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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.  

2017 Grantee

Escobar-Hoyos_90x110.jpgLuisa F. Escobar-Hoyos, MSc, PhD
Postdoctoral Fellow
Memorial Sloan Kettering Cancer Center
New York, New York
mRNA splicing in pancreatic adenocarcinoma

Scientific Statement of Research
Pancreatic ductal adenocarcinoma (PDAC) has recently been identified to be composed of distinct molecular subtypes based on mRNA expression and patient outcome. These findings highlight the importance of elucidating the molecular mechanisms that regulate mRNA expression and diversity in PDAC. Mentored by Dr. Steven Leach, Dr. Escobar-Hoyos will evaluate how mutations in transcriptional regulators and mRNA splicing factors influence gene expression and alternative splicing (AS) of mRNAs, to promote the pathogenesis and aggression of PDAC. Later, Dr. Escobar-Hoyos will continue to evaluate how splicing regulators and alternatively spliced genes enriched in PDAC contribute to tumor maintenance and resistance to therapy. Dr. Escobar-Hoyos hopes to identify novel dependencies related to mRNA splicing and processing for the design of future targeted therapy.

Biography
Dr. Escobar-Hoyos came to the United States after receiving a Fulbright Fellowship to conduct PhD studies at Stony Brook University in the laboratory of Dr. Kenneth Shroyer. Before her PhD studies, Dr. Escobar-Hoyos majored in biology and graduated with a master’s in biomedical sciences in Colombia, South America. After graduating with the President's Award to Distinguished Doctoral Student, Dr. Escobar-Hoyos started as a postdoctoral fellow in the laboratory of Dr. Steven Leach.

Acknowledgement of Support
I am deeply honored to receive the 2017 Pathway to Leadership Grant and am thankful to the Pancreatic Cancer Action Network and the AACR for their generous support. This award will be instrumental in the development of my research and my career as scientist committed to pancreatic cancer research.

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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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      2013 Grantees

      Costas A. Lyssiotis, PhD

      Costas A. Lyssiotis, PhD  
      Assistant Professor
      University of Michigan
      Ann Arbor, Michigan
      Exploration and targeting of metabolic dependencies in pancreatic cancer 

      Cancer cells have different metabolic needs than normal cells and focus their energy on growth and survival. Treating cancer by targeting the way that malignant cells take in and use nutrients (their metabolism) has emerged as a highly promising therapeutic strategy. However, because normal cells and cancer cells often require the same energy sources and metabolic pathways to maintain homeostasis, designing effective metabolism-based cancer therapies has been challenging. By taking a detailed investigation into how pancreatic cancer cells use metabolic fuels, we recently identified several aspects of cancer metabolism that pancreatic tumors are absolutely dependent on for growth and survival. Namely, pancreatic cancers take up glucose and glutamine (the most abundant amino acid in circulation) in vast excess, relative to normal cells, and use these fuels to make DNA and to defend against harmful reactive oxygen species. Importantly, whereas inhibition of these processes in healthy cells has minimal side effects, their inhibition in pancreatic cancer cells is catastrophic. We seek to use our understanding of these newly identified pancreatic cancer-specific metabolism pathways to develop innovative targeted therapies that selectively eliminate diseased cells.

      Selection as a Pathway to Leadership grant recipient is a tremendous honor and provides the necessary support to fully explore these promising therapeutic strategies in the laboratory. Ultimately, we aim to translate the findings from this work into new therapeutic targets and modalities that can be used to treat patients with pancreatic cancer, a disease for which effective clinical options for patients are desperately needed.

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      Yuliya Pylayeva-Gupta, PhD Yuliya Pylayeva-Gupta,PhD 
      Assistant Professor
      The University of North Carolina Lineberger Cancer Center
      Chapel Hill, North Carolina
      Immunomodulatory mechanisms in Kras-driven pancreatic cancer and metastasis         

      Most—if not all—malignant solid tumors are comprised of both cancer cells and reactive stromal cells, the latter of which have often become co-opted to facilitate tumor growth. This phenomenon is particularly relevant in pancreatic cancer development, where pronounced changes in stromal responses and immune surveillance programs are now recognized as some of the major drivers of this disease, and likely contribute to its notorious resistance to therapy. Recent studies have shown that newly generated cancer cells have the ability to activate and/or suppress components of the immune response, which is necessary for tumor development and progression. Our work aims to identify how the immune system is involved in the development of pancreatic cancer and metastasis. An underlying goal of this research is to identify novel diagnostic and therapeutic modalities that may improve clinical outcomes in this deadly disease.

      In the laboratory of Dr. Bar-Sagi at NYU School of Medicine, we have utilized mouse models of mutant Kras-driven pancreatic ductal adenocarcinoma to characterize critical elements of immune response modulation initiated by mutant Kras activation. We developed a mouse model where primary pancreatic ductal epithelial cells are introduced into the pancreata of syngeneic mice with an intact immune system. This model system has allowed us to determine that oncogenic Kras drives expression of the cytokine GM-CSF, which enables accumulation of immunosuppressive myeloid derived precursor cells at the site of pancreatic neoplasia that thwart an effective antitumor adaptive immune response. Our additional preliminary work has revealed that immune cells accumulate not only in the cancerous lesions of the pancreas but also at organ sites of future metastasis, such as the liver. In the course of this project, I will evaluate the role of the adaptive immune response within the tumor microenvironment in regulating primary tumor growth and metastatic progression. I hope to elucidate the mechanism behind primary pancreatic cancer recognition by the adaptive immune system, and identify pathways of cancer escape from such immune surveillance. I will also examine the potential for pancreatic cancer cells to establish a premetastatic niche in distant organ sites, and will investigate components of the immune system that are necessary for sustaining pancreatic cancer metastasis. I believe that understanding the molecular and cellular nature of such interactions, the types of immune cells that are involved, and their functional contribution to pathogenesis of the disease may provide us with tools to better treat this lethal cancer.

      I am extremely thankful to the Pancreatic Cancer Action Network and AACR for their generous support of this research plan at such a critical stage of my research career. In addition to providing me with valuable support during my transition towards an independent academic career, the pathway to leadership award will also integrate me into a vibrant community of world-class pancreatic cancer researchers, with whom I look forward to sharing ideas and collaborating for many years to come.

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      2012 Grantees

      Pancreatic Cancer Action Network-AACR Pathway to Leadership Grant supported by Celgene Corporation

      Stephanie K. Dougan, PhD

      Stephanie K. Dougan, PhD 
      Assistant Professor
      Dana-Farber Cancer Institute
      Boston, Massachusetts
      Transnuclear Mice: Understanding the T Cell Response to Pancreatic Cancer

      The immune system is a powerful resource for fighting tumors. Cytotoxic T cells can distinguish tumor cells from normal tissue with pinpoint precision, and they can migrate to seek out and destroy tumor cells wherever they arise. A second type of T cell, called a regulatory T cell or Treg, blocks the function of cytotoxic T cells and prevents them from effectively fighting the tumor. Pancreatic tumors are notorious for having high numbers of Tregs and relatively few cytotoxic T cells in the tumor mass itself. At this point, we do not understand why Tregs appear in pancreatic tumors or what specific aspects of the tumor recruit and activate these cells. If we knew what aspects controlled the beneficial cytotoxic T cells and the detrimental Tregs and how these two cell types interacted, then we could design therapies to target the immune components of pancreatic cancer. One major roadblock in the design of immune therapies for pancreatic cancer is the lack of good mouse models. Through a collaboration between my mentor Dr. Hidde Ploegh and his fellow Whitehead member Dr. Rudolf Jaenisch, I will use somatic cell nuclear transfer to clone mice from the nuclei of cytotoxic and Treg cells isolated from mouse pancreatic tumors. The resulting transnuclear mice can then be used as a source of pancreatic-tumor specific T cells that can be administered to mice at various stages of pancreatic cancer.

      In order to fully address the T cell response to pancreatic cancer, it is imperative to understand both the positive and negative regulators. Thus the development of transnuclear mice, aiming for lines of both cytotoxic T cell and Treg origin will be essential. This novel approach will not only generate new lines of useful mouse models, but also it will, for the first time, give us an idea of why Tregs go so readily to pancreatic tumors. Such information will allow us to create targeted therapies to specifically suppress or eliminate Tregs, while promoting cytotoxic T cell function. The mice generated here will be the foundation of my lab as an independent investigator and a valuable resource for the pancreatic tumor community at large.   

      I am deeply grateful to the Pancreatic Cancer Action Network and to the AACR for their generous support of my transition to independence. Initially, I will continue development of novel mouse models for pancreatic cancer under the guidance of Dr. Hidde Ploegh at the Whitehead Institute. These mouse models will provide the basis of my independent career elucidating the relationship between the immune system and pancreatic cancer.

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