Deep Creek Pharma is developing novel fluoropyrimidine polymers to improve outcomes in patients with colorectal cancer, pancreatic cancer, and other malignancies. In many cancer patients, targeted therapies specific for their malignancy are unavailable and immunotherapy is not effective. In many of these patients, chemotherapy with regimens that include 5-FU is the most effective treatment option. However, long-term survival rates for patients with advanced disease that are treated with these regimens is very low and many patients treated with these regimens display serious systemic toxicities. Fluoropyrimidine polymers are designed to improve outcomes even while reducing systemic toxicities.
For chemotherapy to be effective, concentrations of key active metabolites derived from the drug must rise above threshold concentrations in cancer cells while concentrations of alternative metabolites that adversely affect the function and viability of non-malignant cells must be kept low in sensitive tissues. For 5-FU, the key active metabolite is FdUMP, which inhibits the target enzyme, thymidylate synthase (TS). However, < 5% of 5-FU administered to cancer patients is converted to FdUMP. Instead, most 5-FU in cancer patients is either degraded, excreted intact, or converted to ribonucleotide metabolites that contribute to systemic toxicities.
Deep Creek Pharma’s Approach to Chemotherapy
To make chemotherapy more effective and less toxic, Deep Creek Pharma is developing fluoropyrimidine polymers. FP polymers provides Pharmacological, Mechanistic, and Chemical Advantages relative to current drugs.
Pharmacological Advantages of FP Polymers
5-FU is widely used to treat colorectal cancer and other malignancies, yet >80% of 5-FU is degraded in the liver, or excreted intact. Fluoropyrimidine polymers are oligodeoxynucleotides and undergo receptor-mediated uptake by the liver. Hepatobiliary routing results in high concentrations of active FP metabolite in the GI-tract which can contribute to efficacy towards primary tumors. Pyrimidines are also readily absorbed from the intestine into the blood and systemic re-circulation via the portal vein results in sustained concentrations of FP metabolites in plasma contributing to anti-tumor and anti-metastatic activity.
Mechanistic Advantages of FP Polymers
FP polymers directly release the TS-inhibitory metabolite FdUMP and as a consequence our lead product CF10 inhibits TS at ~1,000-fold lower concentration than 5-FU in many cancer cell lines, a value that corresponds to increased potency. With strong TS inhibition there is also misincorporation of FdUTP into genomic DNA which Dr. Gmeiner has shown results in poisoning of DNA topoisomerase 1 (Top1). In our lead product, CF10, the nucleoside analog AraC is also released responsible for antitumor activitiy is present in intact form and it is readily liberated from the polymer by nuclease enzymes that are abundant. Our lead compound, CF10, is a 2nd generation polymeric fluoropyrimidine in which two chemical modifications to the polymer, AraC
Chemical Advantages of FP Polymers
Toxicity/Cost Advanatages of FP Polymers