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.