CHEMOTHERAPEUTIC STUDIES IN SOLID TUMORS

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In the revised Solid Tumor Project, we propose studies of new treatment for the non-hematologic malignancies. Each disease serves as a model system in which to test a concept which may have relevance to and subsequently be tested in other solid tumors with a similar biology. Five specific aims focus on new drugs, improved drug and radiation therapy delivery, and genetic mutations as prognostic factors. In Specific Aim 1, high-dose programs as proposed for patients with breast cancer and germ cell tumors. Since these two tumors are responsive to several drugs in different antineoplastic classes, they are excellent model systems in which to test the hypotheses of high-dose theory and new methods of stem cell reconstitution. In Specific Aim 2, we will determine the antitumor activity of combinations of an agent directed at a tumor-specific "target plus traditional cytotoxic drugs. Two agents will be studied initially. First, monoclonal antibody 225, which inhibits the binding of growth factor ligands to the epidermal growth factor receptor, inhibits proliferation in tumors which are dependent on this receptor for growth and is synergistic with cytotoxic drugs in vitro and in vivo. Second, the radiopharmaceutical 186Rhenium-HEDP targets tumor-induced new bone formation in bone metastases and will be studied in combination with chemotherapy in patients with prostate cancer. In Specific Aim 3, the antineoplastic activity of retinoids and other new drugs will be tested, both in traditional Phase II and in randomized trials. In Specific Aim 4, 3-dimensional treatment planning will be used to deliver radiation therapy to the tumor volume with greater precision and lesser local tissue toxicity in combination with chemotherapy. The initial goal is to improve local control of locally advanced non-small cell lung cancer, well-known to be associated with considerable mortality and morbidity from locally recurrent disease. In Specific Aim 5, the association between genetic alterations in TP53 and RB1 and response and survival will be studied in breast and head and neck cancer (in the case of TP53) and bladder cancer (for both TP53 and RB1). As we have demonstrated in the case of i(12p), the marker chromosome for germ cell tumors, genetic defects in tumors can be useful as diagnostic and prognostic tools in treatment selection. After optimization of treatment in Phase II trials, Phase III trials will be conducted and concepts applied in other relevant tumor systems.