Pancreatic adenocarcinoma (PDAC) is an almost uniformly fatal disease that is most commonly diagnosed after the development of metastases. The tumor suppressor gene, p53, is the most commonly altered gene in human cancer and has been recognized as a genetic driver of PDAC in up to 75% of patients with direct roles in metastasis. While the effects of p53 mutations within cancer cells continue to be studied, the effects of such driver mutations on constituents of the tumor microenvironment (TME), and how these contribute to metastasis, remain limited. The ultimate goal of my work is to therapeutically exploit targets that arise in PDAC tumor cells and in the TME as a consequence of p53 mutation and the associated loss of p53-mediated tumor suppression. To this end, the Principal Investigator will utilize PDAC genetically engineered mouse models (GEMMs) and derived model systems to identify genes that partner with mutant p53 to generate invasive phenotypes and to determine genes that are synthetic lethal to mutant p53. The enclosed K08 award application is a comprehensive research, training, and career development plan designed to provide the Principal Investigator with the skill sets and expertise to establish an independent pancreatic cancer research program. As a fully trained surgical oncologist, the Principal Investigator possesses a unique clinical perspective of pancreatic cancer that may be leveraged with additional research training to contribute knowledge and therapeutic options to the field. Under the mentorship of Dr. Gigi Lozano, an international expert in p53 regulation and mutant p53 gain-of-function, the Principal Investigator will be immersed in a stimulating research environment at MD Anderson Cancer Center that will enable the completion of the research strategy. In parallel, the Principal Investigator will fulfill all training and career development goals through formal coursework and scheduled meetings with his mentor, advisors, and collaborators. To oversee the execution of the research strategy and the development of the Principal Investigator's expertise, an external advisory committee comprised of prominent scientists has been assembled, each with expertise that overlaps with the Principal Investigator's fields of study. Dr. Nancy Jenkins, a senior scientist and member of the National Academy of Sciences, has extensive experience with mouse models of cancer including specific experience in defining drivers of pancreatic cancer metastasis in transgenic mice. Dr. Michelle Barton, Dean of the Graduate School of Biomedical Sciences at MD Anderson and a NIH-funded Investigator, has rich experience in p53 biology, epigenetics, and mouse models of cancer. Both advisors have decades of experience educating and preparing trainees for the rigors of establishing independent research programs. Collectively, over the course of the 5-year K08 award period, the PI will utilize the environment, resources, and mentorship available at MD Anderson Cancer Center to launch a career in a new field of investigation as an independent Investigator.

Public Health Relevance

Approximately half of all human cancers exhibit alterations in the p53 tumor suppressor gene, most of which result in the survival, proliferation, and metastasis of tumor cells. Our studies will examine how mutations in the p53 gene support pancreatic tumor cell survival and metastasis through changes in gene expression and physical modifications to the tumor microenvironment. Through advances in our understanding of mutant p53 function, we hope to identify new vulnerabilities that may be therapeutically exploited to kill or limit the spread of pancreatic cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA218690-02
Application #
9530606
Study Section
Subcommittee I - Transistion to Independence (NCI)
Program Officer
Lim, Susan E
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Surgery
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Ivanics, Tommy; Bergquist, John R; Liu, Gang et al. (2018) Patient-derived xenograft cryopreservation and reanimation outcomes are dependent on cryoprotectant type. Lab Invest 98:947-956
Cloyd, Jordan M; Nogueras-González, Graciela M; Prakash, Laura R et al. (2018) Anthropometric Changes in Patients with Pancreatic Cancer Undergoing Preoperative Therapy and Pancreatoduodenectomy. J Gastrointest Surg 22:703-712
Kim, Michael P; Lozano, Guillermina (2018) Mutant p53 partners in crime. Cell Death Differ 25:161-168
Katz, Matthew Hg; Kim, Michael P; Tzeng, Ching-Wei et al. (2018) Preoperative Chemoradiation for Borderline Resectable Pancreatic Cancer: The New Standard? Ann Surg 268:223-224
Wang, Ying-Nai; Lee, Heng-Huan; Chou, Chao-Kai et al. (2018) Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer. Cancer Cell 33:752-769.e8
Yamashita, Suguru; Overman, Michael J; Wang, Huamin et al. (2017) Pathologic Response to Preoperative Therapy as a Novel Prognosticator for Ampullary and Duodenal Adenocarcinoma. Ann Surg Oncol 24:3954-3963