Studying the Effect of PPARG Pathway Modulation on Tumor Immune Microenvironment in Muscle Invasive Bladder Cancer
Abstract
My goal is to become an independent cancer researcher, developing novel therapeutic strategies to treat bladder cancer. Cancer is a dynamic disease and it changes over time in response to the pressures of its environment. Hence, it is important to design treatment regimens that take into account the dynamic behavior of cancer. The treatment options in bladder cancer are limited, with life-compromising treatment options and high medical costs. These needs highlight the urgency in identifying novel therapies for bladder cancer treatment and management. My approach is to translate bladder cancer biology, which is studied on the lab bench, to computational models that allow us to identify targets for the treatment of bladder cancer. The computational models of bladder cancer mimic disease progression over time and can be used to predict how different patients respond to treatments. Under the guidance of my mentor, Dr. Barbara Foster, renowned for studying basic biology and developing animal models of cancer and my co-mentor Dr. Donald Mager, distinguished in the field of computational disease modeling, I am confident in my ability to achieve my project and career goals as a cancer researcher. Working at Roswell Park Comprehensive Cancer Center, one of the leading institutes in bladder cancer research, provides me the platform to receive guidance and training from top scientist and clinicians in bladder cancer. In my early investigations of bladder cancer, I found that cells of the immune system, the cytotoxic T-cells in particular, have a strong association to bladder cancer progression. The cytotoxic T-cells are known to kill cancer cells and cells that infect our bodies. The cytotoxic T-cells form the adaptive component of our immunity and take cues from the cells of the innate immune system, cells like the macrophages. Over the years, investigators have uncovered that macrophages have a wide range of functions in cancer progression, but in the context of my project we will focus on its function to regulate the T-cell entry into the tumors. Access to the tumors is extremely essential for the cytotoxic activity of T-cells. We also found that patients who have low levels of T-cells have high levels of a target called PPARgamma. We already know from previous research that PPARgamma can manipulate the macrophages into a form that reduces immunity and inhibit signals that attract T-cells. Hence, the question we want to answer with our research is; can we inhibit PPARgamma and reprogram the immune system to fight against the cancer? My research is divided into two parts; the first part is to investigate the biological and functional effect of inhibiting PPARgamma, and the second part involves applying the biological data to develop a computational model for clinical translational. The outcome of the research will benefit patients who have low cytotoxic T-cells in their tumors who, as a result of which, have shown poor response to current treatment options. The outcome of my research has direct clinical translatability since the first part provides insight into how we can regulate the immune system to fight bladder cancer, and the computational model provides us tools to predict how different treatment regimens will affect bladder cancer over time. With my research I am hoping to introduce an approach to reprogram the immune system to fight cancer and translate bench findings into computational models that can allow rapid translation of the findings into clinical treatments. According to the bladder cancer advocacy group, Bladder Cancer Advocacy Network, or BCAN, military personnel are at a higher exposure to reagents that cause bladder cancer. Thus, the identification of novel treatments will directly benefit military personnel in addition to the general public for the treatment of bladder cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910636
Entities
People
- Shruti Shah
Organizations
- United States Army