MEDICAL ONCOLOGY PROGRAM PROJECT-THERAPEUTIC RESEARCH

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Individualizing therapy for the cancer patient remains the theme and goal for this renewal application. In the initial years, although projects relating to cancer of the breast predominated, prostate, lung, and head and neck were also represented. Hormone receptors and action were a major focus. We made important discoveries on the prognostic significance of progesterone receptor and its frequent ominous loss during breast cancer treatment, and began long-term studies of Stage I and untreated Stage II breast cancer with regard to receptors and other prognostic factors. We also developed new androgen linkages and a new affinity reagent for androgen receptor purification, and found that, contrary to earlier hopes, this receptor was very low or absent in laryngeal carcinoma, and that antiandrogens were correspondingly ineffective. Breast tumor-associated antigens were another focus. We developed a monoclonal antibody to one antigen specific for tumors of epithelial origin which also marks a high-risk subset of "benign" breast disease, and other antibodies to antigens shed or secreted under estrogen control. Clonogenic soft agar tests for tumor cell drug sensitivity were a third focus. Several cancer types grew poorly, but a new capillary method is improving yield. Tumor cell colonies appeared even from some pathology-negative lung cancer specimens, indicating the presence of tumor; ability to grow in the soft agar was correlated with poorer patient survival. Drug sensitivity screening in vitro identified at least two drugs which are now therefore going on to clinical trials. We now propose to continue efforts to individualize treatment while narrowing the focus to breast cancer, in particular its hormone regulation and prognostic factors which could identify subsets of patients for different therapies. The projects will study: (1) mechanism of antiestrogen action in breast cancer cells, using anti-receptor monoclonal antibodies; (2) monoclonal antibodies to progesterone receptor, for immunochemical and histochemical detection and for basic study of receptor function; (3) prognostic factors, including cell kinetics, histopathology, and new tumor-associated antigens, as well as receptors, all to be correlated with detailed clinical follow-up in our ongoing computerized data base; (4) molecular levels of estrogen regulation, using cDNA's for several regulated proteins eventually including the estrogen and progesterone receptor to dissect regulatory defects in breast tumors; (5) non-immunological cytochemical methods for detection of estrogen and progesterone receptors, including synthesis of new biotin and fluorescein steroid conjugates; and (6) breast tumor-associated antigens and their hormonal control. A monoclonal antibody core laboratory will support all of these highly interactive projects, which together will provide knowledge of as many factors as possible which predict the course and responsiveness of individual patient's tumor and hence the optimum treatment.