Translational Research in Breast Cancer (SPORE)

乳腺癌转化研究 (SPORE)

• 批准号: 9332107
• 负责人: C KENT OSBORNE
• 金额: $ 230万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332107
• 关键词: Adoptive Transfer; Adverse effects; Affect; Antigen Targeting; Apoptosis; Biometry; Breast; Breast Cancer Prevention; Cancer Patient; Cellular biology; Chemoprevention; Clinical; Clinical Sciences; Clinical Trials; Combined Modality Therapy; Development; ERBB2 gene; Endocrine; Environment; Growth; Immunosuppressive Agents; Immunotherapy; Laboratory Finding; Lesion; Long-Term Effects; Malignant Neoplasms; Mammary Gland Parenchyma; Molecular Biology; Mus; Neoplasm Metastasis; Oncogene Activation; Outcome; Pathology; Pathway interactions; Patients; Phosphotransferases; Pre-Clinical Model; Premalignant; Prevention; Program Development; Quality of life; Reproduction spores; Research; Research Personnel; Resistance; Resources; Safety; Science; Specificity; Steroid Receptors; T-Lymphocyte; Technology; Translational Research; Translations; Treatment Failure; Tumor Antigens; Tumor Bank; anticancer research; bisphosphonate; breast cancer survival; breast lesion; career development; cellular engineering; chemotherapy; cytokine; cytotoxicity; efficacy testing; hormone therapy; improved; inhibitor/antagonist; malignant breast neoplasm; mevalonate; mouse model; neoplastic cell; overexpression; preclinical study; prevent; public health relevance; receptor; tissue resource; tumor growth; upstream kinase

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.

描述（由申请人提供）：转化研究，快速适应新的实验室研究结果以改善乳腺癌患者的预防、生活质量和生存率，30 多年来一直是贝勒乳腺中心团队的工作重点。在我们之前的 SPORE 的早期，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为内分泌和化疗耐药性、乳腺癌预防、转移和发展提出了新的临床意义的癌前病变。开发项目更进一步寻求新的转化可能性。 在这个新的 SPORE 提案中，我们在四个项目和几个支持组件中以早期成果以及新发现和技术为基础。 (1)我们发现抗HER2治疗会上调甲羟戊酸途径，并可作为逃逸途径，导致治疗失败。但几种已经批准的药物（他汀类药物和双磷酸盐）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)类固醇受体共激活剂SRC-3在乳腺癌中经常过度表达，促进生长和内分泌抵抗，特别是当HER2也活跃时。我们发现抑制支持SRC-3活性的上游激酶PKC和PKD可以抑制肿瘤生长并恢复内分泌敏感性，因此我们建议在明确的临床前模型中剖析这些激酶对SRC-3的功能，并测试PKC的有效性和安全性在临床试验中将抑制剂添加到内分泌治疗中。 (3) 由于费用和对现有药物长期连续治疗副作用的担忧，乳腺癌化学预防的接受度有限。但我们现在发现，激活的 pSTAT5 可以阻止细胞凋亡，而细胞凋亡通常是通过激活癌基因来诱导的保护机制，并且即使使用鲁索替尼等药物短期抑制 pSTAT5 也可以导致乳腺癌前病变消退，并防止进展为癌症。老鼠。在小鼠模型和早期临床试验中，我们将研究这种有效间歇性化学预防的方法。 (4) 尽管免疫疗法承诺精确的特异性和安全性，但结果令人失望，因为肿瘤细胞会改变靶抗原并产生免疫抑制环境来逃避。在这里，我们建议过继转移T细胞，这些T细胞被设计为攻击两种而不是一种肿瘤相关抗原，并表达一种嵌合受体，该受体会导致抑制性细胞因子1L4促进T细胞的细胞毒性。我们独特且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该 SPORE 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转化乳腺癌研究的新想法和新研究者。