Co-Director,
Department of Pharmacology & Therapeutics,
Roswell Park Comprehensive Cancer Center
Gokul Das, Ph.D, is currently Professor of Oncology, Department of Pharmacology & Therapeutics at the Roswell Park Comprehensive Cancer Center (RPCCC) in Buffalo, NY. He is the Co-Director of Breast Translational Research Group (TRG) at Roswell and member of the graduate faculty at the University at Buffalo/UB (State University of New York/SUNY at Buffalo). Dr. Das obtained PhD in Molecular Biology and Pharmacology from Baylor College of Medicine, Texas Medical Center, Houston, followed by postdoctoral fellowship at the Cold Spring Harbor Laboratory, New York. He is a passionate researcher and teacher.
For the past three decades, Dr. Das’s research has focused on understanding and exploiting molecular mechanisms of cancer to develop effective therapeutic strategies. He has successfully translated innovative research findings from his laboratory to clinical trials in breast cancer patients in collaboration with clinicians. Dr. Das has published in high impact journals and his research has been funded by governmental and non-governmental granting agencies.
” Translating Basic Research from the Laboratory to Patient Care in the Clinic:
Challenges and Rewards “
Despite decades of intense research, cancer remains a challenging disease. Breast cancer is the most diagnosed cancer type globally. In India, breast cancer was fourth in the list of most common cancers three decades ago and now it has jumped to the first position. Approximately 15-20% of breast cancers are classified as triple negative breast cancer (TNBC). Because of their aggressive nature and the lack of targeted therapies, TNBC has greater risk of relapse and metastasis resulting in shorter survival. While immunotherapy in combination with chemotherapy is modestly effective in some patients with metastatic TNBC, a large percentage of patients are unresponsive. Furthermore, adverse side-effects from immunotherapy are of serious concern. Hence, there remains an urgent need to develop new therapeutic strategies.
Our laboratory has been conducting breast cancer research using cutting-edge technologies and translating relevant findings to develop more effective therapies. TNBC does not express estrogen receptor β (ERβ) targetable by tamoxifen, a selective ER modulator (SERM). However, estrogen receptor β (ERβ) is expressed in TNBC. Another major player in TNBC is tumor suppressor p53. p53 is mutated in about 80% of TNBCs, and mutant p53, besides losing tumor suppression capabilities, gains oncogenic functions such as binding and inactivating p73, another tumor suppressor. As ERβ, a canonical target of tamoxifen, is not expressed in TNBC, tamoxifen has not been in clinical practice for the treatment of TNBC patients. Our data challenged this conventional clinical paradigm. We showed that tamoxifen synergized with doxorubicin, a widely used chemotherapeutic agent, to kill TNBC cells. Furthermore, multi- faceted analysis of tamoxifen- and doxorubicin-treated isogenic TNBC cells revealed that the combination therapy impacted various cellular pathways that are tumor suppressive. Consistent with our observations in the in vitro TNBC cell line models, in vivo tumor models revealed that this therapeutic strategy blocked progression of human TNBC. Our studies have revealed an opportunity for repurposing tamoxifen to treat molecularly stratified TNBC. Importantly, therapeutic importance of these findings was corroborated in a clinical case where a patient with TNBC brain metastasis who had significant tumor regression following treatment a treatment regimen that included tamoxifen. (study in collaboration with a clinical team at MGH/Harvard Medical School). Based on these findings, a phase II clinical trial in TNBC patients is getting started at the Roswell Park Comprehensive Cancer Center. This precision medicine approach, once validated in clinical trials, could lead to an effective therapy with low toxicity and cost, and will benefit large number of TNBC patients world-wide.
The challenges of “Bench to bedside” approach and the advantages of drug repurposing to combat diseases will be discussed in the context of the project described above.
Supported by grants from National Cancer Institute (NCI)/ National Institutes of Health (NIH), US DoD Breast Cancer Research Program (BCRP), METAvivor Research Foundation, and Roswell Park Alliance Foundation.