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. The research proposed for funding may be basic, translational, clinical, or epidemiological in nature and must have direct applicability and relevance to pancreatic cancer.
Pancreatic adenocarcinoma (PDA) is an exceedingly deadly cancer that is resistant to most treatment options and metastasizes aggressively in patients. Two key driving forces in PDA are activating mutations in KRAS (>90% of cases) and pancreatic cancer stem cells (PCSCs), a tumor cell subtype that is highly tumorigenic and refractory to therapies. Dr. Abel’s research has found that a transcription factor called HNF1A is highly expressed in PCSCs compared to other tumor cells, and mediates a number of PCSC-associated characteristics, including tumorigenesis and proliferation. He has also found that HNF1A activity is enhanced by targeting mutant KRAS, and that reinforced expression of HNF1A protects PDA cells from KRAS ablation. Lastly, Dr. Abel has found HNF1A to be a target of the oncogene MYC. Dr. Abel’s future research will focus on determining the interplay between HNF1A, KRAS, and MYC as they pertain to PCSCs, drug resistance, and transcriptional regulation in PDA.
Pancreatic cancer is the fourth-leading cause of cancer death in the US with few novel avenues for therapeutic targeting. Recently, chromatin dysregulation has been implicated in many human cancers; in pancreatic cancer, several chromatin-based events – including acinar-ductal transdifferentiation and epithelial-mesenchymal transition – occur early in tumor initiation. In addition, several chromatin regulators, including ARID1A, MLL2, MLL3, and KDM6A, are frequently mutated in human disease. Despite these lines of evidence suggesting a dependency on epigenetic mechanisms, the role of chromatin in pancreatic cancer remains poorly understood. In the laboratory of Dr. Steven Leach, Dr. Chandwani is currently delineating the progressive alteration to chromatin occurring in lineage-traced pre-neoplastic pancreatic acinar cells. Dr. Chandwani will combine these genome-wide analyses of chromatin with the specific evaluation of oft-mutated epigenetic regulators in the development of disease. Together, Dr. Chandwani’s research embarks on a systematic evaluation of chromatin to reveal new molecular susceptibilities of pancreatic cancer.
It is well known that nearly every human pancreatic ductal adenocarcinoma (PDAC) contains oncogenic KRAS mutation, as it is essential for tumor initiation, development and progression. Thus, it is crucial to gain deep molecular insights into how this oncogene drives disease. One important functional aspect of oncogenic KRAS in PDAC is that it can turn on a cellular process termed “macropinocytosis,” which is a reorganization of the cell surface membrane to form a sort of pocket that accumulates extracellular fluids, then the pocket closes and the contents are internalized for cellular utilization. This is a unique way for pancreatic cancer cells to scavenge “food” to fuel their growth. Thus, it stands to reason that blocking the food supply of pancreatic cancer cells by inhibiting macropinocytosis may result in cell death. However, how oncogenic KRAS activates nutrient salvage pathways is not clear and detailed studies are needed to identify the molecular mechanisms that can be exploited therapeutically to block the food supply of PDAC cells. In the laboratory of Dr. Draetta at The University of Texas MD Anderson Cancer Center, Dr. Yao will define the mechanisms that result in KRAS-dependent upregulation of macropinocytosis and illuminate potential therapeutic targets that could starve PDAC cells. Dr. Yao has employed a mouse model of inducible oncogenic KRAS-driven PDAC to identify cell surface proteins that are important for macropinocytosis and thus for the food supply to cancer cells. Dr. Yao’s research will elucidate the mechanism by which KRAS regulates the cell surface proteins that influence PDAC maintenance and progression and to dissect the pathways that regulate macropinocytosis. Further, Dr. Yao’s research aims to determine how upregulation of nutrient salvage pathways impacts PDAC metabolism and tumorigenicity. It is the overall goal of this proposal to increase our knowledge of how KRAS regulates the cell membrane to fuel tumor cell growth in order to gain new insights into opportunities to block essential PDAC cell processes that may be translatable into novel therapies.
Pancreatic cancer has the lowest five-year survival rate of all cancers and the need for new therapies is dire. The KRAS gene is mutated in >95 percent of pancreatic cancers, and thus the development of therapies to block mutant KRAS protein function would make significant strides in improving the survival and quality of life of pancreatic cancer patients. One exciting direction for KRAS drug discovery is the field of metabolism, understanding how cancer cells acquire nutrients to fuel their uncontrolled growth. Dr. Bryant proposes to define the signaling mechanisms that drive KRAS-dependent metabolic alterations, with the goal of targeting these changes to “starve” pancreatic cancer. One major KRAS-dependent process, macropinocytosis, allows cancer cells to engulf extracellular fluids to acquire proteins that fuel the cell’s uncontrolled growth. How KRAS promotes macropinocytosis in pancreatic cancer is not known. Preliminary studies from the Der Lab have implicated a lesser-studied KRAS signaling pathway that has a critical role in activating a protein kinase, which is necessary for macropinocytosis. Because protein kinases are a class of proteins where cancer drug discovery has been the most successful, Dr. Bryant will determine if the use of inhibitors for this kinase will be an effective way to shut down macropinocytosis for pancreatic cancer treatment. A second mechanism utilized by KRAS-mutant pancreatic cancer cells to supply their increased metabolic needs is increased autophagy, a process of self-eating. How KRAS facilitates autophagy has not been addressed. Dr. Bryant will define this relationship and perform preclinical evaluation of a combination inhibitor strategy to block KRAS effector signaling and autophagy for pancreatic cancer treatment. Finally, KRAS has been shown to facilitate the increased dependency of pancreatic cancers on the amino acid glutamine. Dr. Bryant will address the role of KRAS-dependent alterations of glutamine metabolism and gene expression in order to identify new metabolic targets for pancreatic cancer treatments. In summary, Dr. Bryant’s studies aim to understand how KRAS fuels the increased appetite of rapidly growing pancreatic cancer cells – once understood, specific therapies can then be designed to starve pancreatic cancer.