Pancreatic Cancer Action Network-AACR Pathway to Leadership Grants
The Pancreatic Cancer Action Network-AACR Pathway to Leadership Grants represent a joint effort to ensure the future leadership of pancreatic cancer research by supporting outstanding early career investigators beginning in their postdoctoral research positions and continuing through their successful transition to independence. Funded research can be basic, translational, clinical, or epidemiological in nature.
Two key driving forces in pancreatic ductal adenocarcinoma (PDA) are activating mutations in KRAS (>90% of cases) and pancreatic cancer stem cells (PCSCs). Dr. Abel previously found that a transcription factor called HNF1A is highly expressed in PCSCs compared to other tumor cells. He hypothesized that HNF1A is a critical driver of PCSC progression. In the mentored phase of his research project, he demonstrated that depleting HNF1A impaired tumor growth in vitro and in vivo. In the independent phase of his project, he has set out to determine how HNF1A drives resistance to KRAS ablation.
While chromatin dysregulation has been implicated in other cancers, epigenetic alterations in pancreatic malignancies are not well described. Dr. Chandwani aims to characterize the epigenetic alterations in pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) in order to augment the understanding of early tumorigenic events. In the mentored phase of his project, using findings on the epigenomes and transcriptomes of normal acinar and ductal cells, he uncovered a role for the master transcription factor Foxa1 in pancreatic tumor initiation. In the independent phase of his research, he is focusing on the role of frequently mutated chromatin regulators in the initiation and formation of PanIN and PDAC.
Nearly every human pancreatic ductal adenocarcinoma (PDAC) contains an oncogenic KRAS mutation, Oncogenic KRAS turns on macropinocytosis, enabling pancreatic cancer cells to scavenge nutrients form the microenvironment to fuel growth. In the mentored phase of the project, Dr. Yao identified molecular mechanisms underlying syndecan 1 (SDC1)-mediated macropinocytosis, and their role in PDAC growth. In the independent phase of her project, she aims to characterize the role of SDC1 in the metabolic reprogramming of pancreatic cancer cells, and explore the therapeutic potential of SDC1 targeting.
An exciting direction for KRAS drug discovery is the field of metabolism — understanding how cancer cells acquire nutrients to fuel their uncontrolled growth. Previous findings have shown that pancreatic cancer cell lines exhibit elevated basal levels of autophagy. In the mentored phase of her project, Dr. Bryant found that KRAS suppression increases autophagic flux in KRAS-mutant pancreatic cells. She obtained promising results that showed that inhibition of the KRAS effector pathway, MAPK-ERK, can therapeutically synergize with autophagy inhibition. In the independent phase of her project, she is determining the therapeutic potential of the said combination and further defining KRAS-dependent metabolic changes.