Arun J. Singh, PhD
Manipulating the Tumor Microenvironment in Hormone-Receptor Positive Breast Cancer to Increase Immune Surveillance
Summary
Breast Cancer is a leading cause of cancer-related mortality in women, with an estimated 250,000 new invasive cases, and 40,000 deaths in 2017 in the United States alone. The hormone receptor-positive subtype (HRBC), which expressed the estrogen receptor (ER+), accounts for 70% of all BC cases. The standard treatment of endocrine therapy only reduces the risk of relapse by 40% due to resistance that inevitably evolves, which leads to approximately 11,000 deaths per year from relapses. As such, there is a need to develop new therapies that are able to overcome evolved resistances in such cases. These therapies should also demonstrate improved efficacy and tolerability, to both enable a higher patient response rate and alleviate adverse events associated with current treatment options. One such therapy that has shown promise in other cancer types is immunotherapy, which works by strengthening the abilities of the immune system. So far, they have not translated well to HRBC subtype. The reason for this is largely unknown, but likely is due in part to the unique tumor microenvironment that is relatively rich in stroma and low in immune cells. A large portion of the stroma is composed of fibroblasts, which secrete proteins that have been demonstrated to exclude invading immune cells, and confer drug resistance to tumor cells. As such, an opportunity exists to increase the efficacy of endocrine and immunotherapies by developing a deeper understanding of how interactions between immune cells, fibroblasts, and cancer cells cooperate to regulate immune function in HRBC. In particular, this research will focus on strategies to disrupt the stromal barriers that appear to exclude invading immune cells from physical contact with cancer cells. The overall goals of this project are to identify the stromal cell types that form barriers, develop therapeutic strategies that target those cells, and test the efficacy of these therapeutic strategies in disrupting the stromal barriers and increasing cancer cell death in conjunction with immunotherapies.
I am thankful to receive the PhRMA Foundation Fellowship at this juncture in my training. The support from the PhRMA Foundation will grant me more resources to generate a detailed and accurate model of human breast cancer. I am excited for the opportunity to advance my career as an early independent researcher while performing higher-impact experiments.
