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发现，以改善乳腺癌患者的预防，生活质量和生存率，这是现在组成贝勒乳房中心的团队30多年来的重点。在我们之前的SPORE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，乳腺癌预防，转移和癌前病变的发展提供了新的临床意义。在寻求新的翻译可能性方面，发展项目的范围甚至更远。