MEDICAL ONCOLOGY PROGRAM PROJECT -- THERAPEUTIC RESEARCH

癌症患者的个体化治疗仍然是主题和目标 对于这一更新申请。 在最初的几年里，虽然项目 与乳腺癌、前列腺癌、肺癌和脑癌有关， 脖子也有代表性。 激素受体和作用是一个主要的 专心点 我们在以下方面有重要发现： 孕激素受体及其在乳腺癌中的频繁丢失 治疗，并开始对I期和未经治疗的II期进行长期研究 乳腺癌与受体和其他预后因素有关。 我们 还开发了新的雄激素连接和新的亲和试剂， 雄激素受体纯化，并发现，与早期的希望相反， 在喉癌中，该受体非常低或缺失， 抗雄激素相应无效。 乳腺肿瘤相关 抗原是另一个焦点。 我们研制了一种单克隆抗体 对上皮来源的肿瘤特异的抗原，其也标志着 “良性”乳腺疾病的高风险子集，以及其它抗体， 抗原在雌激素控制下脱落或分泌。 克隆形成软琼脂 肿瘤细胞药物敏感性测试是第三个重点。 几种癌症 类型生长不良，但一种新的毛细管方法正在提高产量。 肿瘤 甚至从一些病理阴性的肺癌中也出现了细胞集落 标本，表明肿瘤的存在;在软组织中生长的能力 琼脂与较差的患者存活率相关。 药敏 体外筛选确定了至少两种药物， 进行临床试验 我们现在建议继续努力使治疗个性化， 将焦点缩小到乳腺癌，特别是其激素调节 和预后因素，这些因素可以确定患者的子集， 不同的疗法。 本项目将研究：（1） 乳腺癌细胞中的抗雌激素作用，使用抗受体单克隆抗体 抗体;（2）孕酮受体的单克隆抗体， 免疫化学和组织化学检测及受体基础研究 功能;（3）预后因素，包括细胞动力学，组织病理学， 和新的肿瘤相关抗原，以及受体， 与我们正在进行的计算机化的临床随访相关， 数据库;（4）雌激素调节的分子水平，使用cDNA的 最终包括雌激素在内的几种受调节的蛋白质， 孕激素受体在乳腺肿瘤中的调节缺陷;（5） 检测雌激素的非免疫细胞化学方法， 孕酮受体，包括新生物素和荧光素的合成 类固醇缀合物;和（6）乳腺肿瘤相关抗原及其 荷尔蒙控制 单克隆抗体核心实验室将支持所有 这些高度互动的项目，将共同提供知识， 尽可能多的因素来预测 个体患者的肿瘤，从而获得最佳治疗。

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.