Defining the Biological and Mechanistic Implications of XPO1 Mutations in Hematologic Malignancies

候选人：贾斯汀·泰勒是纪念斯隆·凯特琳癌症中心的医学讲师， 在纪念医院参加白血病服务。他一直在与他推荐的K08导师合作， Omar Abdel-Wahab博士了解转化型临床前剪接因子突变白血病靶向 现在已经开始独立工作，以发现XPO1热点突变在血液学中的作用 将恶性肿瘤作为潜在的治疗靶点。他的目标是制定一项独立的研究计划， 在接下来的5年里，有一个独立的实验室从事转化性血液肿瘤的研究。 职业发展计划：泰勒博士已经战略性地计划解决必要的培训和 这将是他在未来几年成功过渡到独立职业生涯所需的指导 通过精选的课程和强大的指导计划。他还组织了一个咨询委员会 不仅由该领域的领导者组成，而且还包括那些能够直接影响他的职业发展的人。这 将不仅确保泰勒博士的研究项目按计划进行，而且他的进展是 在获得独立研究资金方面得到了促进和支持。他有一个非常令人兴奋的 研究项目与导师的研究有很大的不同，以避免竞争或重叠。 研究计划：癌症亚型的大型发现测序项目，如癌症基因组 Atlas发现了蛋白质编码基因的大量新的重复性突变。的最终目标是 这些测序工作是为了改善癌症患者的治疗方法，并将需要 了解这些突变如何在机制上促进癌症的发生。然而，即使当 基因的功能是已知的，突变的生物效应不能总是从编码中推断出来 序列。在这项提议中，我们计划发现细胞核中体细胞突变的生物学相关性 运输蛋白XPO1。XPO1的体细胞突变已在固体和血液学中被证明 恶性肿瘤，包括约10%的慢性淋巴细胞白血病和25%的原发 纵隔B细胞淋巴瘤和经典型霍奇金淋巴瘤。有选择地禁止核出口 在目前的I/II期临床试验中，抑制XPO1已被用作抗肿瘤药物。然而，尽管 XPO1被认为是癌症的潜在驱动因素，目前还没有直接的致癌证据 XPO1基因体细胞突变的可能性。我们计划通过使用等基因来探索这些突变的影响。 细胞系、基因工程小鼠模型和人体组织。此外，由于XPO1是一种核子 Exporter，我们将研究这些基因改变对蛋白质亚细胞定位的影响。最后，我们的目标是 确定XPO1突变对目前正在开发的XPO1抑制剂的反应的影响。结束 这项研究的目标是按顺序发现XPO1突变的生物学和机制意义 开发合理和知情的靶向治疗方法来治疗这些仍有临床需要的癌症。

Candidate: Justin Taylor is an Instructor in Medicine at Memorial Sloan Kettering Cancer Center and Attending on the Leukemia Service at Memorial Hospital. He has been working with his proposed K08 mentor, Dr. Omar Abdel-Wahab, to learn about targeting splicing factor mutant leukemias in translational preclinical models and now has begun independent work to discover the role of XPO1 hotspot mutations in hematologic malignancies as a potential therapeutic target. His goal is to develop an independent research program over the next 5 years and have an independent laboratory doing translational hematologic malignancies research. Career Development Plan: Dr. Taylor has strategically planned to address the necessary training and mentoring that will be required for his successful career transition to independence over the next few years through select coursework and a robust mentoring plan. He has also organized an advisory committee composed not only of leaders in the field but also those able to directly impact his career advancement. This will not only ensure that Dr. Taylor's research project progresses as planned, but also that his progress is recognized by promotion and support in garnering independent research funding. He has a very exciting research project that is sufficiently different from his mentor's research to avoid competition or overlap. Research Plan: Large discovery sequencing projects of cancer sub-types, such as The Cancer Genome Atlas, have identified a multitude of novel recurrent mutations in protein coding genes. The ultimate goal of these sequencing efforts is to lead to improved therapies for patients with cancer and will require understanding how these mutations mechanistically contribute to carcinogenesis. However, even when the function of a gene is known, the biological effect of the mutation cannot always be inferred from the coding sequence. In this proposal, we plan to discover the biological relevance of somatic mutations in the nuclear transport protein XPO1. Somatic mutations in XPO1 have been demonstrated in solid and hematologic malignancies, including ~10% of cases of chronic lymphocytic leukemia and 25% of cases of primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. Selective inhibition of nuclear export by inhibiting XPO1 has been utilized as an antineoplastic agent in current Phase I/II clinical trials. Yet, despite recognition of XPO1 as a potential driver of cancer, there has been no direct demonstration of the oncogenic potential of somatic mutations in XPO1. We plan to explore the effects of these mutations by using isogenic cell lines, genetically engineered mouse models and human tissues. Furthermore, since XPO1 is a nuclear exporter, we will study the effect of these genetic alterations on protein subcellular localization. Lastly, we aim to determine the effects of XPO1 mutations on response to XPO1 inhibitors currently in development. The end goal of this research will be to discover the biological and mechanistic implications of XPO1 mutations in order to develop rational and informed targeted therapies to treat these cancers for which there is still clinical need.