Pancreatic Cancer Action Network Research Grants
Pancreatic Cancer Action Network Translational Research Grant
The Pancreatic Cancer Action Network Translational Research Grants support independent investigators conducting translational research that has as its endpoint the development of a pancreatic cancer assessment, prevention, or treatment modality.
Principal Investigator: David Allen Boothman,
Associate Director for Translational Research
University of Texas Southwestern Medical Center
Co-Principal Investigator: Muhammad Beg,
Assistant Professor, Internal Medicine
University of Texas Southwestern Medical Center
Use of PARP1 inhibitors to leverage a tumor-selective "kiss of death"
The mission of this proposal will be to exploit mutant KRAS-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) over-expression in >90 percent pancreatic ductal adenocarcinoma (PDA) tumor vs associated normal tissue using the novel NQO1 bioactivatable drug, ARQ761 (ß-lapachone, Arqule, Boston, MA) to make PARP1 inhibitors (Olaparib or Rucaparib) tumor-selective. ARQ761 is currently in phase I clinical trials at UT Southwestern (PI: David E. Gerber), with an AACR/Pancreatic Cancer Action Network-supported phase Ib clinical trial against NQO1+ PDA at Johns Hopkins University and UT Southwestern Medical School (PIs: Daniel Laheru, Muhammad Beg). ARQ761 undergoes a robust tumor-selective (NQO1-dependent), futile redox cycle in PDA cells, producing massive hydrogen peroxide (H2O2) levels, dramatic DNA base and single-strand lesions that ‘hyperactivate’ PARP1. This drains energy and suppresses metabolism in NQO1+ PDA cells, causing ‘NAD+-Keresis’ programmed necrosis. Adding nontoxic PARP1 inhibitors to sub-lethal ARQ761 doses prevents energy depletion, but results in overwhelming tumor-selective (mediated by NQO1) DNA damage that cannot be repaired due to PARP1 inhibition. NQO1+ PDA cancer cells undergo apoptotic cell death. In contrast, normal tissue, including associated normal pancreas, are spared by low NQO1 and concomitantly high Catalase levels. Drs. Boothman, Beg, and their research team will test the hypothesis that an optimal sequence of nontoxic PARP1 inhibitor doses + sublethal ARQ761 (ß-lap) doses will provide tumor-selective, synergistic efficacy against human PDAs, expanding PARP1 inhibitor use for all NQO1+ cancers and reducing dose-limiting hemolysis and methemoglobinemia noted with ARQ761. They will optimize efficacy using specific sequencing of nontoxic PARP1 inhibitor + sublethal ARQ761 doses and develop "predictors of efficacy" and "biomarkers of response" for optimal ARQ761 + PARP1 combination therapies in preclinical mouse and human biopsies derived from the clinical trial which opened in July 2015 . An outstanding clinical and basic research team will exploit unique expertise, and apply a novel ex vivo biopsy assay (developed by Dr. Raj Ganesh, associate professor, Department of Urology, UT Southwestern), where mouse and human patient sample responses to agents alone or in optimal combinations are determined. A near-future goal is to conduct a clinical trial with the best combination.
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Principal Investigator: David C. Linehan, MD
Chair of Surgery
University of Rochester
Rochester, New York
Targeting Inflammatory Monocytes in Metastatic Pancreas Cancer
At the time of diagnosis, the majority of patients with pancreas cancer have distant disease (metastasis) mostly to the liver. Surgery provides the only curative treatment option for a limited number of patients, but most undergoing resection will also develop recurrent, incurable disease in the liver. Thus, targeting metastasis formation with novel therapeutic strategies is critical for achieving PanCAN’s initiative to double survival for pancreas cancer by the year 2020.
Patients with pancreas cancer have high levels of cells called inflammatory monocytes (IMs) in their blood that correlate with poor survival. IMs are produced by the bone marrow and migrate to pancreas tumors and future sites of metastasis where they promote disease progression. IMs express the chemokine receptor CCR2 and its blockade prevents IM mobilization from the bone marrow resulting in decreased tumor growth and metastasis in mouse models of pancreas cancer.
A recently completed phase 1b clinical trial in patients with locally-advanced disease using a small molecule inhibitor of CCR2 (CCR2i) in combination with standard chemotherapy resulted in significant reductions of IMs in primary tumors which nearly doubled response rates compared to chemotherapy alone and in several cases resulted in downstaging of previously unresectable patients allowing them a potentially curative operation. Although these results are promising in patients without metastatic disease, it remains unclear if this is the optimal patient population, drug regimen, or combination therapy.
This project aims to study the role of CCR2 blockade in metastatic pancreas cancer. The experiments will use a novel small molecule inhibitor of CCR2 in a relevant mouse model of pancreas cancer that will inform key issues about future clinical study design and implementation in a metastatic setting. These experiments will help identify the optimal population of patients in whom CCR2i will be the most beneficial and will help determine the appropriate CCR2i regimen and explore additional synergistic therapeutic strategies. This PanCAN Translational Research Grant provides the needed support to make these studies possible.
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Principal Investigator: Kazuki N. Sugahara, MD, PhD
Adjunct Associate Research Scientist, Department of Surgery
Columbia University Medical Center
New York, New York
Investigator: Andrew M. Lowy, MD
Director of Surgical Oncology
University of California, San Diego
La Jolla, California
Clinical development of a tumor-penetrating peptide for enhanced pancreatic cancer therapy
Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging targets for chemotherapy. PDAC tumors are packed with fibrotic stroma that inhibits drug distribution into the tumor tissue. The poor drug penetration leads to failure of initial therapy and acquired drug resistance. Dr. Kazuki Sugahara and his colleagues have discovered a novel class of peptides, tumor-penetrating peptides, which may help solve this issue. iRGD, a prototypic tumor-penetrating peptide delivers deep into extravascular tumor tissue drugs and imaging agents chemically attached to the peptide and even free compounds co-injected with the peptide. iRGD increases vascular permeability specifically in the tumor tissue and triggers a molecular transport pathway through the extravascular tumor tissue to allow systemic drugs to widely distribute into solid tumors. Recent treatment studies in PDAC mouse models including Kras-LSLGD12/p53-LSL172H/Pdx-1-cre mice indicate that iRGD is particularly efficient in penetrating desmoplastic PDAC tumors and enhancing anti-tumor activity of co-administered gemcitabine. In this proposal, Dr. Sugahara’s team will collaborate with Dr. Andrew M. Lowy at the University of California, San Diego, to (1) investigate the utility of iRGD in simultaneously delivering free gemcitabine and nab-paclitaxel, the current first line combination therapy for metastatic PDAC, and (2) perform toxicity and pharmacokinetic studies with a goal of filing an Investigational New Drug application to prepare for a first time in human phase 1 treatment study with iRGD in PDAC patients.
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