Developing novel targeted therapeutics integrated with immunotherapy-based approaches to make breakthroughs in metastatic breast cancer

开发与免疫疗法相结合的新型靶向疗法，以在转移性乳腺癌方面取得突破

• 批准号: 10240658
• 负责人: Jean Zhao
• 金额: $ 100.72万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240658
• 关键词: Accounting; Address; Affect; Cell physiology; Cessation of life; Characteristics; Clinical; Combination Drug Therapy; Dependence; Diagnosis; Disease; Drug Targeting; Drug resistance; Embryo; Face; Family; Genetic; Genetically Engineered Mouse; Immunotherapy; Leucine Zippers; Malignant Neoplasms; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Modeling; Modernization; Molecular; Molecular Abnormality; Normal Cell; Oncogenic; PTEN gene; Pathogenesis; Patient-Focused Outcomes; Patient-derived xenograft models of breast cancer; Patients; Pharmacology; Phenotype; Phosphotransferases; Prognosis; Protein Isoforms; Research; Resistance; Role; Sampling; Signal Transduction; Therapeutic; Translating; United States; base; cancer therapy; clinically relevant; design; drug sensitivity; effective therapy; experience; improved; ineffective therapies; malignant breast neoplasm; mortality; mouse model; neglect; new technology; new therapeutic target; novel; patient derived xenograft model; precision medicine; preclinical study; programs; targeted treatment; therapy resistant; treatment strategy; triple-negative invasive breast carcinoma

Project Summary/Abstract Metastatic breast cancer (MBC) is a devastating disease that accounts for over 90% of breast cancer mortality and for which there are no current effective treatments. With over 230,000 new breast cancer cases diagnosed annually and accounting for more than 40,000 deaths every year in the United States alone, developing safe and effective treatments for MBC is an utmost priority. Our research program proposes to address this important disease by combining basic and pre-clinical studies that can translate into meaningful clinical outcomes for patients with MBC. Prompted by an increasing understanding of the molecular mechanisms underlying oncogenic dependence and resistance to therapy, the advent of targeted therapies, and, most recently, of immunotherapy, has revolutionized our approach to modern cancer treatment. These advances, together with improved models and novel technologies, open the door to tackling some of the hardest challenges in cancer treatment. We will capitalize on our expertise on signal transduction and pharmacology, as well as on our previous findings on targeted drug resistance and sensitivity, to design safe and effective targeted therapies against MBC. Specifically, we will investigate the role of PTEN and specific PI3K isoforms in metastatic spread using multiple genetically-engineered mouse models (GEMMs) and patient-derived xenografts (PDXs). We will also evaluate the use of combined immunotherapy and targeted PI3K isoform- specific inhibition on syngeneic mouse models of MBC. In addition, we will thoroughly research two recently discovered and promising novel targets, Maternal Embryonic Leucine-zipper Kinase (MELK) and CDK7, which proved to be essential in basal-like or triple negative breast cancer, but dispensable in normal cells, for their role in normal cell physiology and cancer pathogenesis, and for potential targeting in MBC. Importantly, we will invest considerable efforts into researching breast cancer brain metastasis (BCBM), a disease that has been largely neglected due to a lack of clinically relevant models and the difficulty to explore new treatment approaches. To this end, we will use novel orthotopic PDX models of BCBM that faithfully recapitulate genetic and phenotypic characteristics of the original patient samples, to investigate targeted drug combination therapies and resistance. There is a yet unmet need to develop safe targeted therapies against MBC, to thoroughly investigate combined immunotherapy and targeted therapies in breast cancer, and to discover effective treatments against BCBM. We have the experience, expertise and support to carry out these studies, and we are confident that we can make a significant contribution to the field of metastatic breast cancer, and to the many patients and families afflicted by this disease.

项目概要/摘要 转移性乳腺癌 (MBC) 是一种毁灭性疾病，占乳腺癌死亡率的 90% 以上 目前尚无有效的治疗方法。新增乳腺癌确诊病例超过 23 万例 仅在美国，每年就有超过 40,000 人死亡，开发安全 有效治疗 MBC 是当务之急。我们的研究计划旨在解决这个问题 通过结合基础研究和临床前研究来研究重要疾病，这些研究可以转化为有意义的临床 MBC 患者的结局。由于对分子机制的了解不断加深 潜在的致癌依赖性和对治疗的耐药性、靶向治疗的出现以及大多数 最近，免疫疗法彻底改变了我们现代癌症治疗的方法。这些进步， 结合改进的模型和新技术，为解决一些最困难的问题打开了大门 癌症治疗中的挑战。我们将利用我们在信号转导和药理学方面的专业知识， 以及我们之前关于靶向耐药性和敏感性的发现，设计安全有效的 针对 MBC 的靶向治疗。具体来说，我们将研究 PTEN 和特定 PI3K 亚型在 使用多个基因工程小鼠模型 (GEMM) 和患者来源的转移扩散 异种移植物（PDX）。我们还将评估联合免疫疗法和靶向 PI3K 亚型的使用 对同基因小鼠 MBC 模型具有特异性抑制作用。另外，近期我们还将深入研究两个 发现并有希望的新靶标，母体胚胎亮氨酸拉链激酶 (MELK) 和 CDK7， 被证明在基底样或三阴性乳腺癌中是必需的，但在正常细胞中是可有可无的，因为它们 在正常细胞生理学和癌症发病机制中的作用，以及 MBC 中的潜在靶向。重要的是，我们将 投入大量精力研究乳腺癌脑转移（BCBM），这种疾病已被 由于缺乏临床相关模型且难以探索新的治疗方法而在很大程度上被忽视 接近。为此，我们将使用 BCBM 的新型原位 PDX 模型，忠实地再现遗传 和原始患者样本的表型特征，以研究靶向药物组合 疗法和抵抗力。开发针对 MBC 的安全靶向疗法的需求尚未得到满足， 深入研究乳腺癌的联合免疫治疗和靶向治疗，并发现 针对 BCBM 的有效治疗方法。我们拥有开展这些研究的经验、专业知识和支持， 我们有信心能够为转移性乳腺癌领域做出重大贡献，并 许多患者和家庭都受到这种疾病的困扰。