Defining mechanisms of thalidomide analog resistance

项目总结 沙利度胺及其类似物来那度胺和泊马度胺使患者的治疗发生了革命性变化。 多发性骨髓瘤(MM)和其他血液系统恶性肿瘤。然而，治疗耐药性仍然限制了他们 这是一种有效的治疗方法，是一种严重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， 致癌蛋白的靶向降解。因为只有药物靶标的蛋白质水平会受到影响， 使用传统技术很难对它们进行研究。我们开发了一种新的靶向质量 光谱分析来测量这些蛋白质，现在在目标1中建议使用这种分析方法来研究 沙利度胺类似物水平与来那度胺耐药性的关系 病人。在一项确定底物下游沙利度胺类似耐药性介体的正交研究中 我在多发性骨髓瘤细胞系中进行了多个基因筛选，并鉴定出维甲酸 受体α和核辅阻遏子作为来那度胺抵抗的潜在媒介。在目标2中，我建议 进一步研究这些基因及其在调节MM细胞对沙利度胺类似物反应中的作用。 总的来说，这项工作将进一步勾勒出对一类临床重要药物产生耐药性的两条主要途径 并为克服阻力的方法提供了新的线索。申请者亚当·斯珀林博士是一名肿瘤学家， 达纳-法伯癌症研究所(DFCI)。他80%的时间用于翻译研究，20%用于临床研究 练习照顾癌症患者。他概述了一项五年职业发展计划，以实现他的目标 成为翻译研究领域的独立调查者。斯珀林博士收集了一份建议 由国际公认的专家组成的委员会提供科学和职业指导。他已经确立了 与癌症表观遗传学、质谱学和应用生物统计学方面的专家合作，提供 实验建议和实地的具体培训。斯珀林博士将在DFCI进行这项研究 充分利用DFCI、哈佛和布罗德学院卓越的研究和教学环境。这个 达纳-法伯癌症研究所，拥有杰出的研究社区和长期的记录 对于独立内科科学家的成功指导，是完成这些任务的理想环境 实验和实现斯珀林博士作为一名独立医生的长期职业目标- 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.