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​Pancreatic Cancer Action Network-AACR Pathway to Leadership Grants

The Pancreatic Cancer Action Network-AACR Pathway to Leadership Grant represents 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.  

2016 Grantees

Ethan V. Abel, PhD
Postdoctoral Research Fellow
University of Michigan
Ann Arbor, Michigan
The role and regulation of HNF1A in pancreatic cancer cells

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.

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Rohit Chandwani, MD, PhD
Postdoctoral Research Fellow
Memorial Sloan Kettering Cancer Center
New York, New York
The epigenetic plasticity of pancreatic adenocarcinoma

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.

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Pancreatic Cancer Action Network-AACR Pathway to Leadership Grant, in memory of Carina Rogerson

Wantong Yao, MD, PhD 
Postdoctoral Research Fellow
University of Texas MD Anderson Cancer Center
Houston, Texas
Syndecan-1 is a novel regulator for nutrient salvage pathway

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.

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      2015 Grantee

      Kirsten L. Bryant, PhD 
      Postdoctoral Fellow
      The University of North Carolina at Chapel Hill
      Chapel Hill, North Carolina
      Exploiting pancreatic cancer cell metabolism for therapeutic gain

      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.

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      2014 Grantee

      Gina M. DeNicola, PhD

      Gina M. DeNicola, PhD 
      Postdoctoral Fellow
      Joan and Sanford I. Weill Cornell Medical College
      New York, New York
      Therapeutic targeting of NRF2-regulated metabolism in pancreatic cancer

      Pancreatic ductal adenocarcinoma is one of the deadliest cancers due to its late detection and it being relatively refractory to traditional cytotoxic agents and radiotherapy. Mutations in the oncogene KRAS are found in 95 percent of pancreatic ductal adenocarcinomas; however, efforts to develop drugs targeting this mutant protein have so far been unsuccessful. Therefore, the need to develop effective therapies that target the molecular mechanisms involved in this disease has never been greater.

      With Dr. David Tuveson, Dr. DeNicola identified that KRAS regulates the activity of a protein called NRF2, which is critical for suppressing the toxic byproducts of cellular metabolism, known as reactive oxygen species. Although they found that NRF2 promotes pancreatic tumorigenesis, the precise mechanism is unclear. Her current work in the laboratory of Dr. Lewis Cantley focuses on the role of NRF2-regulated metabolism in pancreatic cancer development. Dr. DeNicola is characterizing how NRF2 regulates the activity of the pathway responsible for making the amino acids serine and glycine, and how pancreatic cancer cells use serine and glycine to generate important molecules that allow them to grow, resist chemotherapy, and suppress reactive oxygen species. Importantly, she will use genetically modified mouse models to determine whether these metabolic pathways represent potential therapeutic targets for pancreatic cancer. Furthermore, Dr. DeNicola will examine these models for potential metabolite biomarkers for early detection of pancreatic cancer, an area that has been underexplored thus far.

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