Dormancy and Pancreatic Adenocarcinoma Recurrence

About This Grant

PROJECT SUMMARY Contemporary surgical and systemic therapies for pancreatic ductal adenocarcinoma (PDAC) have limited benefit. Median overall survival at 5 years is only 64% even in those who have complete pathologic response to neoadjuvant chemotherapy. This means most patients have resistant minimal residual dormant disease (MRD) at the time of curative intent surgery. The reason for this MRD is best explained by a cellular dormancy based on solitary PDAC disseminated tumor cell (DTC) analysis in livers of humans and mice. The recurrence of PDAC after combined surgery and chemotherapy provides strong clinical suggestion of a dormancy phenotype in patients with locoregional stages. Despite these clinical observations and due to the apparent aggressive nature of PDAC, the notion of dormancy in PDAC is dubious. Yet, a critical need remains to better understand the phenotype MRD in PDAC which will in turn allow the medical community to leverage this information toward truly innovative therapies. The contribution and mechanistic underpinnings of DTC dormancy in PDAC are poorly described. We have identified two pathways that may provide mechanistic insights into how MRD dormancy proceeds in PDAC and importantly these two pathways have identified therapeutics targets that can be leveraged to improve survival. Two key regulators of the dormancy phenotype have emerged: Nuclear Receptor Subfamily 2 Group F member 1 (NR2F1) and RNA-like ER kinase (PERK) of the integrated stress response. The role of NR2F1 and PERK in PDAC dormancy and the efficacy of targeting these in PDAC is unknown. We hypothesize that metastatic competent PDAC DTCs undergo a dormancy phase that is targetable and may curtail metastatic relapse. We propose to determine whether circulating and disseminated PDAC cells in mice and humans express NR2F1 and activate the PERK pathway. We will also determine whether an agonist of NR2F1 in combination with a PERK inhibitor improves the survival of mice with locoregional PDAC via dormancy induction and dormant DTC killing. This proposed study will confirm NR2F1 and PERK activation as markers for dormancy and survival of PDAC disseminated disease. Also, we will determine whether targeting dormancy pathways impacts survival in PDAC. Expected results will provide the rationale for clinical development of targeting dormancy and improving the survival of people with locoregional PDAC. The rationale and methods proposed represent pilot and feasibility studies to explore the biology of MRD and dormancy in PDAC.