UAB/UMN SPORE in Pancreatic Cancer
The SPORE program in pancreatic cancer at the University of Alabama at Birmingham, led by PI, Dr. Buchsbaum, Director of Radiation Biology and Selwyn Vickers, M.D. (formerly of UAB) chair Department of Surgery University of Minnesota. The projects and supporting infrastructure stem from the cancer center's expertise, including tumor biology, virology/gene therapy, immunobiology and targeted immunotherapy. Specific research projects draw from previously established efforts that have demonstrated the most relevance and promise.
The UAB/UMN SPORE in Pancreatic Cancer is committed to reducing the morbidity and mortality of pancreatic cancer. Our intent is to take major advantage of the scientific expertise, resources, and patient populations of two productive Comprehensive Cancer Centers (UAB and UMN) in pursuit of our interdisciplinary and translational pancreatic cancer research efforts. Our research efforts include biomarker discovery for early stage disease, diagnosis and progression (Project 1 and 3) and novel therapeutic strategies (Projects 2, 3, 4) as our major goals. Both UAB and UMN have identified institutional funds to recruit pancreatic cancer clinician-scientists as well as funds together with the SPORE to fund Developmental Projects and Career Development to further expand our pancreatic cancer agenda.
Project 1 — Biomarker Discovery for Early Detection of Pancreatic Ductal Adenocarcinoma
Christopher Klug, Ph.D.
This project began as a UAB/UMN SPORE in Pancreatic Cancer pilot project to develop a transgenic model with loss of Smad4 and activating KrasG12D mutation which was accomplished and promoted the development of pancreatic adenocarcinoma. This funding also allowed acquisition of several established Kras mutation models. Drs. Klug, Posey, and Mobley devised a novel strategy using transgenic mouse models and cutting edge proteomic technology to develop biomarkers for the detection of early stage pancreatic cancer.
Project 2 — Combined Modality Targeted Therapy of Pancreatic Cancer with Death Receptor Monoclonal Antibodies
Donald J. Buchsbaum, Ph.D.
James Posey, III, M.D.
This project is led by Drs. Don Buchsbaum, James Posey, Tina Wood, and Patsy Oliver. It was part of the original SPORE program funded in 2004 and is a continuation of that anti-DR5 research and clinical trials resulting from that work. This project team initially studied the biology of epidermal growth factor receptor (EGFR) and demonstrated the efficacy of combining C225 (Erbitux; anti-EGFR) with chemoradiotherapy (gemcitabine and external beam radiation) in an animal model of pancreatic cancer. Through a funding supplement from the NCI SPORE program, the team carried out a Phase I trial of Erbitux, gemcitabine and radiation for treatment of newly diagnosed cases of loco-regional pancreatic cancer at both UAB and UMN which is completed. This group concurrently began the study of a UAB generated anti-death receptor 5 monoclonal antibody (TRA-8) as a potential therapeutic agent in pancreatic cancer. Pancreatic cancer cell lines expressed DR5 and were variably sensitive to TRA-8 mediated cytotoxicity and in vivo anti-tumor efficacy in animal models. In orthotopic pancreatic cancer models, gemcitabine or CPT-11 dramatically enhanced TRA-8 efficacy. With our industry partner (Daiichi Sankyo) who developed a humanized version of TRA-8 (CS-1008), we carried out a Phase I trial in patients with metastatic cancer (single institution, UAB). We then wrote and implemented a multi-institutional Phase II trial in newly diagnosed metastatic pancreatic cancer patients with CS-1008 plus gemcitabine. This trial completed enrollment at UAB, UMN, and 6 other institutions and is currently in follow-up.
Project 3 — Identifying and Targeting Pathways of Pancreatic Cancer Progression and Metastasis
David A. Largaespada, Ph.D.
David Tuveson, M.D., Ph.D.,
Christine Iacobuzio-Donahue, Ph.D.
The overall objective of this project is to utilize genomic and genetic data obtained from human pancreatic cancer samples and observations from mouse models of pancreatic cancer to understand the genetic events that drive tumor progression and treatment resistance in this disease. These mouse models include recent observations about pancreatic cancer genesis and novel Sleeping Beauty transposon-based, forward genetic screens for pancreatic cancer. The human pancreatic cancer samples have been obtained from a novel collection via a rapid autopsy program developed by Dr. Iacobuzio-Donahue and fine needle aspirations (FNA) obtained by members of the UAB/UMN SPORE in Pancreatic Cancer. These samples are being profiled for genetic alterations and markers identified in the mouse models. This has provided insight into the genetic drivers of pancreatic cancer development and candidates for causing specific pancreatic cancer phenotypes such as metastatic spread. We will discover novel genetic correlates of tumor progression, metastasis, and outcome using gene copy number, mRNA levels, sequence alterations and immunohistochemistry. Functional validation of novel targets will take place using gene overexpression or shRNA gene “knockdown” in pancreatic cancer cell lines, xenografts, and mouse transgenic models. Moreover, these multi-dimensional data will be the basis for investigating pharmacological suppression of pathways that cooperate to drive pancreatic cancer development and progression. Our initial focus is on a novel regulator of the TGF-beta and other pathways called Usp9x, and PTEN-regulated pathways. These experiments will set the stage for new clinical trials for pancreatic cancer.
Project 4 — Development of Oncolytic Adenovirus Targeting Pancreatic Cancer Stem Cells
David Curiel, M.D., Ph.D.
Masato Yamamoto, M.D., Ph.D.
The poor response of existing treatment options for unresectable pancreatic cancer is the result of a subset of cancer cells exhibiting chemoresistance. Evidence has shown that the capacity of a tumor to grow and propagate is dependent on this small subset of cells, identified as pancreatic cancer stem (or stem-like) cells (CSCs). Due to their vital role in tumor maintenance and the formation of metastases, CSCs are integral targets to treat pancreatic cancer, as current therapeutic regimens cannot effectively treat this cell population because of its intrinsically resistant nature. Adenovirus-based oncolytic viruses have unique advantages for targeting and eradicating pancreatic CSCs along with inclusively targeting the general pancreatic cancer cell population and thereby represent a promising novel therapeutic strategy. Adenovirus replication specificity can be achieved by placing viral replication genes under the control of tumor-specific promoters, thereby generating conditionally replicative adenoviruses (CRAds). The keys to developing a pancreatic cancer CRAd that inclusively targets CSCs are: 1) effective transduction and 2) replication specificity of pancreatic cancer cells and CSCs. We have developed innovative strategies and breakthrough technologies which can be rapidly applied for designing such CRAds. Our advanced infectivity enhancement strategies allow efficient transduction of pancreatic cancer cells and CSCs. To confer replication specificity, we have developed the CXCR4 promoter as a CRAd replication control element. CXCR4 expression is a signature of pancreatic cancer and CSCs. SA 1: To construct infectivity-enhanced, CXCR4 promoter controlled CRAds for pancreatic cancer, inclusively targeting pancreatic CSCs. SA 2: To validate the efficacy of CRAds with in vitro models of chemoresistant pancreatic CSCs. SA 3: To demonstrate efficacious targeting and replication of CXCR4 CRAds with in vivo models of pancreatic cancer. SA 4: To validate the efficacy and specificity of pancreatic CSC-targeted CRAds with primary CSCs derived from human patient tumors. Development of an effective therapy for the advanced pancreatic cancer is predicated on efficiently targeting and eradicating pancreatic CSCs, which represent the chemoresistant nature of this disease. The strategy proposed herein, of exploiting CRAd agents based on the CXCR4 axis to inclusively target pancreatic CSCs offers a promising treatment approach. On the basis of these studies, we will thus understand the direct utility of our novel system for clinical application and will facilitate a rapid clinical translation. We will submit an IND application concurrently with this proposal to rapidly translate the agents herein for clinical trial.