Project Two

Pancreatic cancer (PCa) can vary between individuals, chemotherapy should ideally be tailored to each patient based on the nature of their particular disease. The detection of potentially chemo-sensitive tumors would significantly improve response rates and facilitate the selection of effective individualized regimens. Developing a method of assessing the likely effectiveness of anticancer drugs using resected or biopsied tissues of Blacks and Latinos before treatment will provide PCa patients with a survival advantage. Therefore, we seek to conduct mutational analysis to identify a set of key ‘cancer pathways’ operating in PCa tumors from Blacks versus Latinos that will allow the classification of tumors into distinct groups, or genetic sub-types, with a similar biological basis.

Gemcitabine (Gem) is an anticancer drug commonly used to treat PCa. It can be administered alone to cancer patients in poor health, or it can be combined with other drugs such as fluorouracil (5-FU), capecitabine, erlotinib or paclitaxel. However, in many cases the efficacy is limited due to systemic instability and tumor insensitivity. For example in blood and liver, Gem is rapidly metabolized to, inactive metabolite, 2′,2′-difluorodeoxyuridine through its 4-amino group by cytidine deaminase. By developing 4-(N)-stearoyl-Gem nanoparticle-surface modified anti-epidermal growth factor receptor (EGFR) antibody, (GemEnps), Gem is expected to become resistant to cytidine deaminase attack. Another barrier to Gem delivery is hyaluronan which occurs in 87% of stromal compartment of pancreatic cancer. This fortifies the cancer epithelium and creates a drug-free sanctuary for PCa. Breaking down hyaluronan is mainly mediated by enzyme, hyaluronidase (Hase). Recent clinical trials have demonstrated that Hase could significantly increase chemotherapeutic efficacy in tumors previously deemed chemoresistant. Ribonucleotide reductase subunit M1 (RRM1) is a critical barrier to Gem delivery: The overexpression of RRM1 plays a key role in Gem resistance. Published reports reveal that 4-(N)-stearoyl Gem inhibits the expression of RRM1 and increase the level of Gem triphosphate (dFdCTP) in Gem resistant tumor cells.

In this proposal, we seek to investigate the use of molecular profile to predict the sensitivity of PCa to Gem and, improve on the delivery and stability of Gem. We propose to expand on the health inequity in PCa and establish better efficacies for existing therapeutics. The rationale for our proposal is based on historical data where molecular profiling of lung, prostate, and breast cancer in Blacks patients has defined more effective therapeutic regimens.

We hypothesized that Genetic differences between tumors underlie the biological basis of differences in disease presentation and treatment response in PCa patients and, GemEnps, represents a novel therapeutic alternative that can significantly inhibits PCa growth.