SOLID TUMOR

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DESCRIPTION: (Applicant's Description) The Solid Tumor Project supports investigation of new therapy and predictors of outcome for cancers other than leukemia and the Lymphomas. Three specific aims focus on single and combination programs using specific malignancies as model systems on which hypotheses are tested. Specific Aim 1 evaluates new strategies and novel agents. Optimal dose-density achieved through dose escalation or shorter inter treatment intervals, or both, will be tested in patients with germ cell tumors and bladder cancer. Novel drugs, including the geldanamycins (GDM) (which interfere with normal hsp90 function), a new antifol (10-propargyl-10- den7~nnlinopterin; PDX), and an epothilone derivative (desoxyepothilone B; dEPL-B) will be tested in single-agent and combination Phase II trials. Over the next five years, small cell and non-small cell lung cancer (NSCLC), bladder cancer, and head and neck cancer (H/N) will be model systems. Specific Aim 2 tests the hypothesis that drugs aimed at known cellular targets or with putative differentiating activity will be effective anticancer therapy. In this aim, vaccines aimed at known peptide, ganglioside, or carbohydrate antigens will be effective immunogenstigenic target. A polyvalent vaccine will be developed and tested prior to clinical trials to test the hypothesis that outcome will improve with treatment of minimal residual disease after surgery, radiation therapy, and/or chemotherapy in patients with breast and prostate cancer. An histone deacetylase inhibitor with putative differentiating capability, pyroximide, will be tested in breast and prostate cancer. In Specific Aim 3, new markers of survival and drug resistance and toxicity will be investigated. Comparative genomic hybridization will be performed on paraffin-embedded tumor tissue to test the hypothesis that highly amplified regions of chromosomal gain will occur more frequently in drug-resistant tumors than drug-sensitive tumors using breast; NSCLC, and H/N cancer as models. Magnetic resonance spectroscopy will test the hypothesis that changes in phospholipid metabolism predicts tumor sensitivity and/or outcome in H/N cancer and in patients with hepatic metastases. Limited sampling strategies will be applied across Phase II trials of PDX, GDM, dEPL-B, and pyroximide to determine pharmacodynamic relationships important to combination and Phase II trials. Most new agents to be studied in this project are the result of new drug development conducted at MSKCC. After Phase II trials, Phase III triais will be conducted if appropriate.