Translational Research in Breast Cancer

乳腺癌的转化研究

• 批准号: 7547090
• 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: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547090
• 关键词: Advocate; Agonist; Androgen Receptor; Antibodies; Aromatase Inhibitors; Bexarotene; Biometry; Breast; Breast Cancer Prevention; Cancer Center; Cancer Patient; Cells; Characteristics; Clinical; Clinical Treatment; Clinical Trials; Clinical Trials Design; Collaborations; Communication; Complex; Core Facility; Country; DNA; Data; Development; ERBB2 gene; Endocrine; Estrogen Receptors; Floods; Funding; Grant; Growth; High Risk Woman; Histologic; Institution; Insulin Receptor; Insulin-Like-Growth Factor I Receptor; Laboratories; Laboratory Finding; Laboratory Study; Leadership; Lesion; Mammary Gland Parenchyma; Medicine; Methodology; Microarray Analysis; Microdissection; Microscopy; Molecular and Cellular Biology; Neoplasm Metastasis; Pathologist; Pathology; Pathway interactions; Premalignant; Prevention; Property; Proteomics; Quality of life; RXR; Raloxifene; Reproduction spores; Research; Research Personnel; Resistance; Resources; Role; Sampling; Scientist; Selective Estrogen Receptor Modulators; Source; Specimen; Stem cells; Tamoxifen; Techniques; Tissues; Toxic effect; Translational Research; Translations; Trastuzumab; Travel; Tumor Bank; Visit; Work; anticancer research; assay development; base; cancer stem cell; career development; chemotherapy; college; cross reactivity; data management; design; experience; hormone therapy; improved; malignant breast neoplasm; meetings; neoplastic cell; new technology; overexpression; pre-clinical; prevent; programs; protein profiling; response; stem cell population; therapeutic target; tissue processing; tissue resource; tumor

DESCRIPTION (provided by applicant): Translational research, bringing new laboratory findings quickly to improve prevention, treatment, quality of life, and survival for breast cancer patients, has been the focus of the team now forming the Baylor Breast Center for over 25 years. During the first years of our 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 SPORE renewal, we build on the results developed in our earlier work and on new findings and new technologies, in five projects and several supporting components. (1) Targeting HER2 with agents such as trastuzumab has become an important treatment, but resistance often develops. We will explore and take to clinical trials our promising preclinical evidence that more complete blockade of the complex HER network or of its cross-talk with the estrogen receptor may overcome this resistance. (2) Based on our data suggesting that a small subpopulation of resistant tumor cells with stem-cell-like properties may be the source of tumor re-growth after apparently successful chemotherapy, we will investigate this potential "cancer stem cell" population and begin trials of treatments targeting these cells along with the more numerous, more differentiated tumor cells for more complete and enduring responses. (3) Prevention trials have shown that SERMs like tamoxifen or raloxifene can greatly reduce ER-positive but not ER-negative breast cancer in high-risk women. Now we will apply our prevention experience with RXR agonists such as bexarotene to develop preclinical and clinical combinations with SERMs to prevent both ER-positive and ER-negative breast cancer. (4) Surprising new clinical and laboratory data suggests that overexpression of the androgen receptor may be an important cause of resistance to endocrine therapy with either tamoxifen or aromatase inhibitors. We will seek the mechanisms behind this interaction, and will initiate a clinical trial designed to reverse this resistance with an already-approved AR antagonist. (5) The IGF pathway has been shown to be important in breast cancer development and progression, but therapeutic targeting is complicated by high cross-reactivity with the insulin receptor. We will investigate the efficacy of a new, specific IGF-I receptor antibody and explore strategies to lessen toxicities associated with collateral insulin receptor blockade by other IGF pathway targeting approaches. Though parts of our unique breast Tissue Resource were lost in the floods of 2001, much remains, and new accessions are further enhancing this critical resource. Biostatistics, Pathology, and Administrative Cores also1 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. Our new Dan L. Duncan Cancer Center provides valuable direct support and collaboration for this SPORE effort.

描述（由申请人提供）：转化研究，迅速带来新的实验室发现，以改善乳腺癌患者的预防，治疗，生活质量和生存，一直是该团队的重点，现在组成了贝勒乳房中心已有25年了。在孢子的头几年中，使这种快速翻译成为可能的大部分肿瘤库成为了国家资源，而基本细胞和分子生物学研究提出了对内分泌和化学疗法耐药性，预防乳腺癌的转移，转移和前病前病变的发展的新临床意义。发展项目在寻求新的翻译可能性方面的进一步范围。在此孢子更新中，我们基于早期工作以及新的发现和新技术，在五个项目和几个支持组件中发展的结果。 （1）将HER2靶向曲妥珠单抗等药物已成为一种重要的治疗方法，但抗药性经常发展。我们将探索并接受临床试验，我们有希望的临床前证据，即她的网络或与雌激素受体的串扰更完整地阻断了该复合物，可能会克服这种耐药性。 （2）基于我们的数据表明，具有类似干细胞的特性的抗性肿瘤细胞的少量亚群可能是肿瘤重新生长后显然成功化疗后的来源，我们将研究这种潜在的“癌症干细胞”种群，并开始针对这些细胞的治疗方法，以及对这些细胞的靶向较多，与更多的差异化肿瘤细胞，以使其更完整和更完整的肿瘤细胞更完整和耐力。 （3）预防试验表明，在高危女性中，诸如他莫昔芬或雷洛昔芬之类的Serms可以大大降低ER阳性但不能降低ER阴性乳腺癌。现在，我们将在RXR激动剂（例如Bexarotene）中运用预防经验，以与Serms开发临床前和临床组合，以防止ER阳性和ER阴性乳腺癌。 （4）令人惊讶的新临床和实验室数据表明，雄激素受体的过表达可能是对他莫昔芬或芳香酶抑制剂对内分泌治疗的抗性的重要原因。我们将寻求这种相互作用背后的机制，并将启动一项临床试验，旨在通过已经批准的AR拮抗剂扭转这种抗性。 （5）IGF途径已被证明在乳腺癌的发育和进展中很重要，但是与胰岛素受体的高交叉反应性使治疗靶向变得复杂。我们将研究一种新的，特定的IGF-I受体抗体的功效，并探索策略，以减少其他IGF途径靶向方法与抵押胰岛素受体阻断相关的毒性。尽管我们独特的乳腺组织资源的一部分在2001年的洪水中丢失了，但剩下的很多，新的加入进一步增强了这一关键资源。生物统计学，病理学和行政核心也为此为孢子提供了重要的支持。我们非常成功的发展项目和职业发展计划将继续鼓励新的想法和新的研究者转化乳腺癌研究。我们的新Dan L. Duncan癌症中心为这项孢子工作提供了宝贵的直接支持和协作。