Translational Research in Breast Cancer (SPORE)

描述(申请人提供)：转化性研究，快速调整新的实验室结果，以提高乳腺癌患者的预防、生活质量和生存率，30多年来一直是贝勒乳房中心成立团队的重点。在我们之前的孢子早期，我们的肿瘤库使这种快速翻译成为可能，成为国家资源，而基础细胞和分子生物学研究在内分泌和化疗耐药性、乳腺癌预防、转移和癌前病变的发展方面提出了新的临床意义。发展项目在寻求新的翻译可能性方面甚至走得更远。 在这项新的孢子提案中，我们在四个项目和几个支持部分的早期成果和新的发现和技术的基础上再接再厉。(1)我们发现甲氧戊酸途径被抗HER2治疗上调，并可作为一条逃逸途径，导致治疗失败。但几种已经批准的药物(他汀类和双膦酸类)可以抑制这一途径，我们将在临床前研究和临床试验中探索它们的机制及其克服这种治疗失败的潜力。(2)类固醇受体辅活化子SRC-3在乳腺癌中经常过表达，并促进生长和内分泌抵抗，特别是当HER2也激活时。发现抑制上游支持SRC-3活性的PKC和PKD可以抑制肿瘤生长和恢复内分泌敏感性，我们建议在已定义的临床前模型中剖析这些激酶在SRC-3上的功能，并在临床试验中测试加入PKC抑制剂进行内分泌治疗的有效性和安全性。(3)由于费用和对现有药物长期持续治疗的副作用的担忧，乳腺癌的化学预防被接受的程度有限。但我们现在发现，激活的pSTAT5阻止了通常由癌基因激活作为一种保护机制而诱导的细胞凋亡，而且即使用Ruxolitinib等药物短期抑制pSTAT5也可以导致癌前乳腺病变的消退，并防止小鼠的癌症进展。在两个小鼠模型和早期临床试验中，我们将研究这种有效的间歇性化学预防方法。(4)尽管免疫治疗承诺具有极高的特异性和安全性，但由于肿瘤细胞改变靶向抗原并产生免疫抑制环境以逃避治疗，结果一直令人失望。在这里，我们建议过继转移被设计为攻击两个肿瘤相关抗原而不是一个的T细胞，并表达导致抑制性细胞因子1L4促进T细胞杀伤的嵌合受体。我们独特的、广泛使用的乳腺组织资源/病理学核心，以及生物统计学和管理核心为这一孢子提供了关键支持。我们非常成功的发展项目和职业发展计划将继续鼓励在转化型乳腺癌研究中的新想法和新的研究人员。

DESCRIPTION (provided by applicant): Translational research, adapting new laboratory findings quickly to improve prevention, quality of life, and survival for breast cancer patients, hs been the focus of the team now forming the Baylor Breast Center for over 30 years. In the early years of our previous SPORE, our tumor bank which made much of this rapid translation possible became a national resource, while basic cell and molecular biology research suggested new clinical implications for endocrine and chemotherapy resistance, breast cancer prevention, metastasis, and development of premalignant lesions. Developmental projects ranged even further in seeking new translational possibilities. In this new SPORE proposal, we build on our earlier results and on new findings and technologies, in four projects and several support components. (1) We have discovered that the mevalonate pathway is upregulated by anti-HER2 therapy and can serve as an escape pathway, leading to treatment failure. But several already approved agents (statins and bisphosphonates) can inhibit this pathway, and we will explore their mechanisms and their potential to overcome this treatment failure, both in preclinical studies and a clinical trial. (2)The steroid receptor coactivator SRC-3 is frequently overexpressed in breast cancer and promotes growth and endocrine resistance, especially when HER2 is also active. Finding that inhibiting upstream kinases PKC and PKD that support SRC-3 activity can suppress tumor growth and restore endocrine sensitivity, we propose to dissect the functions of these kinases on SRC-3 in defined preclinical models, and test the efficacy and safety of a PKC inhibitor added to endocrine therapy in a clinical trial. (3) Chemoprevention of breast cancer has had limited acceptance due to expense and concerns about side effects of long-term continuous treatment with existing agents. But we have now discovered that activated pSTAT5 blocks the apoptosis that is typically induced as a protective mechanism by activation of oncogenes, and that even short-term suppression of pSTAT5 with agents like ruxolitinib can cause regression of premalignant breast lesions and prevent progression to cancer in mice. In both mouse models and an early clinical trial, we will investigate this approach for effective intermittent chemoprevention. (4) Though immunotherapy promises exquisite specificity and safety, results have been disappointing as tumor cells alter targeted antigens and generate an immunosuppressive environment to escape. Here we propose to adoptively transfer T cells engineered to attack two tumor-associated antigens rather than one, and to express a chimeric receptor that causes the repressive cytokine 1L4 to promote T cell cytotoxicity instead. Our unique, widely used breast Tissue Resource/Pathology Core, along with Biostatistics and Administrative Cores give key support to this SPORE. Our highly successful Developmental Projects and Career Development programs will continue to encourage new ideas and new investigators in translational breast cancer research.