• Home
  • Funding
  • Pancreatic Cancer Action Network-AACR Career Development Awards

Pancreatic Cancer Action Network-AACR Career Development Awards

The Pancreatic Cancer Action Network-AACR Career Development Awards represent a joint effort to encourage and support junior faculty, who have completed their most recent doctoral degree or medical residency within the past 11 years, to conduct pancreatic cancer research and establish successful career paths in this field. 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

Pancreatic Cancer Action Network-AACR Career Development Award, funded by an anonymous foundation

Amber Simpson, PhD 
Assistant Attending Computational Biologist
Memorial Sloan Kettering Cancer Center
New York, New York
  CT texture analysis: A radiomics approach to predicting malignancy in IPMN

Incidental pancreatic cysts are being identified at an increasing rate due to the widespread use of abdominal cross-sectional imaging. Current laboratory, endoscopic, cytologic, and imaging technologies are limited in their ability to distinguish between intraductal papillary mucinous neoplasms (IPMN) at low- or high-risk of becoming an invasive cancer. The yield from resecting branch duct IPMN is low, with about 18 percent demonstrating malignancy on pathology report. Thus, a significant proportion of these patients will undergo unnecessary surgery for benign precursor lesions. The goal of this interdisciplinary research is to develop quantitative imaging markers that define malignancy. Dr. Simpson’s hypothesis is that CT-based quantitative imaging features can better predict malignancy in IPMN than visual assessment by radiologists and can achieve comparable discriminatory power as state-of-the-art fluid markers, thus providing non-invasive disease surveillance. Dr. Simpson was the first to apply quantitative imaging techniques in the pancreas, identifying markers predictive of survival in patients with pancreatic adenocarcinoma.

Top of page

Pancreatic Cancer Action Network-AACR Career Development Award, funded by an anonymous foundation

Shuibing Chen, PhD 
Assistant Professor
Weill Cornell Medical College
New York, New York
  Targeting chemoresistant stem cells in pancreatic cancer

Chemoresistance is a primary cause of treatment failure in pancreatic cancer. Identifying cell surface markers specifically expressed in chemoresistant cancer cells (CCCs) could facilitate targeted therapies to overcome chemoresistance. From an antibody-based screen, TRA-1-60 and TRA-1-81, two “stemness” cell surface markers, were identified to be highly enriched in chemoresistant cancer cells. Moreover, TRA-1-60+/TRA-1-81+ cells are chemoresistant compared to TRA-1-60-/TRA-1-81- cells. Furthermore, a high content chemical screen of a library of 2000 FDA-approved and international drugs identified a lead hit that specifically eliminates the TRA-1-60+/TRA-1-81+ cells and increases the sensitivity of pancreatic cancer cells to chemotherapy. The aims of the proposal are 1) Define the molecular basis for chemoresistance of the TRA-1-60+/TRA-1-81+ cells; and 2) Validate the hit compounds using primary tumor samples. The proposed studies will significantly improve our knowledge of chemoresistance and repurpose an antiarrhythmic reagent for combinational therapy of otherwise intractable cancers.

Top of page

Pancreatic Cancer Action Network-AACR Career Development Award, in memory of Skip Viragh

Rushika M. Perera, PhD 
Assistant Professor
University of California, San Francisco
San Francisco, California
  Targeting nutrient scavenging pathways that fuel pancreatic cancer growth

Pancreatic adenocarcinoma (PDA) is a highly aggressive malignancy that thrives in nutrient poor, hypoxic environments. Recent evidence suggests that this remarkable resilience to nutrient limitation is overcome through constitutive activation of nutrient scavenging pathways namely autophagy (cellular self-catabolism) and macropinocytosis (bulk uptake of extracellular material). Importantly, both of these pathways converge on the lysosome, an acidic organelle that harbors within its lumen a complex series of enzymatic reactions that enable degradation of incoming cargo material. Dr. Perera’s recent work has shown that the lysosome is greatly expanded and qualitatively different in PDA cells compared to normal tissue. Moreover, she identified the MiT/TFE transcription factors (TFE3, MITF, and TFEB) as master regulators of autophagy-lysosome activation in PDA where they orchestrate transcriptional control of the biogenesis and function of the autophagosome-lysosome system. Furthermore, Dr. Perera determined that autophagy-lysosomal activation is specifically required to maintain intracellular amino acid (AA) pools. Thus, contrary to the long held view that the lysosome is a metabolic "dead end," devoid of any regulation or fine-tuning Dr. Perera proposes that lysosomes function as major integrators of extracellular and intracellular information and are important mediators of global rewiring of cellular state. Building on these findings, Dr. Perera and her team will test the hypothesis that the lysosome actively remodels PDA metabolism to enable adaptation to a variety of stress conditions. By developing and systematically applying novel proteomics and metabolomics approaches, the proposed studies aim to uncover dynamic changes in lysosome composition during tumor evolution and following exposure to cellular stress, particularly in the form of nutrient starvation and treatment with anti-cancer agents. Through a comprehensive analysis of lysosome function in PDA, Dr. Perera’s goal is to identify key targets for development of novel lysosome-based inhibitors.

Top of page

Pancreatic Cancer Action Network-AACR Career Development Award, supported by Laurie MacCaskill

Kian-Huat Lim, MD, PhD 
Assistant Professor
Washington University in St. Louis
St. Louis, Missouri
  Deactivating the innate immune defense mechanism of pancreatic cancer

Extreme resistance to anticancer agents and radiation underlies the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC). Mechanisms that contribute to such malignant feat of PDAC include strong intrinsic survival signaling events including expression of KRas oncoprotein and upregulation of the NF-kB pathway, as well as an intensely inflamed extrinsic tumor microenvironment which limits the delivery of anticancer agents. Dr. Lim’s team recently found that PDAC cells commonly upregulate their intrinsic innate immune defense mechanism through activating the Interleukin-1 Receptor Associated Kinase 4 (IRAK4). Notably, presence of activated IRAK4 in resected PDAC tumors is significantly associated with poor prognosis, indicating IRAK4 as a regulator that drives the aggressive behavior of PDAC. His team went on to show that therapeutic targeting of IRAK4 significantly reduces the NF-kB activity, cripples the in vivo tumorigenic ability of various PDAC lines, augments the effect of chemotherapeutics and reduce stromal formation in xenograft models.

Dr. Lim’s team will now go on to investigate the mechanism that leads to activation of IRAK4 by focusing on the contribution of the closely associated Toll-like receptors. Using the state-of-the-art genetically-engineered mouse model, the KPC mice, Dr. Lim’s team will further dissect the role of IRAK4 in stromal and immune cells, which will have important clinical implication in the future. Finally, Dr. Lim’s team will test the preclinical efficacy of a newly developed IRAK4 inhibitor as single agent and in combination with chemotherapeutics in mouse models. 

In summary, Dr. Lim’s team believes that deactivating the innate immune defense mechanism of PDAC cells represents a promising therapeutic strategy that could improve patient outcome.

Top of page

Pancreatic Cancer Action Network-AACR Career Development Award, supported by The Daniel and Janet Mordecai Foundation

Christopher Vakoc, MD, PhD 
Associate Professor
Cold Spring Harbor Laboratory
Cold Spring Harbor, New York
  Enhancer reprogramming as a driver of pancreatic cancer progression

An emerging body of evidence has linked deregulation of enhancers to the pathogenesis of human cancer. In this proposal, the Vakoc laboratory will perform mechanistic research that tests the hypothesis that enhancer deregulation by transcription factors promotes metastasis in late-stage pancreatic cancer. This proposal is based on preliminary evidence that identifies massive aberrations of enhancer activity in organoid cultures derived from distal metastases relative to primary pancreatic tumors. A key hypothesis underlying the proposed research is that aberrant enhancer activation is a major reason why pancreatic cancer cells gain the ability to metastasize to distant organs, such as the liver. To test this idea, enhancers will be genetically modified in pancreatic cancer cells to examine how this alters the behavior of the disease. In addition, experiments will investigate how transcription factors bind to enhancers to turn nearby genes ON or OFF. It is anticipated that targeting transcription factors might allow restoration of enhancer configurations back to their normal state, and an attenuation of metastatic potential of cancer cells.

Top of page

2015 Grantees

Pancreatic Cancer Action Network – AACR Career Development Award, in memory of Skip Viragh

Cosimo Commisso, PhD  
Assistant Professor
Sanford-Burnham Medical Research Institute
La Jolla, California

Targeting macropinocytosis via Na+/H+ exchanger inhibition in PDAC

Oncogenic KRAS mutations initiate the progression of pancreatic cancer and have been found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC). A prominent feature of oncogenic KRAS-expressing cells is the stimulation of macropinocytosis, an endocytic mechanism of fluid-phase uptake. Recently, we have linked macropinocytosis to nutrient internalization in pancreatic tumor cells. By stimulating the uptake of extracellular serum albumin and targeting it for lysosomal degradation, macropinocytosis functions as an amino acid supply route. Macropinocytosis is unique in relation to other endocytic pathways because it is selectively sensitive to 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and other amiloride analogs that target Na+/H+ exchange. Na+/H+ exchange is regulated by a family of integral membrane transporters known as Na+/H+ exchangers (NHEs). We found that targeting NHEs in vivo via treatment with EIPA attenuates macropinocytosis and causes growth suppression or regression of pancreatic tumor xenografts. While the antitumor effects exerted by EIPA could be multifactorial in nature, the selectivity of the drug for tumors with a high macropinocytic index suggests that the abrogation of macropinocytosis accounts for the majority of this effect. In addition, our preliminary data indicates that the pharmacological inhibition of NHEs has the capacity to diminish the growth of syngeneic tumors and to modulate the tumor stroma. It is unclear which of the NHEs play a role in the fitness of pancreatic cancer cells and whether more potent, next-generation NHE inhibitors can be effective at modulating pancreatic tumor growth. Moreover, how NHE inhibition leads to a stromal collapse-like phenotype and whether this feature can be harnessed for the delivery of chemotherapeutics is unknown. These questions are the conceptual motivators for this new project in which we propose to investigate the functionality of the NHEs in pancreatic cancer and determine whether the targeting of NHEs is a potential novel therapeutic strategy for PDAC.

Top of page

Pancreatic Cancer Action Network – AACR Career Development Award, supported by an anonymous foundation

Nada Y. Kalaany, PhD 
Assistant Professor
Boston Children's Hospital
Boston, Massachusetts

Role of arginine metabolism in obesity-associated pancreatic cancer

A strong correlation exists between obesity and the incidence of/mortality from pancreatic cancer. Interestingly, this correlation is also evident in lean patients that display a prediabetic state characterized by elevated blood insulin and insulin-like growth factor-1 (IGF-1) levels that typically accompany obesity. However, the mechanisms underlying this association remain unknown.

Pancreatic cancer is a highly lethal malignancy, whose poor outcomes have remained stagnant for several decades. Thus, alternative therapeutic approaches are urgently needed. Recognized as a hallmark of cancer formation, altered cellular metabolism is evident in pancreatic tumors. However, how distinct metabolic pathways are differentially regulated in the pancreatic tumors under an obese/prediabetic state, and whether elevated insulin and IGF-1 blood levels mediate these effects, remain unknown.

Dr. Kalaany plans to investigate whether and how obesity and its associated metabolic changes can alter pancreatic tumor metabolism, so as to enhance its growth and worsen disease outcome. Preliminary studies using human pancreatic cancer cells implanted into the pancreas of lean or obese mice indicate a striking enhancement in the utilization of a specific metabolic pathway (arginine metabolism) by pancreatic tumors grown in obese mice, compared to lean mice. Interestingly, this pathway is largely mediated by a pro-tumorigenic protein (Akt), whose activity can be induced by elevated insulin and IGF-1 levels, independent of obesity.

Using lean or obese transplant and genetically engineered mouse models of pancreatic cancer, Dr. Kalaany's team will investigate the significance of these findings, with regards to pancreatic cancer growth and progression. To that end, a variety of molecular, biochemical, and metabolic approaches will be applied, to alter the arginine metabolic pathway within the tumor cell and suppress its utilization by the tumors.

Accomplishing these studies will identify and underscore a novel metabolic dependency in pancreatic cancers harboring activated Akt, resulting from either tumor-promoting mutations, or elevated insulin/IGF-1 levels that accompany obesity. This metabolic liability could serve as an Achilles heel for therapeutic targeting in both lean and obese pancreatic cancer patients. Importantly, it will pave the way for the development of novel antipancreatic cancer strategies that could be used in combination with currently available chemotherapies.

Top of page

Pancreatic Cancer Action Network – AACR Career Development Award, supported by an anonymous foundation

Gregory L. Beatty, MD, PhD 
Assistant Professor of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania

Immune escape mechanisms in metastatic pancreatic cancer

Metastatic disease remains the primary cause of morbidity and mortality in pancreatic ductal adenocarcinoma (PDAC). However, the factors that regulate metastasis in PDAC remain ill-defined. The process of metastasis is dependent on cancer cell-intrinsic properties as well as the receptiveness of the local microenvironment where tumor cells seed. To study metastasis in PDAC, Dr. Beatty's laboratory has used a mouse model, called the KPC model, in which mice spontaneously develop PDAC. This model reproduces many of the salient features of human disease including metastasis. In both KPC mice and humans, Dr. Beatty's research team has found that the immune response to PDAC can be reprogrammed with antitumor properties. However, antitumor immune responses are often short-lived and heterogeneous indicating a need for understanding the mechanisms by which malignant cells escape immune elimination. Because the liver is the most common site of metastasis in PDAC, Dr. Beatty plans to focus his team's efforts on liver metastasis. He and his team hypothesize that immune cells recruited to the liver microenvironment are critical for establishing a niche that is supportive of cancer cell metastasis. Because of the inherent plasticity of the immune system, Dr. Beatty has proposed that this leukocyte reaction may also be redirected to inhibit metastasis. To test this hypothesis, he and his research team will study the capacity of immune stimuli to shift the phenotype of leukocytes within the liver from pro- to antitumor. In addition, they will examine the role of cancer cell intrinsic properties in promoting immune evasion during metastasis. It is expected that findings from these studies conducted in clinically relevant mouse models will 1) provide insight into factors that regulate metastasis in PDAC; and 2) inform the development of novel immunotherapeutic approaches for inhibiting and treating metastatic disease.

Top of page

2014 Grantees

Pancreatic Cancer Action Network – AACR Career Development Award, in memory of Skip Viragh

Eugene J. Koay, MD, PhD Eugene J. Koay, MD, PhD   
Assistant Professor
University of Texas MD Anderson Cancer Center
Houston, Texas

Changes in Mass Transport as a Biomarker of Response in Pancreatic Cancer 

There has been significant progress in the understanding of the biology of pancreatic cancer. As novel strategies emerge from these scientific discoveries and are tested in phase I/II clinical trials, it will be increasingly important to have an early biomarker of response to therapy so that promising strategies can reach patients quickly. Currently, such a biomarker has not been identified for pancreatic tumors.

Dr. Koay’s pilot studies have revealed a promising candidate for this purpose. He worked with a multidisciplinary team to develop a method to quantify enhancement properties of pancreatic tumors from diagnostic computed tomography (CT) scans and correlated these properties with patient outcome. In two trials of chemoradiation for unresectable pancreatic cancer, patients who had a measureable decrease in enhancement of their pancreatic tumors after chemoradiation treatment showed significantly better tumor control (86 percent with tumor control at two years) compared to patients whose tumors exhibited stable or increased enhancement after treatment (34 percent with tumor control at two years), independent of therapy regimen, change in tumor size, and receipt of curative-intent surgery.

This PanCAN proposal involves a multi-institutional collaboration to test the idea that tumor control is associated with changes in tumor enhancement. In collaboration with investigators at Johns Hopkins, the measurements of enhancement from CT scans before and after treatment will be compared with tumor control for large datasets of patients with pancreatic cancer who received chemotherapy and radiation. Simultaneously, a prospective registry trial at MD Anderson will test the same idea for patients who receive chemotherapy alone for unresectable, non-metastatic pancreatic cancer. To understand the underlying biology of the observation, the researchers will analyze pancreatic tumors that were treated with chemoradiation prior to surgery, correlating the CT enhancement profiles with specific markers of therapy resistance in the specimens.

In summary, Dr. Koay and his team will perform a large-scale validation plan to establish a clinically useful and scientifically meaningful method to help accelerate promising new treatment strategies for pancreatic cancer and more rapidly improve patient outcomes.

Top of page

Florencia McAllister, MDFlorencia McAllister, MD
Assistant Professor
University of Texas MD Anderson Cancer Center
Houston, Texas

Targeting IL-17 signaling Axis in Pancreatic Ductal Adenocarcinoma 

Even though a Kras mutation is enough to initiate early pre-malignant lesions, the mechanisms required for the progression to pancreatic cancer are unknown. It is well known that inflammation is a risk factor for cancer and it has been well established that pancreatic chronic inflammation can accelerate the development of pancreatic cancer. Dr McAllister has recently found that activation of KrasG12D in murine adult acinar cells induces expression of functional IL-17 receptors (IL-17RA) on emerging PanIN epithelial cells, accompanied by pancreatic infiltration by IL-17-producing CD4+ and gd-T cells. Furthermore, she has shown that IL-17-producing T cells are early drivers of pancreatic neoplasia and mediate much of the increase in PanIN formation observed in chronic pancreatitis. She is now going to extend these studies to determine the role of IL-17 signaling in advanced disease, including the preclinical evaluation of clinical-grade neutralizing antibodies targeting IL-17 signaling in established murine pancreatic cancer. Furthermore, she is planning to dissect the specific compartment required for the pro-tumorigenic IL-17 signaling in pancreatic tumor development. Finally, she will also investigate how systemic TH17 immune responses, including changes in the gut microbiome, can affect pancreatic tumorigenesis.

In sum, she considers that better understanding of the pancreatic hematopoietic-to-epithelial pro-tumorigenic IL-17 signaling axis can result in more effective strategies for the prevention and treatment of pancreatic cancer.  

Top of page

Search other AACR research funding opportunities.