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.

项目总结/摘要 候选人雅各布·D Soumerai博士是哈佛医学院的医学助理教授 学校（HMS）和马萨诸塞州总医院（MGH）的血液科医生/肿瘤内科医生 他指导淋巴瘤和慢性淋巴细胞白血病（CLL）的临床研究。 他在未来5年的目标是过渡到一个R 01资助的，独立的调查领导 一个临床试验和转化生物标志物研究计划，促进患者的护理 淋巴瘤/CLL指导、职业发展和培训活动。以确保他 成功过渡到独立后，Soumerai博士制定了一个强大的职业发展计划， 通过有针对性的培训/课程和辅导来解决他的培训差距。他的导师是 世界知名的淋巴瘤和CLL专家，直接拥有非重叠的技术专长 与Soumerai博士提出的K 08研究计划和职业目标相关，其中包括Jeremy Abramson医学博士，Timothy Graubert医学博士和Andrew Zelenetz医学博士，博士。Soumerai博士的K 08职业生涯 开发计划将提供翻译生物标志物测定开发方面的必要培训， 用于生物标志物研究的先进生物统计技术、监管要求/程序 和临床效用评估，以开发用于临床使用的经验证的生物标志物。Research.验证 需要反应的预测标志物来开发个性化治疗， 改善CLL患者的健康和生存。他的中心目标是从临床上识别 经验证的反应预测标志物，有助于指导个性化CLL的发展 治疗为了实现这一目标，他将使用他的共同导师的BCL 2抑制剂（BCL 2 i）的试验为基础， 治疗，根据Δ MRD 400状态（400倍最小残差）修改治疗持续时间 疾病（MRD）消耗超过4个月），以验证Δ MRD 400作为预测标志物， 治疗持续时间，以实现不可检测的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的试验的BCL 2 i再治疗疗效数据来确定是否 既往BCL 2 i治疗的Δ MRD 400状态，生存期的BALL风险因素（B2-微球蛋白， 贫血、LDH、距上次治疗的时间）或TP 53突变/17 p缺失可以预测BCL 2 i 再治疗成功/失败（目标2）。最后，他将对连续基线/治疗中患者进行研究 将他的共同导师的试验样品用于PhasED-Seq/CAPP-Seq，以鉴定 预测无法实现uMRD，这可能会识别导致 新的治疗方法（目标3）。完成本提案/培训计划后， Soumerai具有必要的经验和技能，成为R 01资助的独立 领导淋巴瘤/CLL临床试验/转化生物标志物研究项目的研究者。