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.

项目摘要/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 目前没有有效的治疗方法。已诊断出超过230,000例新的乳腺癌病例 仅在美国，每年每年每年有40,000多人的死亡，制造安全 MBC的有效治疗是最重要的。我们的研究计划建议解决这个问题 重要疾病通过结合基本和临床前研究，这些研究可以转化为有意义的临床 MBC患者的结果。由于对分子机制的越来越了解 潜在的致癌依赖性和对治疗的抵抗力，目标疗法的出现以及大多数 最近，免疫疗法彻底改变了我们的现代癌症治疗方法。这些进步， 再加上改进的模型和新颖的技术，打开了解决一些最困难的大门 癌症治疗的挑战。我们将利用我们在信号转导和药理学方面的专业知识， 以及我们先前关于靶向耐药性和灵敏度的发现，以设计安全有效 针对MBC的靶向疗法。具体而言，我们将研究PTEN和特定PI3K同工型在 使用多种基因工程的小鼠模型（GEMM）和患者衍生的转移扩散 异种移植物（PDXS）。我们还将评估合并免疫疗法和靶向PI3K同工型的使用 对MBC的合成小鼠模型的特定抑制作用。此外，我们最近将彻底研究两个 发现且有希望的新型靶标，母体胚胎亮氨酸Zipper激酶（MELK）和CDK7，它们 事实证明，在基础样或三重阴性乳腺癌中至关重要，但在正常细胞中可置 在正常细胞生理和癌症发病机理以及MBC中的潜在靶向中的作用。重要的是，我们会的 在研究乳腺癌脑转移（BCBM）上投入大量努力，这种疾病一直存在 由于缺乏临床相关模型，很大程度上被忽视了，并且难以探索新的治疗方法 方法。为此，我们将使用忠实地概括遗传的新型BCBM的原位PDX模型 和原始患者样品的表型特征，以研究靶向药物组合 疗法和抗药性。尚未满足于开发针对MBC的安全靶向疗法，以 彻底研究乳腺癌中的免疫疗法和靶向疗法，并发现 有效针对BCBM的治疗方法。我们有经验，专业知识和支持来进行这些研究， 我们有信心，我们可以为转移性乳腺癌的领域做出重大贡献，并为 遭受这种疾病困扰的许多患者和家庭。