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

项目摘要/摘要 转移性乳腺癌(MBC)是一种破坏性疾病，占乳腺癌死亡的90%以上。 而且目前还没有有效的治疗方法。新确诊的乳腺癌病例超过23万例 每年，仅在美国每年就有超过4万人死亡，开发出安全的 而有效的治疗MBC是当务之急。我们的研究计划建议解决这个问题 通过将基础研究和临床前研究相结合，可转化为有意义的临床研究，从而获得重要的疾病 MBC患者的预后。促使人们对分子机制的理解不断加深 潜在的致癌依赖性和治疗耐药性，靶向治疗的出现，以及大多数 最近，免疫疗法的出现彻底改变了我们现代癌症治疗的方法。这些进步， 加上改进的模型和新颖的技术，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， 以及我们之前在靶向耐药性和敏感性方面的发现，以设计安全有效的 针对MBC的靶向治疗。具体地说，我们将研究PTEN和特定的PI3K亚型在 使用多种基因工程小鼠模型(GEMM)和患者来源的转移性传播 异种移植(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模型的特异性抑制作用。另外，我们最近还将深入研究两个 发现并有前景的新靶点，母体胚胎亮氨酸拉链酶(Melk)和CDK7，它们 证明在基底细胞样癌或三阴性乳腺癌中是必不可少的，但在正常细胞中是必不可少的，因为它们的 在正常细胞生理学和癌症发病机制中的作用，以及在MBC中的潜在靶向。重要的是，我们会 投入大量精力研究乳腺癌脑转移(BCBM)，这种疾病已经 由于缺乏临床相关模型和探索新疗法的困难，很大程度上被忽视了 接近了。为此，我们将使用BCBM的新型原位PDX模型，该模型忠实地概括了遗传 和原始患者样本的表型特征，以研究靶向药物组合 治疗和抵抗。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。我们拥有开展这些研究的经验、专业知识和支持， 我们有信心为转移性乳腺癌领域做出重大贡献，并为 许多受这种疾病折磨的病人和家属。

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.