Pancreatic Cancer Action Network-AACR Innovative Grants are available to independent junior and senior investigators to develop and study new ideas and approaches that have direct application and relevance to pancreatic cancer. The research proposed for funding may be basic, translational, clinical or epidemiological in nature. The Pancreatic Cancer Action Network-AACR Innovative Grants were formally known as the Pancreatic Cancer Action Network-AACR Pilot Grants and have been renamed to emphasize the focus on funding new, creative, and cutting-edge ideas and approaches.
- David Allen Boothman, Ph.D. (2012)
- Paul Chiao, Ph.D. (2012)
- Channing J. Der, Ph.D. (2012)
- Peter John Espenshade, Ph.D. (2012)
- Tyler Jacks, Ph.D. (2012)
- Lisa A. Cannon-Albright, Ph.D. (2011)
- James R. Eshleman, M.D., Ph.D. (2011)
- Matthias Hebrok, Ph.D. (2011)
- Hidde L. Ploegh, Ph.D. (2011)
- Diane M. Simeone, M.D. (2010)
- Amy H. Tang, Ph.D. (2010)
Pancreatic Cancer Action Network-AACR Innovative Grant, supported by The George and June Block Family Foundation
David Allen Boothman, Ph.D.
Associate Director for Translational Research, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
NQO1-mediated 'Kiss of death' Targeted Therapy For Pancreatic Cancer
"Pancreatic cancers have significant up-regulation of the two-electron oxidoreductase, NAD(P)H:quinone oxidoreductase 1 (NQO1), 20- to 100-fold elevated levels compared to normal tissue, and importantly, to normal pancreatic tissue. mRNA analyses also reveal a significant loss of Catalase expression in pancreatic and nonsmall cell lung cancers, while normal tissue express elevated levels.
"ß-Lapachone (current clinical agents known as Arq501 or Arq761) specifically kills cancer cells that have elevated levels of NQO1. Its well delineated mechanism of action involves NQO1-mediated futile redox cycling resulting in dramatic elevations of reactive oxygen species (ROS), superoxide and hydrogen peroxide in the cytoplasm. Long-lived hydrogen peroxide causes specific DNA base damage and DNA single strand breaks (SSBs). The overwhelming levels of SSBs created in cancer cells by just a two hour ‘kiss of death’ exposure of NQO1+ cancer cells with >90 Units of NQO1 to ß-lapachone results in the hyper-activation of poly(ADP-ribose) polymerase 1 (PARP1), a DNA repair protein, and tumor-specific programmed necrosis, marked by strong TUNEL+ staining. Elevated Catalase levels (Bey et al., submitted) and lack of significant NQO1 expression provide significant resistance to normal tissue throughout the body to ß-lapachone and other NQO1 bioactivatable drugs.
"The hypothesis to be tested in this grant is that alterations in base excision repair (BER), using selective BER component knockdown (e.g., XRCC1), PARP1 inhibitors, or the BER modifier, methoxyamine (MeOX), can be used to synergistically kill NQO1+ expressing pancreatic cancers. If correct, this strategy will confer tumor-specificity to DNA repair inhibitors, including PARP1 inhibitors developed (or being developed), since DNA damage to tumors is specifically generated in an NQO1-dependent manner. Furthermore, lowered Catalase levels in pancreatic cancers would augment SSB formation and induce cell death in pancreatic cancer tissue. In contrast, normal tissue (including the pancreas) will be ‘protected’ by the lack of NQO1 expression and Catalase-dependent detoxification of hydrogen peroxide. Intriguingly, blocking BER using MeOX for synergistic cell death with ß-lapachone will be fundamentally different than cell death caused by ß-lapachone and PARP1 inhibitor treatment. ß-Lapachone + MeOX will result in synergistic programmed necrosis, mediated by PARP1 hyperactivation. In contrast, PARP1 inhibitors will shift cell death caused by ß-lapachone to caspase-dependent apoptosis, driven by conversion of repairable SSBs into irrepairable DSBs that trigger Caspase-dependent cell death. Either approach will result in NQO1-dependent, tumor-selective cell death responses leading to effective therapies against NQO1 over-expressing pancreatic cancers. Since most solid tumors, namely pancreatic, nonsmall cell lung, breast (specifically triple-negative) and prostate cancers, have elevated levels of NQO1, such synergistic regimen using ß-lapachone should be applicable to various difficult-to-treat neoplastic diseases."
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Pancreatic Cancer Action Network-AACR Innovative Grant, supported in part by the Lefkofsky Family
Paul Chiao, Ph.D.
Professor, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
TAK1 is a Novel Therapeutic Target in Pancreatic Cancer
"Despite advances in pancreatic cancer research, current therapeutics against pancreatic cancer remain largely ineffective. Discovery of novel drug targets against pancreatic cancer is the first step for improving patient survival. One of the most promising approaches that we are currently investigating is to target the downstream signaling pathways of the signature genetic alterations such as Kras mutation found in pancreatic cancer. We demonstrate that activation of TAK1 kinase is induced by mutant Kras, that genetic approach to silence the expression of TAK1 suppressed the tumorigenesis in multiple pancreatic cancer cell lines, and that TAK1 overexpression is associated with poor survival in pancreatic cancer patients. We hypothesize that TAK1 plays key roles in pancreatic cancer cell growth and is a novel therapeutic target for pancreatic cancer. In this funded proposal, we aim to establish genetically-engineered mouse models to further study the function of TAK1 in pancreatic tumorigenesis, and develop TAK1 inhibitor, a potential novel therapeutic agent, and test the activity of TAK1 inhibitor in mouse models for pancreatic cancer."
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Pancreatic Cancer Action Network-AACR Innovative Grant, supported by Tempur-Pedic Retailers
Channing J. Der, Ph.D.
Professor of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, Chapel Hill, NC
TAK1 is a Novel Therapeutic Target in Pancreatic Cancer
"The near 100 percent incidence of KRAS oncogene mutations in pancreatic cancer, together with compelling evidence that ablation of mutant K-Ras protein function can greatly impair pancreatic cancer growth, has stimulated strong interest in developing K-Ras inhibitors for pancreatic cancer treatment. However, despite three decades of intense effort, to date no effective anti-K-Ras inhibitors have been developed. Perhaps the most attractive current approach for anti-K-Ras targeted therapy involves inhibitors of the most central K-Ras effector signaling pathway, the Raf-MEK-ERK mitogen-activated protein kinase (MAPK) cascade. However, despite their promise for blocking K-Ras function, inhibitors of Raf or of MEK have also met with disappointing outcomes in the clinic. This is due to the ability of pancreatic cancers to adapt and compensate to overcome pathway blockade, often by upregulating other kinases. In this PanCAN-AACR Innovative Grant, our goal is to elucidate the mechanisms of resistance and to establish new directions to overcome this compensatory process. We will focus on the final step in this pathway, the ERK protein kinases. We believe that important keys to our studies are the novel experimental tools that we will develop to study the ERK MAPKs, as well as our utilization of cell culture models of pancreatic cancer that better reflect the tumor cell heterogeneity of pancreatic cancer in the patient. Our studies will define mechanisms of acquired ERK MAPK inhibition-induced resistance. With this information, we will then identify therapies inhibiting specific combinations of protein kinases that are capable of more effective impairment of K-Ras-dependent pancreatic cancer growth."
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Pancreatic Cancer Action Network-AACR Innovative Grant, in memory of Bonnie L. Tobin
Peter John Espenshade, Ph.D.
Associate Professor, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD
SREBP Pathway as a Target for Pancreatic Cancer Therapy
"Pancreatic cancer is one of the most lethal cancers with a five-year survival rate of less than 5 percent. While detection and early treatment are the best approach to reducing deaths due to pancreatic cancer, improved therapeutics that effectively manage tumor growth are an essential component of the anti-cancer armamentarium.
"Tumor growth requires that cancer cells adapt to a low nutrient environment since tumor expansion outpaces the blood supply. Adaptation to low oxygen supply (a condition known as hypoxia) is critical for tumor growth because production of essential cell building blocks, such as cholesterol and fat, requires oxygen. Using a model yeast system, our lab discovered that hypoxia activates the SREBP signaling pathway and that SREBP is required for hypoxic adaptation and growth. SREBP is the master regulator of cholesterol and fat production in cells.
"In this project, we propose that blocking the ability of tumor cells to adapt to hypoxia through the SREBP pathway will prevent the essential production of cholesterol and fat, thus blocking pancreatic tumor growth. We will test whether existing chemical and genetic inhibitors of the SREBP pathway prevent proliferation of pancreatic tumor cells and development of pancreatic cancer in mice. Collectively, these studies will validate the SREBP pathway as a new target for treatment of pancreatic cancer.
"To date, SREBP inhibitors have been tested for their properties in preventing atherosclerosis and heart disease, but this is the first use of SREBP inhibitors as anti-tumor agents. Our lab has partnered with experts in pancreatic cancer at Johns Hopkins to test this idea because our lab is new to cancer biology. Funding from PanCAN-AACR demonstrates their commitment to sponsoring innovative research in pursuit of a cure for pancreatic cancer."
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Pancreatic Cancer Action Network-AACR Innovative Grant, supported by Blum-Kovler
Tyler Jacks, Ph.D.
Director, David H. Koch Institute for Innovative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
Mechanisms of K-RAS Independent Growth in Pancreatic Cancer
"Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States and remains a major unsolved problem worldwide. Despite advances in surgical techniques, radiation approaches and chemotherapy regimens, nearly all patients eventually die of their disease. While newer targeted therapies have vastly improved the care of patients with chronic leukemia, lung cancer, melanoma and breast cancer, the same improvements in drug response and survival with targeted therapies have not manifest in the treatment of pancreatic cancer. Several important genetic mutations involved in pancreatic tumor formation have been identified, including mutations in the K-ras gene, yet drugs that target K-RAS have not been effective to date. Further research to understand alternate mechanisms of growth and tumor formation in pancreatic cancer is needed to find new targets for therapy.
"Our laboratory has developed a K-ras mutation-based mouse model of pancreatic cancer that closely mimics the human disease. We have derived pancreatic cancer cell lines from these mice as a tool for discovering mechanisms of cell growth. Using RNA interference technology to knockdown K-RAS and abrogate its function, we have observed that cells in culture can persist and continue to grow, suggesting K-RAS independent means of pancreatic cancer cell growth. We plan to analyze these cells through various genetic and biochemical approaches to understand the important players in promoting growth in a K-RAS independent manner.
"Additionally, we propose to validate the results from our mouse cells in human pancreatic cancer cell lines derived from patient biopsies and surgical specimens. We will test drug inhibitors of pathways that mediate K-RAS independence in mouse models developed through the transplant of mouse and human pancreatic cancer cell lines directly into the pancreas of mice. Our mouse models provide a method for the preliminary testing of the safety and effectiveness of potential drug therapies prior to introduction into clinical trials for pancreatic cancer patients.
"We anticipate that our results will reveal new targets that may be amenable to drug therapy and provide advanced knowledge of mechanisms of resistance to K-RAS inhibitors when they become available."
Lisa A. Cannon-Albright, Ph.D.
Professor, University of Utah Health Science Center, Salt Lake City, UT
Informative Linkage Analysis of High-Risk Pancreatic Cancer Pedigrees
Nearly every person to be diagnosed with pancreatic cancer will eventually die from it, usually in less than four to six months. Not only does this highlight pancreatic cancer as a clinically significant disease, but it has also resulted in significantly limited resources for genome-wide linkage studies. About 10 percent of pancreatic cancer is recognized to have a familial component. Although pedigrees with multiple pancreatic cancer cases have been identified, they are typically small, and few DNA samples from cases are available. It is well recognized that the late age at onset and short survival have made it difficult or impossible to build resources of high-risk pancreatic cancer pedigrees. Since few collections of powerful high-risk pedigrees exist, informative linkage studies of high-risk pancreatic cancer pedigrees have not been performed.
Genome-wide association studies (GWAS) have been performed for pancreatic cancer. Such studies are expected to find common variants with low penetrance, but are not informative for rare variants. A rare variant(s) hypothesis may be one explanation for the relatively small amount of heritability that is explained by current GWAS findings in pancreatic cancer. An important aspect of this proposal is that an optimal search for genes affecting pancreatic cancer risk has not been completed. A genome-wide linkage scan could identify rare segregating variants.
“We will create the first powerful linkage resource for pancreatic cancer, making innovative use of existing resources in Utah. We will use a computerized genealogy of Utah, linked to cancer registration in Utah from 1966, to identify extended high-risk pancreatic cancer pedigrees. The difficulty will be in obtaining DNA samples for the cases in these extended pedigrees, most of whom are deceased. We will collect stored DNA samples from the two largest health care systems in Utah, together serving 80-90 percent of the state, which have collected and stored DNA and tissue samples for over six decades. We will identify and collect DNA samples from cases seen locally since 2000, and for all other cases we will extract DNA from normal tissue, stored as part of FFPE tissue blocks, from two statewide bio-repositories that together serve the entire state of Utah. The largest bio-repository has stored all tissue samples for over six decades, and serves 60-70 percent of Utah. We will identify and gather DNA samples in 15 informative extended high-risk pedigrees with at least six sampled cases each. We innovatively propose that sufficient genotyping data for a linkage analysis can be derived from these DNA samples, and that an informative linkage scan can thus be performed for the first time in multiple high-risk pancreatic cancer pedigrees.”
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James R. Eshleman, M.D., Ph.D.
Professor, Johns Hopkins University, School of Medicine, Baltimore, MD
Identifying Familial Pancreatic Cancer Predisposition Genes
Pancreatic cancer is generally a lethal cancer with a five-year survival of less than 5 percent. One bright spot is the discovery of several genes, in which defective copies are inherited and these are the direct cause of pancreatic cancer in these families. Since these genes are critical for one way that our cells repair DNA (so called double-strand break repair), and since the cancer cells have inactivated the second normal copy of the same gene, this creates a potential Achilles’ heel for the cancer. Parp inhibitor drugs inhibit a second type of DNA repair (single-strand break repair) and others have recently demonstrated that these drugs are synergistically toxic to cancer cells with double-strand break repair defects.
“We recently discovered another such gene by “brute force” sequencing all genes that a familial pancreatic cancer patient received at birth, in addition to all genes in their cancer. Based on the work of the human genome project, we were able to identify genes where this patient inherited one defective copy, and their cancer had mutated the second copy. In this way, we were able to identify the Partner and Localizer of BRCA2 (Palb2) gene.”
“Because of our longstanding interest in this problem, over the past eight years, the Eshleman lab has been producing familial pancreatic cancer cell lines. Using this panel of nine familial pancreatic cancer cell lines and the corresponding patient DNA, we will use the same approach to identify the predisposition gene defect in these cases. We will then confirm any candidate familial predisposition genes in a panel of 96 additional cases. This work only can be accomplished because of the Pancreatic Cancer Action Network-AACR Innovation Grant funding and an outstanding collaborative team, including Drs. Kinzler, Vogelstein, Velculescu, Klein, Goggins, Kern and Hruban.”
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Pancreatic Cancer Action Network-AACR Innovative Grant, in memory of Abby Sobrato
Mattias Hebrok, Ph.D.
Professor, University of California, San Francisco, San Francisco, CA
Role of miRNAs in Pancreatic Adenocarcinoma
“In this proposal, we aim to analyze the functions of novel regulators of gene activity in the development and progression of pancreatic adenocarcinoma (PDA). We have recently learned that micro RNAs (miRNAs), small sequences of nucleic acid, can affect the activity of a variety of other genes. We also know that the expression of these miRNAs changes during the initiation and progression of many cancers, including PDA. Therefore, miRNAs might not only serve as novel biomarkers for specific early stages of PDA formation, information that could be used for early diagnosis before the cancer has grown too big or already spread, but also to better understand what signaling cascades are activated at different stages. This latter information should be useful to instruct development of novel therapeutic strategies to combat this aggressive cancer in human patients.
In this proposal, we take advantage of extensive prior information that we have gathered in my laboratory with the aim to understand which miRNAs are expressed during what stages of cancer progression. Furthermore, others have previously established excellent mouse models in which all aspects of human PDA formation are present. In one of these mouse models, we have shown that elimination of miRNAs speeds up the development of metaplastic/pre-neoplastic tissue. Importantly, loss of miRNAs does block the progression towards cancer at a critical stage in these mice. Therefore, our results clearly indicate that miRNAs play different roles during early and late stages of this cancer.
In addition, we have developed tools in collaboration with colleagues at our university to eliminate individual miRNAs in a mouse model of PDA. This is a critical advance and we have already started to look at cancer formation in a transgenic mouse lacking one specific miRNA. The results are astonishing as they reveal a requirement for this particular miRNA to block the development of early defects associated with cancer formation. While this is a very interesting and encouraging result that demonstrates our strategy is working, we need to understand the function of this miRNA in more detail and propose to do so in this application.”
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Pancreatic Cancer Action Network-AACR Innovative Grant, in honor of the Kovler Family
Hidde L. Ploegh, Ph.D.
Professor, Whitehead Institute for Biomedical Research, Cambridge, MA
Generation of Transnuclear Mice from Pancreatic Cancer Infiltrating T Cells
“There is strong evidence that the immune system protects us from certain types of cancer. The immune system almost certainly evolved to deal with bacteria and viruses first and foremost, but there is increasing optimism that its discriminatory powers and precision of recognition may be used also to attack different types of cancer. It may even be possible to provide the immune system with the proverbial shot in the arm, so that it can fight cancers that would not normally be attacked by immune cells. To bring such methods closer to a practical application in man, animal models remain very important. Two post-docs, Oktay Kirak and Stepahnie Dougan, in a collaboration between my lab and that of Rudi Jaenisch, have applied a technique called somatic cell nuclear transfer to generate cloned mice (in a procedure not unlike that used to generate the cloned sheep Dolly) from immune cells. Such immune cells make use of indelible alterations in their genetic material to learn not only how to recognize foreign invaders (viruses, bacteria), but also cancer cells. We already have evidence that this technology can be used to study the immune response against melanoma, and we now intend to extend this approach to pancreatic cancer. At the Koch Center for Cancer Research/MIT, investigators led by Tyler Jacks have developed a mouse model for pancreatic cancer that should allow us to examine the presence and specificity of immune cells that recognize pancreatic cancer. Such cells will be "turned into mice" and should then serve as a small animal model for immune recognition of pancreatic cancer. Support from the Pancreatic Cancer Action Network will be used to launch these efforts.”
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Pancreatic Cancer Action Network-AACR Innovative Grant, supported by The Randy Pausch Family
Diane M. Simeone, M. D.
Professor, University of Michigan, Ann Arbor, MI
Targeting Notch Signaling in Pancreatic Cancer Stem Cells
"Pancreatic cancer is a deadly disease and current therapies remain largely ineffective. This may be due to the fact that existing therapies target primarily a cancer cell population with limited tumorigenic potential. Recent data supports the existence of pancreatic cancer stem cells (CSC), a small population of cancer cells with stem cell-like properties, that are resistant to chemotherapy and radiation. Recent preclinical studies in our laboratory suggest that targeting the notch signaling pathway may help eradicate pancreatic CSC within human pancreatic cancers. In this PanCAN-AACR Innovative Grant, we propose to characterize pancreatic CSC in a neoadjuvant clinical setting and to determine the effect of inhibition of notch signaling on that CSC compartment. We have received approval from the NCI (CTEP) to lead a multi-institutional neoadjuvant clinical trial to test the effects of the R0 gamma secretase inhibitor on patient outcomes and CSC metrics in human patients. Eligible patients with resectable pancreatic cancer will be randomized to receive either the notch inhibitor R0 or placebo for two weeks. Operative evaluation and surgical resection will occur on week three. Resected surgical specimens from the treatment and the placebo groups will be compared and analyzed for extent of Notch inhibition and effects on pancreatic CSC number and function. Following resection and recovery, patients in the RO arm of the trial will receive adjuvant RO and gemcitabine compared to the control arm which will receive gemcitabine alone. Clinical outcomes will be measured. This grant will support the translational research accompanying this clinical trial."
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Amy H. Tang, Ph.D.
Assistant Professor, Eastern Virginia Medical School, Norfolk, VA
SIAH is a Novel and Effective anti-K-RAS Drug Target in Pancreatic Cancer
"Hyperactive K-RAS signaling is a major menace that drives aggressive tumor growth and metastasis in pancreatic cancer. Currently, there are no effective ways to treat pancreatic cancers that have oncogenic K-RAS mutations that confer drug resistance, aggressive tumor growth and metastasis and poor clinical outcome. Therefore, finding effective means and new molecular targets to inhibit oncogenic K-RAS is an urgent goal and major challenge in pancreatic cancer therapy. Hyperactive K-RAS protein acts like a car’s gas pedal that is permanently stuck in the ACCELERATION position and propels the pancreatic cancer cells to grow and metastasize uncontrollably. Instead of targeting the upstream signaling modules, we attempt to stop “such runaway cars” by attacking the downstream signal transmission – the SIAH E3 ligases – in the K-RAS signaling pathway, and find that an anti-SIAH-based anti-K-RAS strategy is very effective in stopping pancreatic tumorigenesis and metastasis. Through our work, SIAH has begun to emerge as a new and effective drug target against oncogenic K-RAS activation in pancreatic cancer. Using anti-SIAH molecules to block K-RAS signaling in human pancreatic cancer is an excellent example of science going “from the bench (basic science in fruit flies) to the bedside (preclinical and ultimately clinical studies)." Arising from the extensive genetic studies of the RAS signal transduction pathway in Drosophila, SIAH is uniquely positioned to become the next generation anti-K-RAS drug target. Our preclinical studies have demonstrated that “SIAH-dependent proteolysis” is an Achilles' heel in human pancreatic cancer. Albeit at an early preclinical stage, knowledge gained from this study has great promise and immediate translational value. Inhibiting SIAH function may represent an innovative way to inhibit K-RAS activation, halt tumor growth and metastasis and provide novel strategies for therapeutic intervention in pancreatic cancer. This generous AACR grant will endow us with a coveted opportunity to contribute to the great mission of AACR-Pancreatic Cancer Action Network to accelerate pancreatic cancer research as fast as possible."