The American Pancreatic Association/Hirshberg Foundation Symposium Celebrating the 10th Anniversary of the Seed Grant Program

Abstract

The Hirshberg Foundation for Pancreatic Cancer Research was founded by Agi Hirshberg in 1997, following her husband Ronald Hirshberg’s 8-month, 7-day battle with the disease. (http://www.pancreatic.org/). At the time, the Hirshberg family viewed pancreatic cancer as the “unknown enemy” (http://www.pancreatic.org/site/c.htJYJ8MPIwE/b.8276835/k.66CB/Agi_Hirshbergs_Story.htm). In the years since Ronald Hirshberg’s death, Agi Hirshberg has made it her mission to unmask the unknown for others facing the same enemy. When patients present with a new diagnosis of pancreatic cancer, most are already in an advanced stage of the disease. Pancreatic cancer is resistant to most chemotherapeutic agents and radiotherapy. These factors combine to make pancreatic cancer a highly lethal disease, and according to the National Cancer Institute (NCI) 2013 estimates, pancreatic cancer was diagnosed in approximately 45,220 US citizens, and some 38,460 died of the disease.1 The Annual Report to the Nation on the Status of Cancer, 1975–2009, shows that overall cancer death rates continued to decline in the United States among both men and women, among all major racial and ethnic groups, and for all of the many common cancer sites, including lung, colon and rectum, female breast, and prostate. However, this trend does not hold true for pancreatic cancer. The report demonstrates that death rates continued to increase during the latest time period (2000 through 2009) for pancreatic cancer.2 Only about 23% of patients with cancer of the pancreas will still be living 1 year after diagnosis, and only about 4% will survive 5 years. Even for those diagnosed with pancreatic cancer that has not spread to other organs or systems, the overall 5-year survival rate approaches only 15%. The Hirshberg Foundation’s vision is to advance pancreatic cancer research and provide information, resources, and support to pancreatic cancer patients and their families. The mission of the Foundation is as follows: To find a cure for pancreatic cancer in honor of Ron Hirshberg and the thousands of people who are diagnosed with this disease each year. To create a premier Pancreatic Cancer Center where all needs of pancreatic cancer patients can be met in one location with the most advanced treatment options. To be recognized as a patient support reference source for pancreatic cancer patients and their families. To fund projects and programs designed to improve patient care, treatment, and, ultimately, pancreatic cancer survival rates. To integrate and unite generations, young and old, through physical fitness participation, while creating public awareness and raising money to find a cure for pancreatic cancer.3 The Foundation began by funding 2 key research projects at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). The Foundation first established the Ronald S. Hirshberg Translational Pancreatic Cancer Research Laboratory under the directorship of Dr Howard Reber and then created the Ronald S. Hirshberg Chair in Translational Pancreatic Cancer Research, which was awarded to Prof Enrique Rozengurt. Since then, the Foundation has continued its research commitment to the pancreatic cancer research program at UCLA. HIRSHBERG FOUNDATION SEED GRANT PROGRAM In 2003, the Foundation launched its national Seed Grant program. Ms Agi Hirshberg stated that the Hirshberg Foundation’s efforts have “significantly raised awareness and understanding of the biology, treatment, and prevention of pancreatic cancer, a disease that continues to be one of the most fatal and least funded of all cancer types.”4 The NCI spent only 0.9% ($42,300,000) of its approximate $4.6 billion cancer research budget on pancreatic cancer in 2003, when the program began.5 The aim of the program is to increase interest and investment in research by recruiting established scientists and encouraging new investigators to enter the field. The seed grants are designed to allow researchers in all fields to develop the preliminary data necessary to pursue additional funding from the National Institutes of Health (NIH) and other funding agencies. The Foundation established a national Scientific Advisory Board chaired by Vay Liang W. (Bill) Go, with Laszlo G. Boros, MD; Murray Korc, MD; Laurence J. Miller, MD; Stephen J. Pandol, MD; Howard A. Reber, MD; Lee S. Rosen, MD; and Diane M. Simeone, MD. Ashok Saluja, PhD and Anirban Maitra, MD, joined the board in 2014. The number of seed grant applications has quadrupled since the initial 12 applications received in 2003. The Scientific Advisory Committee reviews and assigns priority scores for all submitted seed grant applications based on the NIH review and funding guidelines, and the Foundation makes the final award decision. The seed grant recipients are listed in Table 1. To date, the program has provided more than $5 million in seed grants to research programs involving the molecular mechanism of pancreatic cancer, early diagnosis, surgical and chemotherapeutic management, psychosocial approaches, and prevention strategies. The yearly recipients are invited to present their research at the annual Agi Hirshberg Symposium on pancreatic cancer research held at the UCLA Faculty Center. Previous presentations and videos are available on the Hirshberg Foundation Web site. The Hirshberg Seed Grant recipients have contributed significantly to pancreatic cancer research and have generated more than $45 million in additional grant support from the NIH and other funding agencies to support their research programs to date.TABLE 1: Seed Grant RecipientsThe Foundation has funded Seed Grant Award recipients at such institutions as Beth Israel Medical Center; City of Hope; Columbia University; Dana-Farber Cancer Institute; Duke University Medical Center; Fox Chase Cancer Center; Harbor–UCLA Medical Center; Harvard Medical School; Johns Hopkins University; Loma Linda University; Massachusetts General Hospital; Mayo Clinic and Mayo College of Medicine; MD Anderson; Memorial Sloan-Kettering Cancer Center; Tel Aviv University; Thomas Jefferson University; University of Arizona Cancer Center; University of California, Los Angeles; University of California, San Diego; University of Southern California; University of Minnesota; University of Pittsburgh; and Vanderbilt Medical School. Highlights of some supported studies include genetic markers in saliva associated with pancreatic cancer, the potential role of fructose in helping pancreatic cancer cells to multiply, the role of the antidiabetic drug, metformin, on inhibiting pancreatic cancer cell growth, key molecular and cellular pathways that control pancreatic cancer cell growth and survival, the microenvironment for pancreatic cancer cell growth and the interaction with inflammatory processes, the efficacy of phytonutrients to inhibit pancreatic cancer development and growth in preclinical models and human clinical trial studies, and the role of dietary factors, obesity, and diabetes mellitus in pancreatic cancer prevention. The Seed Grant program has fulfilled its mission by bringing new investigators into the field and also promoting collaboration between investigators from different disciplines. The Seed Grant program has been an important part of this effort during the last 10 years and will continue to provide an essential contribution to pancreatic cancer research in the years to come. THE AMERICAN PANCREATIC ASSOCIATION/HIRSHBERG FOUNDATION SYMPOSIUM CELEBRATING THE 10TH ANNIVERSARY OF THE SEED GRANT PROGRAM The 10th Annual Agi Hirshberg Symposium was presented in 2 parts. The scientific portion occurred at the 44th annual meeting of the American Pancreatic Association (APA) in Miami, Fla, from October 30 to November 2, 2013. The patient support portion was held at the UCLA Faculty Center on February 8, 2014, in collaboration with the UCLA Center for Pancreatic Diseases. The patient support symposium focused on the current state of the art in pancreatic cancer management. The 2013 APA annual meeting started with the Hirshberg Foundation Key Note Symposium on October 30, 2013, which focused on paraneoplastic metabolic complications of pancreatic cancer and followed with the celebration of the 10th anniversary of the Foundation seed grant program on November 2, 2013. Previous seed grant awardees were selected to present their scientific contributions on the mechanics of carcinogenesis, therapeutic advances, and the early detection and prevention of pancreatic cancer. HIRSHBERG FOUNDATION KEYNOTE SYMPOSIUM PARANEOPLASTIC METABOLIC COMPLICATIONS OF PANCREATIC CANCER The 2013 APA annual meeting started with the Hirshberg Foundation keynote symposium on paraneoplastic metabolic complications of pancreatic cancer. Agi Hirshberg began the proceedings by outlining the history of the Foundation with an emphasis on the important partnerships with the APA, European Pancreatic Club, and the Japan Pancreas Society. Suresh Chari, MD, of the Mayo Clinic spoke on paraneoplastic diabetes in pancreatic cancer followed by Michael J. Tisdale, PhD, from Aston University, Birmingham, United Kingdom, on the mechanism and treatment of cachexia in patients with pancreatic cancer and concluded with F. Charles Brunicardi, MD, PhD, from UCLA on the vertically integrated translational studies of pancreatic and duodenal homeobox 1 (PDX1) as a therapeutic target for pancreatic cancer via a novel bifunctional RNAi platform. Here are the highlights of their respective presentations. Paraneoplastic Diabetes in Pancreatic Cancer by Suresh T. Chari, MD, Mayo Clinic College of Medicine, Rochester, Minn There is growing evidence that pancreatic cancer causes diabetes. About 50% to 67% of pancreatic cancer patients have diabetes, and another 35% have impaired glucose tolerance. Diabetes usually manifests in the 3 years before pancreatic cancer diagnosis. New-onset diabetes in pancreatic cancer resolves with cancer resection. Conversely, the risk of pancreatic cancer in new-onset diabetes is about 8-fold higher than in the general population. Epidemiologic and experimental evidence strongly suggests that diabetes in pancreatic cancer is a paraneoplastic phenomenon caused by tumor secreted products. β Cell dysfunction and peripheral insulin resistance are seen in type 2 diabetes as well as pancreatic cancer–associated diabetes. However, in contrast to type 2 diabetes, onset and progression of glucose intolerance in pancreatic cancer–induced diabetes occur paradoxically in the face of ongoing, often profound, weight loss. Recently, adrenomedullin, which is overexpressed in pancreatic cancer, was reported as a potential mediator of β-cell dysfunction. Selective loss of subcutaneous adipose tissue with preservation of visceral adipose tissue may explain lack of improvement in diabetes despite weight loss. We believe that the extremely high prevalence of hyperglycemia in pancreatic cancer is not accidental or incidental, but rather an adaptive mechanism developed by the tumor to counter a hostile tumor microenvironment low in oxygen and glucose. Understanding the mechanism and mediators of pancreatic cancer–induced diabetes mellitus could lead to identification of novel biomarkers for early diagnosis of the cancer. However, to cost-effectively screen for pancreatic cancer, the cohort of new-onset diabetes will need further enrichment for pancreatic cancer. In a Mayo study (EXamination of the PAncreas in New Diabetes [EXPAND]), we will identify 1000 subjects older than 50 years with new-onset diabetes (“first sieve”), of whom 100 with weight loss and/or elevated CA-19-9 (“second sieve”) will be screened for pancreatic cancer using endoscopic ultrasound. To rapidly bring this strategy to clinical practice, additional studies better defining the first and second sieves are urgently needed. Mechanism and Treatment of Cachexia in Patients With Pancreatic Cancer by Michael J. Tisdale, PhD, School of Life and Health Sciences, Aston University, Birmingham, United Kingdom Eighty-five percent of patients with pancreatic cancer experience a wasting syndrome called cachexia, with loss of adipose tissue and skeletal muscle and eventually death when the weight loss reaches 30%. There are several proposed mediators of the cachectic process including cytokines (tumor necrosis factor α, interleukin 6, interleukin 1, and interferon γ) and tumor catabolic products such as a lipid-mobilizing factor and proteolysis-inducing factor (PIF). Our own studies have concentrated on the latter factors. Most investigators agree that loss of body fat in cachectic subjects is due to an increase in lipolysis. Extracts of the MAC16 tumor, which produces cachexia in mice, as well as urine from patients with pancreatic cancer showed evidence for a lipid-mobilizing factor, and on purification, this was shown to be zinc-α2-glycoprotein (ZAG), a known protein with unknown function. Zinc-α2-glycoprotein is produced not only by cachexia-inducing tumors, but also by adipose tissue (both white [WAT] and brown [BAT]), and mRNA for ZAG is increased up to 10-fold in animals and cancer patients with cachexia. In contrast, expression is low in obese humans. Zinc-α2-glycoprotein mRNA shows a negative correlation with body mass index, but a positive correlation with weight loss. In obese mice, ZAG produces selective loss of body fat by an increased heat generation through increased expression of uncoupling proteins (UCP-1 and UCP-3) in BAT and skeletal muscle. Loss of skeletal muscle in cachexia arises from an increase in protein degradation and/or a decrease in synthesis. Studies on the MAC16 tumor in mice identified PIF, which is also present in the urine of patients with pancreatic cancer and lung tumors of patients with cachexia. In mice, PIF causes loss of lean body mass through an increase in protein degradation through the ubiquitin-proteasome pathway and a decrease in synthesis. Clones of a human breast tumor expressing short hairpin RNA (shRNA) to the PIF core peptide showed no expression of PIF and no loss of body weight when transplanted into nude mice, whereas the vector control produced progressive weight loss. Eicosapentaenoic acid attenuates PIF-induced weight loss in mice and weight reduction in both experimental animals and pancreatic cancer patients with cachexia. Clinical studies show this increase in body weight is due to an increase in lean body mass. Vertically-Integrated Translational Studies of PDX1 as a Therapeutic Target for Pancreatic Cancer Via a Novel Bifunctional RNAi Platform by F. C. Brunicardi, MD, PhD, UCLA David Geffen School of Medicine, Los Angeles, Calif Pancreatic and duodenal homeobox 1 regulates embryonic pancreatic development, β-cell maturation, normal β-cell function, and most recently pancreatic cancer. Short hairpin RNA is synthetic molecules that mimic endogenous siRNA, involved in gene silencing. Mouse and human bifunctional (bi)-shRNAPDX1 was developed using mouse and human PDX1 gene sequences accessed via GenBank. Human pancreatic cancer cell lines, PANC1 and MIA PaCa2, as well as PDX1 overexpressing HEK293 cells were used to form xenograft tumors in SCID mice. Murine models of islet hyperplasia and insulinoma, SSTR1/5(−/−) and SCID mice with implanted β TC-6 cells, were also studied. Study mice received 3 intravenous infusions of bi-shRNAPDX1. Yucatan miniature pigs were administered a single intravenous infusion of Good Medical Practice–quality bi-shRNAPDX1 to evaluate safety in a biorelevant large animal model. Systemic infusion of human bi-shRNAPDX1 ablated the xenograft tumors in mice and led to increased survival. Systemically delivered mouse bi-shRNAPDX1in SSTR1/5(−/−) mice and mice with insulinoma resulted in mild, temporal hyperglycemia and decreased insulin secretion, followed by return to baseline levels. Single infusion of Good Medical Practice–bi-shRNAPDX1 was well tolerated in pigs with premedication with no signs of acute toxicity. Bifunctional shRNAPDX1 suppressed PDX1 expression in pig islets but did not alter circulating insulin and glucose levels. Bifunctional shRNAPDX1 successfully treats human xenograft tumors in mice and exhibits minimal off-target effects on glucose metabolism. Future toxicology studies are planned to justify a phase I clinical trial. APA/HIRSHBERG FOUNDATION SYMPOSIUM CELEBRATING 10 YEARS OF THE SEED GRANT PROGRAM Agi Hirshberg welcomed the participation of the APA in the celebration of the 10th anniversary of the seed grant program and on its accomplishments. The presenters were all former awardees of the seed grant program. The symposium included keynote speeches by Anirban Maitra, MD, Ashok Saluja, PhD, and Diane Simeone, MD. The presentations covered mechanism and carcinogenesis, therapy and early detection, prevention, and stratification of pancreatic cancer. Pancreatic Cancer—Making Mountains Out of Genomic Molehills by Anirban Maitra, MD, Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research University of Texas MD Anderson Cancer Center The sequencing of the pancreatic cancer genome has identified somatic mutations of KRAS as the most preponderant alteration in this neoplasm, but unlike lung cancer or melanomas, no major subsets have emerged in terms of actionable mutations. Therapeutic targeting of mutant KRAS (mtKRAS) per se has not been successful in the clinic, although significant research efforts are underway to develop novel targeting strategies, including a concerted federally funded project at the NCI. In the interim, blocking proximate downstream effectors of oncogenic KRAS, particularly as combination therapies to account for compensatory pathway activation, remains a tractable choice that is being explored in the clinic. While mtKRAS remains the big “enchilada” in pancreatic cancer, parsing the genomic data does identify other minor subsets (“genomic molehills”) with potential for therapeutic intervention. The best cited example is biallelic loss-of-function mutations of the Fanconi anemia genes, which render the neoplastic cells exquisitely sensitive to poly (ADP-ribose) polymerase inhibitors or platinum agents. Other minor subsets include tumors with activating mutations of ERBB2, tumors that are wild type for KRAS, and those with alterations of the PIK3CA pathway. Given the relative infrequency of these alterations, it is unlikely that one can conduct pancreatic cancer–centric clinical trials that would require a priori documentation of any given somatic mutation. Instead, a more pragmatic approach might be to conduct “basket” trials that are tumor agnostic and enroll by mutational profile. An unexplored dimension in pancreatic cancer pertains to the significant subset (25%–30%) of tumors that harbor loss of function mutations of chromatin modifying genes, such as MLL3, MLL2, ARID1A, KDM2B, and so on. Genetically engineered models recapitulating these mutations should provide a platform for co–clinical trials, to identify therapeutic targets that are synthetic lethal to these loss of function mutations. Acetylation of Mutant KRAS Lysine 147 Is an Oncogenic Posttranslation Modification Directed by SIRT2 by David Gius, MD, PhD, Department of Radiation Oncology, Robert Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Ill KRAS activating mutations are present in up to 35% of lung adenocarcinomas; however, as is observed in other human malignancies, additional aberrant genetic and/or biochemical events are required for carcinogenesis. In addition, it has been shown that mtKRAS activity in lung cancer cells, whether mouse or human, is highly elevated, as compared with adjacent, untransformed cells with similar mtKRAS levels. These observations point to the importance of mtKRAS enzymatic activity in lung and pancreas adenocarcinoma and imply that modulating enzymatic activity influences carcinogenesis. Thus, our results suggest that cells lacking Sirt2, or exhibiting decreased SIRT2 activity, will have increased aberrant mtKRAS acetylation and enzymatic activity, and this plays a role in the establishment of an adenocarcinoma permissive phenotype. A significant percentage of human lung and pancreas adenocarcinomas contain mtKRAS protein, and mice lacking SIRT2 develop lung adenocarcinomas suggesting a potential mechanistic oncogenic connection. SIRT2 interacts with, deacetylates, and directs mtKRAS enzymatic activity. Mass spectrometry and an anti–KRASAc-K147 antibody showed that SIRT2 deacetylates KRAS lysine 147, and a substitution mutant (KRASG12D to KRASG12D-K147Q) that mimics an acetylated lysine, exhibited increased enzymatic activity and a more in vitro transformed phenotype. Sir2−/−KrasG12D mice exhibited lung and pancreas tumors earlier than the KrasG12D mice. Finally, anti–KRAS-Ac-K147 antibody staining tumors showed increased mtKRAS acetylation in the murine Sirt2−/−KrasG12D and KrasLSL tumors and human lung and pancreas adenocarcinoma samples. These results suggest that mtKRAS contains a potential oncogenic acetyl-lysine posttranslation modification. The Increasingly Important Roles of Posttranscriptional Regulation in Pancreatic Cancer by Isidore Rigoutsos, PhD, Jefferson Medical College, Thomas Jefferson University Pancreatic cancer remains one of the most lethal types of cancer despite tremendous progress in elucidating the molecular events of pancreatic tumorigenesis. Over the years, research efforts focused largely on the genetic aspects of the disease. By comparison, the contributions beyond genetic and transcriptional events remained underexplored. MicroRNAs (miRNAs) are short noncoding RNAs approximately 22 nts in length that are potent mediators of posttranscriptional regulation. MicroRNAs target messenger RNAs in their untranslated and amino acid coding regions in a sequence-dependent manner. MicroRNAs also bind pseudogenes and other noncoding RNAs. Posttranscriptional regulation by miRNAs exhibits tissue- and cell-state–dependent characteristics and is critical to many fundamental biological processes. Links to miRNAs have been demonstrated in development, neurodegeneration, immunity, aging, many cancers, and so on. Consequently, “signatures” composed of dysregulated miRNAs have been determined for many of these contexts including pancreatic cancer. We and others have been generating evidence for several years, in both human and mouse, that the “canonical model” of miRNA targeting is incomplete and that a far more complex “expanded model” is at work: according to the latter, miRNAs regulate many more genes than originally believed and do so through more complex and intricate interactions. Recent technological and methodological advances now make it possible to begin improving our mechanistic understanding of the rules that govern miRNA regulation of the transcriptome in pancreatic cancer and in other settings. Using a combination of newly developed computational methods and Ago CLIP-seq (=deep sequencing of RNA after UV cross-linking and immunoprecipitation with an Ago antibody) in pancreatic cancer cell lines, we uncovered unexpected facets of miRNA activity with far-reaching implications about the roles of miRNAs. Our findings confirm that the “expanded model” is in effect in pancreatic cancer cells and provide a solid foundation for an in-depth exploration of these posttranscriptional aspects of the disease process and their relationships to chemotherapeutic efficacy and resistance mechanisms. An Emerging Novel Therapy Against Pancreatic Cancer: Minnelide by Ashok K. Saluja, PhD, University of Minnesota Pancreatic cancer is one of the most lethal human malignancies, with an all-stage 5-year survival of less than 5%, a number that highlights the urgent need for more effective therapeutic strategies. Our studies have shown that triptolide, a diterpenoid, is effective against pancreatic cancer cells in vitro as well as in vivo. However, triptolide is poorly soluble in water, limiting its clinical utility. We have recently synthesized a water-soluble prodrug of triptolide, Minnelide, which has shown tremendous promise in preclinical studies. Since its synthesis, Minnelide has been extensively evaluated in preclinical studies. In orthotopic mouse models with very aggressive cell lines, the Minnelide-treated mice showed a definite regression and reduction in tumor burden. A survival study analysis showed that untreated mice had a median survival of 36 days, whereas mice treated with Minnelide continued to live for a year. In the same study, the tumors did not recur even when treatment with Minnelide was discontinued. Similar studies using human tumor xenografts implanted and propagated in mice also showed a dramatic decrease in tumor volume when treated with Minnelide. Tumors as large as 1 cm3 in volume regressed on treatment with Minnelide. Our studies also showed that prolonged Minnelide treatment did not result in any obvious toxicity in the animals, and the tumors did not recur even when treatment was stopped. Although Minnelide has been extremely efficient in inducing pancreatic cancer cell death, the signaling pathways leading to this are still unclear. Previous studies have demonstrated that Minnelide down-regulates the prosurvival protein heat shock protein 70 (HSP70). We have now unraveled the relationship between several pro-proliferation pathways that are targeted by triptolide leading to down-regulation of HSP70, eventually leading to cell death. Our studies have shown that triptolide induces endoplasmic reticulum (ER) stress and inhibits nuclear factor κB (NF-κB), thereby affecting 2 pathways that play a prominent role in carcinogenesis. Furthermore, our data suggest that triptolide affects these 2 pathways by down-regulating specificity protein 1 (Sp1). Specificity protein 1 is a transcription factor that is not expressed in terminally differentiated pancreatic cells but is overexpressed in pancreatic cancer cell lines. Both NF-κB and ER stress proteins are regulated by transcriptional activity of Sp1. Triptolide inhibits the activity of Sp1 leading to down-regulation of NF-κB on one hand and induction of ER stress on the other hand. This leads to down-regulation of HSPs and results in lysosomal membrane permeabilization, which culminates in cell death. Our study shows for the first time that triptolide-induced cell death in pancreatic cancer is mediated by down-regulation of prosurvival pathways (like ER stress, HSP70, and NF-κB) controlled by Sp1. This molecular analysis of the mode of action of triptolide or Minnelide is of great usefulness in delineating its biological function as it is undergoing phase 1 clinical trials since August 2013. Insights Into the Translation of HSP Inhibitors to the Treatment of Pancreatic Cancer by Gabriela Chiosis, PhD, Memorial Sloan-Kettering Cancer Center, New York, NY The development of a malignant phenotype is associated with dysregulation of multiple pathways and molecules. To adapt, cells co-opt HSPs to help maintain a functional cellular state under the transforming pressure. Among the major HSPs are HSP90 and HSP70, proteins that act in an interconnected but also distinct fashion to regulate and maintain the disease phenotype. In pancreatic cancer, these HSPs have a major role in maintaining the altered signaling pathways and the elevated antiapoptotic threshold characteristic of these tumors. Consequently, approaches that target these HSPs are especially promising for inclusion in the pancreatic cancer treatment regimens. This talk will present some of our efforts in the design, development, and clinical translation of HSP inhibitors and in the rational selection of pancreatic patients who are more likely to draw a benefit from such drugs. Novel Therapeutic Targets (EphB4, Axk, GRP78) in Pancreatic Cancer by Parkash Gill, MD, University of Southern California, Los Angeles, Calif Locally advanced or metastatic pancreatic carcinoma is primarily treated with cytotoxic chemotherapy. Most recent entries to these agents include Abraxane and Erbitux. Understanding the genetic basis and pathways activated in pancreatic carcinoma provides opportunities to develop novel therapeutics. We are investigating 2 novel targets, which include receptor kinases EphB4 and GRP78. EphB4 receptor kinase is aberrantly expressed in tumor cells, and its ligand EphrinB2 is expressed in the tumor endothelial cells. EphB4-EphrinB2 interaction leads to bidirectional signaling promoting tumor cell survival and progression. We are investigating the induction of EphB4 in pancreatic ductal adenocarcinoma (PDAC) in spontaneous tumor model in which mtKRAS is induced, and p53 is deleted. Preliminary data support the hypothesis. Second, we are investigating if the deletion of EphB4 in the same cells will reduce the development of PDAC. Once proven, we will investigate the efficacy of blocking EphB4-EphrinB2 interaction and signaling using decoy soluble EphB4 receptor extracellular domain (sEphB4) fusion protein containing full-length human serum albumin (sEphB4HSA). Albumin fusion promotes drug delivery into the tumor and markedly enhances pharmacokinetics. sEphB4HSA has potent antitumor activity as a single agent and when combined with gemcitabine in orthotopic models. Studies will become the basis for the conduct of clinical investigation in patients with pancreatic carcinoma. GRP78, a stress response protein, is highly induced in pancreatic cancer. GRP78 also translocates from the ER to the tumor cell surface where it interacts with several membrane proteins and activate PI3K pathway. Genetic deletion of GRP78 attenuates several genetically defined spontaneous tumor models. We are thus targeting surface GRP78 as a potential therapeutic agent. We have identified a monoclonal antibody that binds surface GRP78 with high affinity, induces endocytosis and degradation, and inhibits PI3K signalin