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FINDING CURES TOGETHER<sup>SM</sup>
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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.

2015 Grantees

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 

Co-Principal 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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