Fluorouracil plus leucovorin remains the standard first-line chemotherapy for metastatic colorectal cancer. Overall response rates, however, are low, with the majority of patients experiencing toxicity, but little or no benefit from treatment. The ability to predict response or failure in the individual patient would clearly improve palliation, and would have substantial implications for directing adjuvant treatment for high-risk resected patients. Recent data from the laboratory of Dr. Peter Danenberg indicate that a high relative expression of thymidylate synthase mRNA (determined by quantitative RT-PCR) strongly predicts for failure to respond to FU/LV. Further data suggest that low expression of both thymidine phosphorylase and dihydropyrimidine dehydrogenase are consistent with responsiveness to FU/LV, while high expression of either TS, TP or DPD correlates with resistance to these agents. Irinotecan (CPT-11), a topoisomerase I inhibitor, has been shown to have activity in some patients with CRC refractory to FU/LV, presenting for the first time a viable alternative to treatment with FU-based regimens. The applicant hypothesizes that specific molecular determinants of response can be used to accurately predict response or failure to treatment of advanced CRC. He will perform two clinical trials, with closely coordinated laboratory studies, to test this hypothesis. In protocol 1, he will obtain core needle biopsies, snap-frozen, on patients with newly diagnosed metastatic CRC for determination of relative TS expression. Patients with TS levels favorable to response to FU/LV will receive a standard FU/LV regimen. Patients with TS levels incompatible with response to FU/LV (high TS expression) will be treated with CPT-11. A panel of putative determinants of response (TP, DPD, p53 mutational status, ERCC1, bcl-2/bax, and topo 1) will be investigated for all patients. This study will attempt to 1) validate preliminary data that low expression of TS, TP, and DPD strongly predict for response to FU/LV, 2) establish the response rate for front-line treatment with CPT-11 in high TS patients, and 3) establish molecular determinants of response to CPT-11. In Protocol 2 he will treat patients with FU-refractory, technically resectable, high-risk metastatic CRC with neoadjuvant CPT-11. Pretreatment biopsies will be obtained, and patients will receive 12 weeks of CPT-11 therapy, followed by resection, if feasible, with initial biopsy and resected tissue analyzed for prognostic determinants, in order to assess the effect of CPT-11 treatment on levels of gene expression, as well as correlation of these molecular determinants with clinical response.
| Hung, M C; Hortobagyi, G N; Ueno, N T (2000) Development of clinical trial of E1A gene therapy targeting HER-2/neu-overexpressing breast and ovarian cancer. Adv Exp Med Biol 465:171-80 |
