Thermally Targeted Cell Cycle Inhibitors for the Treatment of Pancreatic Cancer

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DESCRIPTION (provided by applicant): Surgical resection, followed by chemotherapy and/or radiotherapy, is the most common therapeutic modalities used to treat pancreatic cancer. However, current treatment of localized pancreatic cancer is limited by normal tissue tolerance and/or inherent tumor resistance to radiation or chemotherapy, resulting in a low therapeutic index. To overcome these limitations, our goal is to develop a targeted therapeutic approach for localized pancreatic cancer that increases the specificity and efficacy of the therapy and reduces the cytotoxicity in normal tissues. We have designed a thermally responsive polypeptide which blocks cell cycle progression, induces apoptosis, and inhibits proliferation of pancreatic cancer in cell culture. The objective of the proposed research is to demonstrate that after systemic administration, these genetically engineered polypeptides can be targeted to the tumor site by applying local hyperthermia and can inhibit pancreatic tumor growth. The amino acid sequence of the thermally responsive polypeptides is based on elastin-like polypeptide (ELP) biopolymers, which are soluble in aqueous solution below physiological temperature (37 oC), but aggregate when the temperature is raised above 41 oC. A cell-penetrating peptide, Bactenecin (Bac), is conjugated to the ELP to facilitate cell entry, and a peptide derived from the cyclin-dependent kinase inhibitor p21 is added to inhibit the cell cycle. Our in vitro results demonstrate that Bac-ELP-p21 is a potent inhibitor of pancreatic cancer cell proliferation. Our hypothesis is that intravenously delivered Bac-ELP-p21 will be cleared from circulation under physiological conditions (37 oC), but will accumulate in pancreatic tumors grown in mice where externally induced local heat (42 oC) will be applied. The accumulated polypeptides will inhibit the cell cycle, induce apoptosis, and consequently inhibit proliferation of the cancer cells. In order to address this hypothesis, the following specific aims will be pursued: (1) measure the plasma kinetics and in vivo distribution of Bac-ELP-p21 in normal and neoplastic tissue and (2) evaluate the therapeutic efficacy of Bac- ELP-p21 in the treatment of pancreatic tumor xenografts in mice through repeated administration of the agent coupled with local hyperthermia. The successful completion of the proposed research will provide the in vivo data necessary to establish a new technology that has a competitive advantage over existing/alternate technologies for treatment of pancreatic cancer. Specific targeting of the proposed therapeutic polypeptides to pancreatic tumors by local hyperthermia would improve the efficacy and reduce the side effects relative to current drugs, and it would provide a means to substitute or augment present therapy for treatment of localized pancreatic cancer. PUBLIC HEALTH RELEVANCE: Current treatment of solid tumors is limited because only a small fraction of the administered drug dose reaches the tumor site while the rest of the drug is distributed throughout the body. This causes undesirable side effects to normal tissues when drugs are used in the doses required to eradicate cancer cells. Our long term goal is to overcome this limitation and reduce toxicity in normal tissues by developing an approach to specifically deliver therapeutics to the tumor site.