The thymidylate synthase (TS) inhibitor 5-fluorouracil (5FU) is the """"""""backbone"""""""" of cancer treatment in many malignancies. Unfortunately, tumors can be resistant to 5FU due to upregulation of TS. FAU (1-(2'-deoxy-2'- fluoro-2-D-arabinofuranosyl) uracil) is a pyrimidine nucleoside which acts as a suicide prodrug, taking advantage of high TS activity as part of its mechanism of drug activation. Preclinical studies have shown that FAU is first phosphorylated by human deoxythymidine (dThd) kinase (TK), then methylated by TS and incorporated into DNA, inducing cytotoxicity. FAU is a novel investigational agent that has not been extensively studied in humans and never with therapeutic intent. The Karmanos Cancer Institute (KCI) Phase I service has recently received approval from the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) to conduct a Phase I clinical trial of FAU in patients with advanced stage (metastatic or unresectable) solid tumors for which standard curative or palliative measures do not exist or are no longer effective. The primary aims of this Phase I study are to determine the safety profile of FAU when administered as a 1-hour infusion on days 1-5 of a 28-day cycle, to determine the dose limiting toxicities (DLT), and to establish the maximum tolerated dose (MTD). The clinical and pharmacokinetic (PK) analysis portions for this Phase I study will be funded by NCI Grant# U01-CA062487-15. However, because Translational Research Initiative (TRI) funding is no longer provided by the NCI to support critical correlative investigations, we are submitting this application to request funding that will enable the exploratory assessment of surrogate endpoints in hopes of defining a patient population that will benefit from FAU. The ability of positron emission tomography (PET) to produce images of tumor physiology has led to its increasing application in oncology. Chemotherapeutic compounds, labeled with positron emitting radiopharmaceuticals, allow biodistribution of the chemotherapeutic to be imaged in vivo, as well as determination of its uptake and retention in tumors. Our pilot studies demonstrate that 18F-radiolabeled FAU can be imaged and unlabeled therapeutic FAU can be measured in tumors. We hypothesize that tumors expressing TK and over expressing TS will have higher metabolism/activation of FAU, leading to increased tumor cell death, and that the use of tracer doses of 18F-FAU will be predictive of the uptake of unlabeled FAU into tumors and ultimate response to treatment. In this application, we propose correlative studies to explore this hypothesis in support of the Phase I trial. Correlative PET imaging studies using 18F-FAU will be conducted prior to therapy and following treatment with unlabeled FAU to measure uptake of drug into tumor and normal tissues. In addition, we will collect archival tissue blocks or pre-treatment biopsies to perform pharmacodynamic (PD) analyses and post- treatment biopsies to assess FAU metabolism. Both TS and TK will be measured in tumor tissue and compared to imaging and therapeutic results.
Cancer is a major cause of death in the world and cancer patients are in need of more effective treatment options. The clinical trial NCI#7916 is designed to test treatment of the novel cancer drug FAU in patients with advanced solid tumors;this application seeks funding for studies designed to obtain a better understanding of this drug. If successful, the proposed experiments may point the way to assays that identify patients who are more or less likely to respond to this therapy, thereby permitting individualized therapy of patients in the future.
|Li, Jing; Kim, Seongho; Shields, Anthony F et al. (2016) Integrating Dynamic Positron Emission Tomography and Conventional Pharmacokinetic Studies to Delineate Plasma and Tumor Pharmacokinetics of FAU, a Prodrug Bioactivated by Thymidylate Synthase. J Clin Pharmacol 56:1433-1447|