MEDICAL ONCOLOGY PROGRAM PROJECT-THERAPEUTIC RESEARCH

癌症患者的个体化治疗仍然是主题和目标 是次续期申请。在最初的几年，尽管项目 与以乳腺癌为主的前列腺癌、肺癌和头癌有关的 颈部也有代表。激素受体和作用是主要的 全神贯注。我们在预后意义上有了重要的发现 孕激素受体及其在乳腺癌中频繁的不祥丢失 治疗，并开始第一阶段和未治疗第二阶段的长期研究 乳腺癌与受体和其他预后因素的关系。我们 还开发了新的雄激素连接和一种新的亲和试剂 雄激素受体纯化，并发现，与早先的希望相反， 这种受体在喉癌中很低或不存在，而且 相应地，抗雄激素无效。与乳腺肿瘤相关的 抗原是另一个焦点。我们研制了一种针对其中一种的单抗。 上皮源性肿瘤的特异性抗原，它也标志着 “良性”乳房疾病的高危亚群，以及其他针对 在雌激素控制下，抗原脱落或分泌。克隆软琼脂 肿瘤细胞药物敏感性测试是第三个重点。几种癌症 类型的植物生长不佳，但一种新的毛细管方法正在提高产量。肿瘤 甚至在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。药物敏感性 体外筛选确定了至少两种药物，因此现在是 正在进行临床试验。 我们现在建议继续努力使治疗个体化，同时 缩小对乳腺癌的关注范围，特别是其激素调节 和预后因素，可以确定患者的亚组 不同的疗法。这些项目将研究：(1)机制 抗受体单抗在乳腺癌细胞中的抗雌激素作用 抗体；(2)抗孕酮受体的单抗 免疫组织化学检测及受体的基础研究 功能；(3)预后因素，包括细胞动力学、组织病理学、 以及新的肿瘤相关抗原和受体，所有这些都将是 与我们正在进行的计算机化的详细临床随访相关 数据库；(4)雌激素调节的分子水平，使用cDNAs 几种受调控的蛋白质最终包括雌激素和 孕激素受体用于剖析乳腺肿瘤的调节缺陷；(5) 雌激素和雌激素的非免疫细胞化学检测方法 孕酮受体，包括新生物素和荧光素的合成 类固醇结合物；和(6)乳腺肿瘤相关抗原及其 荷尔蒙控制。一个单抗核心实验室将支持所有 这些高度互动的项目，这些项目将共同提供知识 尽可能多的因素来预测进程和反应 对个别病人的肿瘤进行治疗，因此是最佳治疗方法。

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.