Molecular Correlates--Oxaliplatin/5FU/XRT, Esophageal CA

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DESCRIPTION (Provided by applicant): There is a pressing need for new agents in the treatment of esophageal cancer and to identify intratumoral molecular markers predictive for tumor response to chemotherapy. Although cisplatin/5-fluorouracil (5FU) plus radiation (XRT) is considered standard therapy for patients with locally advanced esophageal cancer, distant tumor recurrence, representing chemotherapy failure, is the rule. Moreover, the toxicity profile for cisplatin may be disabling. Oxaliplatin (OXP) a diaminocyclohexane platinum complex has a more manageable toxicity profile. Clinical/pre-clinical data suggest OXP-5FU synergy; mechanisms behind the synergy are not understood. Prior studies have shown that response and survival after therapy with 5FU (colon cancer) or 5FU/cisplatin (gastric cancer) are inversely associated with thymidylate synthase (TS), dihydropyrmidine dehydrogenase (DPD) and the excision repair cross-complementing-1 (ERCC-1) gene expressions. Studies of OXP resistant cell lines indicate that resistance is multifactorial, as evidenced by lowered drug accumulation, increased glutathione and decreased DNA-Pt adducts. Resistant cells also had elevated expression of gamma-glutamyltranspeptidase (gamma-GT) and ERCC- 1 genes. Thus, the underlying hypotheses in this application are: A) molecular markers within a primary esophageal tumor will predict sensitivity or resistance to chemotherapy, B) oxaliplatin affects 5FU by lowering TS gene expression and C) pharmacokinetics (PK) of OXP will influence the changes in gene expression. The specific aims of this study are to determine: 1) the intra-tumoral mRNA expression of TS, DPD, gamma-glutamylcysteine synthetase (gamma-GCS), gamma-GT, multidrug resistance associated protein-2 (MRP-2), ERCC-1 and xeroderma pigmentosum A (XPA) at pretreatment, 1 week after OXP alone, and after 1 cycle (with 5FU/radiation), exploring the relationship between these expression levels and response/resistance to treatment; 2) the PK of ultrafilterable platinum on day 1 when OXP is given alone and again on day 15 a week after combination with 5FU + XRT and 3) the relation between PK and changes in intratumoral gene expression and 4) maximum tolerated dose (MTD), dose limiting toxicity (DLT), and the potential therapeutic responses to OXP when given with continuous infusion 5FU + XRT. The gene expression studies will be carried out using real time quantitative RT-PCR (Taqman( r )) assays in endoscopic biopsies. Preliminary results indicate that the regimen is tolerable, the proposed gene expression measurements can be carried out using endoscopic biopsies and changes in gene expression are being detected for some genes during therapy. The long term objectives are to identify a drug combination for better clinical outcome and to identify molecular parameters predictive for response or resistance.