This is a resubmission application for a K22 Career development award for Dr. David R. Soto Pantoja, an NCI-Cancer Training Award Fellow at, National Institutes of Health. Dr. Pantoja has extensive expertise in the areas of molecular biology and cancer biology. He has been successful in obtaining competitive support for his research through a Department of Defense predoctoral training award and as a postdoctoral fellow obtaining a NCI Directors Career Development Innovation Award. He has assembled a multidisciplinary committee and will participate in course work to complement his expertise in cancer biology to ensure the successful transition into an independent career. This grant will be essential for the completion of Dr. Pantoja's career goals. The objectives of this proposal are to find novel mechanisms to reduce tumor growth, overcome development of resistance to chemotherapy and reduce metastasis of breast cancer, which is responsible for over 40,000 deaths every year in the United States. Published evidence shows that blockade of CD47 enhances local radiation growth delay of tumors while protecting normal tissue. Dr. Pantoja's key publications show of that the mechanism of radioprotection with CD47 blockade is through activation of protective autophagy. This application proposes that this mechanism is activated to sensitize cancer cells to therapy by the selective activation of mitophagy increasing mitochondrial turnover. Cancer cells develop resistance to chemotherapy in part to accumulation of mitochondria leading to increase in reactive oxygen species that stimulate pro-survival pathways. The current mechanism to overcome this issue is poorly understood. Therefore it is proposed in this application that blockade of CD47 sensitizes breast cancer cells by regulating bioenergetics mainly by reducing the active glucose metabolism and through increased activation of mitophagy. This proposal is strengthened by the complementary and rich tool set used to investigate the hypothesis, the vast resources available within the National Cancer Institute and collaborators at the University of Pittsburgh and Georgetown University and captures the pioneering work of Dr. Pantoja's advisors in the areas of breast cancer resistance, cell bioenergetics, autophagy and the CD47 signaling axis. The combination of these fields and the completion of these studies will validate novel therapeutic targets for treating invasive breast cancer as well as other major cancers.
The continuing high rates of diagnosis and death due to cancer indicate an urgent need for novel treatment modalities to reduce disease morbidity and mortality. Breast cancer in particular accounts for over 40,000 deaths in the United States alone. Most of these deaths are caused by metastatic spread of breast tumors. Over 70% of breast cancers end up developing resistance to chemotherapy contributing to patient demise due to this disease. Our studies indicate that blockade of CD47 sensitizes breast tumors to chemotherapy in a murine model of breast cancer. Our preliminary observations indicate that blockade of CD47 reduces glycolytic flux to sensitize cells to chemotherapy. Moreover, this reduction in metabolic demand is associated to activation of mitophagy which increases turnover of damaged mitochondria reducing resistance to chemotherapy. Understanding how CD47 blockade modifies the tumor microenvironment merits further exploration and could lead to novel approaches for the treatment of breast carcinoma and other cancers. Our findings indicate that agents targeting CD47 will sensitize tumors to chemotherapy, by regulation of cell bioenergetics and mitophagy. The K22 funding mechanism will provide the candidate with a unique set of skills and expertise in cancer biology cellular bioenergetics and bioinformatics to make highly translational contributions to reduce mortality due to invasive breast cancer.
|Soto-Pantoja, David R; Wilson, Adam S; Clear, Kenysha Yj et al. (2017) Unfolded protein response signaling impacts macrophage polarity to modulate breast cancer cell clearance and melanoma immune checkpoint therapy responsiveness. Oncotarget 8:80545-80559|
|Cook, Katherine L; Soto-Pantoja, David R; Clarke, Pamela A G et al. (2016) Endoplasmic Reticulum Stress Protein GRP78 Modulates Lipid Metabolism to Control Drug Sensitivity and Antitumor Immunity in Breast Cancer. Cancer Res 76:5657-5670|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Soto-Pantoja, D R; Sipes, J M; Martin-Manso, G et al. (2016) Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the Apc(Min/+) model of colon cancer. Oncogenesis 5:e230|
|Miller, Thomas W; Soto-Pantoja, David R; Schwartz, Anthony L et al. (2015) CD47 Receptor Globally Regulates Metabolic Pathways That Control Resistance to Ionizing Radiation. J Biol Chem 290:24858-74|