Defining mechanisms of thalidomide analog resistance

项目摘要 沙利度胺及其类似物，来那度胺和泊马度胺，已经彻底改变了对患有糖尿病的患者的治疗。 多发性骨髓瘤（MM）和其他血液恶性肿瘤。然而，治疗耐药性仍然限制了他们的 有效性，代表了一个关键的未满足的医疗需求。这些药物通过一种独特的机制发挥作用， 到癌蛋白的靶向降解。因为只有药物靶点的蛋白质水平受到影响， 用常规技术难以研究。我们开发了一种新的靶向物质 光谱测定法来测量这些蛋白质，现在在目标1中提出使用该测定法来研究这些蛋白质。 沙利度胺类似物靶点水平与来那度胺耐药发生之间的关系 患者在一项正交研究中，以确定底物下游沙利度胺类似物耐药的介质 我已经在MM细胞系中进行了多次遗传筛选，并鉴定了维甲酸 受体α和核辅阻遏物作为来那度胺耐药的潜在介质。在目标2中，我建议 以进一步表征这些基因及其在介导MM细胞中对沙利度胺类似物的应答中的作用。 总的来说，这项工作将进一步概述两个主要的途径耐药的一类临床重要的药物 并揭示了克服抗药性的新方法。申请人，亚当·斯珀林博士，是一名肿瘤学家， Dana-Farber癌症研究所（DFCI）他将80%的时间用于转化研究，20%用于临床研究。 练习照顾癌症患者。他概述了一个五年职业发展计划，以实现他的目标， 成为翻译研究的独立调查员。斯珀林博士召集了一个顾问团 国际公认的专家委员会，提供科学和职业指导。他建立 与癌症表观遗传学、质谱学和应用生物统计学专家合作， 实验建议和实地具体培训。Sperling博士将在DFCI进行这项研究， 利用DFCI、哈佛和布罗德研究所卓越的研究和教学环境。的 丹娜-法伯癌症研究所，拥有一个杰出的研究社区，并有着悠久的历史 对于独立医生科学家的成功指导，是完成这些课程的理想环境。 斯珀林博士的长期职业目标是成为一名独立的医生- 科学家

PROJECT SUMMARY Thalidomide and its analogs, lenalidomide and pomalidomide, have revolutionized the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. However, therapeutic resistance still limits their efficacy and represents a critical unmet medical need. These drugs work through a unique mechanism leading to the targeted degradation of oncoproteins. Because only the protein levels of the drug targets are affected, they have been difficult to study using conventional technologies. We developed a novel targeted mass spectrometry assay to measure these proteins and now propose in Aim 1 to use this assay to study the relationship between the level of thalidomide analog targets and the development of lenalidomide resistance in patients. In an orthogonal study to identify mediators of thalidomide analog resistance downstream of substrate degradation I have performed multiple genetic screens in a MM cell line and have identified the retinoic acid receptor alpha and the nuclear corepressor as potential mediators of lenalidomide resistance. In Aim 2 I propose to further characterize these genes and their roll in mediating the response to thalidomide analogs in MM cells. Collectively, this work will further outline two major pathways of resistance to a clinically important class of drugs and shed new light on methods to overcome resistance. The applicant, Dr. Adam Sperling, is an oncologist at the Dana-Farber Cancer Institute (DFCI). He spends 80% of his time in translational research and 20% in clinical practice caring for patients with cancer. He has outlined a five-year career development plan to meet his goal of becoming an independent investigator in translational research. Dr. Sperling has assembled an Advisory Committee of internationally recognized experts to provide scientific and career mentorship. He has established collaborations with experts in cancer epigenetics, mass spectrometry, and applied biostatistics to provide experimental advice and specific training in the field. Dr. Sperling will conduct this research at the DFCI and leverage the exceptional research and teaching environment at the DFCI, Harvard, and the Broad Institute. The Dana-Farber Cancer Institute, which harbors an outstanding research community and has a long track record for successful mentorship of independent physician scientists, is an ideal environment for completion of these experiments and the realization of Dr. Sperling’s long-term career goal of being an independent physician- scientist.