Tanmoy Saha, PhD
Investigator (Associate Bioengineer)
Tanmoy Saha, Chinmayee Dash, Ruparoshni Jayabalan, HaeLin Jang, Shiladitya Sengupta
Research Category: Cancer
Despite of revolutionary advancement of the immunotherapy, cancer cells deploy a range of mechanisms to subvert immune system. Intercellular transfer of mitochondria via nanoscale bridges between cancer cells and immune cells is one of the key drivers of immune evasion. The cancer cells acquire metabolic activation by hijacking mitochondria from T cells, whereas the T cell deplete because of metabolic deactivation. The nanoscale communications are mainly composed of actin cytoskeletal elements and the formation is primarily synchronized by a group of GTPases along with exocyst complex. Inhibition of nanobridge formation offers a major therapeutic potential. We have used medicinal chemistry approach to introduce a collection of small molecule-based inhibitors, which can specifically perturb the function of exocyst complex. At first we have performed molecular dynamic simulations to identify the potential inhibitors for the exocyst proteins. We have identified one of the dug candidates (TS-1), which successfully inhibit the mitochondria transfer from immune cell to cancer cell and increase the immune response in tumor. TS-1 has shown remarkable anticancer efficacy in syngeneic 4T1 murine tumor model. A combination of TS-1 with traditional immunotherapy offered remarkable anticancer outcome in aggressive breast cancer mouse model, which is insensitive to immunotherapy alone.
Cancer progresses by escaping the immune system. Recently we have reported a unique cellular mechanism by which cancer cell hijack mitochondria, the power source of the cell, from immune cells through tiny tentacles. The cancer cells work as a vampire for extracting the energy source and use them for their energy production; on the other hand, the immune cells die because of energy starvation. The process is so impulsive that immune cell gets deactivated even before the immunotharepy, the most advanced cancer treatment, cannot even make any significant impact. We have extended our effort to develop a drug-which can block the nanotube formation and mitochondria hijack from immune cell to cancer cells. Computational algorithms and organic chemistry concepts have been used to find out drug candidates, which can bind with the specific proteins and perturb the communication between cancer and immune cells by tiny tentacles. We have identified a few potential drug candidates and observed reduction of tumor in mouse tumor model. Moreover the outcome of immunotherapy has been increased dramatically in presence of the TS-1 drug. The small molecule-based immunomodulatory drug used in this study emerges as a next generation therapeutic strategy to combat cancer.