Predictive markers for personalized therapy in chronic lymphocytic leukemia

慢性淋巴细胞白血病个体化治疗的预测标记

• 批准号: 10591089
• 负责人: Jacob Soumerai
• 金额: $ 28.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591089
• 关键词: 17p; Abbreviations; Achievement; Address; Aftercare; Anemia; Antibodies; BCL2 gene; Biological Assay; Biological Markers; Biometry; Bone Marrow; Cancer Personalized Profiling by Deep Sequencing; Chronic Lymphocytic Leukemia; Clinical; Clinical Research; Clinical Trials; Clonal Evolution; Data; Detection; Development; Development Plans; Disease remission; Doctor of Philosophy; Ensure; Evaluation; Failure; Fellowship; Funding; General Hospitals; Globulins; Goals; Health; Hematologist; Kinetics; Knowledge; Lactate Dehydrogenase; Lymphoma; MS4A1 gene; Massachusetts; Medical Oncologist; Medicine; Mentors; Mentorship; Mission; Mutation; Patient Care; Patient-Focused Outcomes; Patients; Persons; Phase; Positioning Attribute; Procedures; Public Health; Recurrent disease; Relapse; Research; Research Personnel; Residual Neoplasm; Resistance; Retreatment; Risk; Risk Factors; Sampling; Scientific Advances and Accomplishments; TP53 gene; Technical Expertise; Techniques; Testing; Therapeutic; Time; Training; Training Activity; Translations; Treatment Efficacy; Variant; assay development; biomarker development; biomarker validation; career; career development; clinical translation; detection limit; experience; genomic predictors; genomic signature; high risk; improved; improved outcome; inhibitor; inhibitor therapy; leukemia treatment; medical schools; novel therapeutic intervention; peripheral blood; personalized medicine; phase II trial; predictive marker; predictive signature; professor; prognostic model; programs; prospective; relapse patients; resistance mechanism; response biomarker; skills; success; targeted sequencing; therapy duration; treatment duration; tumor DNA

PROJECT SUMMARY/ABSTRACT Candidate. Jacob D. Soumerai, MD is an Assistant Professor of Medicine at Harvard Medical School (HMS) and Hematologist/Medical Oncologist at Massachusetts General Hospital (MGH) who conducts mentored clinical research in lymphoma and chronic lymphocytic leukemia (CLL). His goal over the next 5 years is to transition to an R01-funded, independent investigator leading a clinical trials and translational biomarker research program that advances the care of patients with lymphoma/CLL. Mentorship, Career Development, and Training Activities. To ensure his successful transition to independence, Dr. Soumerai developed a robust career development plan to address his training gaps through focused training/coursework and mentoring. His mentors are world-renowned experts in lymphoma and CLL with non-overlapping technical expertise directly related to Dr. Soumerai’s proposed K08 research plan and career objectives, and include Jeremy Abramson MD, Timothy Graubert MD and Andrew Zelenetz MD, PhD. Dr. Soumerai’s K08 career development plan will provide necessary training in translational biomarker assay development, advanced biostatistical techniques for biomarker research, regulatory requirements/procedures and clinical utility evaluation to develop validated biomarkers for clinical use. Research. Validated predictive markers for response are needed to develop personalized therapies and ultimately to improve the health and survival of people living with CLL. His central goal is to identify clinically validated predictive markers for response that help guide development of personalized CLL therapies. To achieve this goal, he will use his co-mentor’s trial of BCL2 inhibitor (BCL2i)-based therapy, which modifies therapy duration based on ΔMRD400 status (400-fold minimal residual disease (MRD) depletion over 4 months) to validate ΔMRD400 as a predictive marker to guide treatment duration to achieve undetectable MRD (uMRD) and identify high-risk patients (Aim 1). Next, he will use BCL2i retreatment efficacy data from his co-mentor’s trial to determine if ΔMRD400 status with prior BCL2i therapy, BALL risk factors for survival (B2-microglobulin, Anemia, LDH, time from Last therapy), or TP53 mutation/17p deletion can predict BCL2i retreatment success/failure (Aim 2). Finally, he will subject serial baseline/on-treatment patient samples from his co-mentor’s trial to PhasED-Seq/CAPP-Seq to identify genomic signatures that predict for failure to achieve uMRD, which might identify therapeutic vulnerabilities leading to novel therapeutic approaches (Aim 3). Completion of this proposal/training plan will position Dr. Soumerai with the necessary experience and skills to become an R01-funded independent investigator leading a clinical trials/translational biomarker research program in lymphoma/CLL.

项目概要/摘要 Jacob D. Soumerai，医学博士，哈佛医学院医学助理教授 马萨诸塞州总医院 (MGH) 学校 (HMS) 和血液科医生/肿瘤内科医生 他在淋巴瘤和慢性淋巴细胞白血病（CLL）方面进行指导性临床研究。 他未来 5 年的目标是转变为由 R01 资助的独立调查员，领导 促进患者护理的临床试验和转化生物标志物研究计划 淋巴瘤/CLL 的指导、职业发展和培训活动，以确保他的健康。 成功过渡到独立，Soumerai 博士制定了稳健的职业发展计划 通过集中培训/课程和指导来解决他的培训差距。 淋巴瘤和慢性淋巴细胞白血病领域的世界知名专家，具有直接不重叠的技术专长 与 Soumerai 博士提出的 K08 研究计划和职业目标相关，包括 Jeremy Abramson 医学博士、Timothy Graubert 医学博士和 Andrew Zelenetz 医学博士、哲学博士 Soumerai 博士的 K08 职业生涯。 开发计划将为转化生物标志物测定开发提供必要的培训， 用于生物标志物研究、监管要求/程序的先进生物统计技术 和临床效用评估，以开发经过验证的生物标志物以供临床使用。 需要反应的预测标记来开发个性化疗法并最终 改善 CLL 患者的健康和生存，他的中心目标是临床识别。 经验证的反应预测标记，有助于指导个性化 CLL 的开发 为了实现这一目标，他将使用他的合作导师基于 BCL2 抑制剂 (BCL2i) 的试验。 治疗，根据 ΔMRD400 状态修改治疗持续时间（400 倍最小残留 疾病（MRD）耗尽超过 4 个月），以验证 ΔMRD400 作为预测标记来指导 治疗持续时间以达到不可检测的 MRD (uMRD) 并识别高风险患者（目标 1）。 接下来，他将使用来自他的共同导师试验的 BCL2i 再治疗疗效数据来确定是否 既往 BCL2i 治疗的 ΔMRD400 状态、BALL 生存风险因素（B2-微球蛋白、 贫血、LDH、距离上次治疗的时间）或 TP53 突变/17p 缺失可以预测 BCL2i 最后，他将对连续基线/治疗中的患者进行研究。 从他的合作导师的 PhasED-Seq/CAPP-Seq 试验中提取样本来识别基因组特征 预测未能实现 uMRD，这可能会识别导致 新颖的治疗方法（目标 3）的完成将定位博士。 Soumerai 拥有成为 R01 资助的独立人士所需的经验和技能 领导淋巴瘤/CLL 临床试验/转化生物标志物研究项目的研究员。