems.