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.

项目摘要/摘要 候选人。医学博士Jacob D. Soumerai是哈佛医学的医学助理教授 马萨诸塞州综合医院（MGH）的学校（HMS）和血液学家/医学肿瘤学家 他在淋巴瘤和慢性淋巴细胞性白血病（CLL）方面进行了指导的临床研究。 他在接下来的5年中的目标是过渡到R01资助的独立调查员领导者 一项临床试验和翻译生物标志物研究计划，该计划推进了患者的护理 淋巴瘤/CLL。指导，职业发展和培训活动。确保他的 成功过渡到独立性，Soumerai博士制定了强大的职业发展计划 他的精神是通过重点培训/课程和心理来解决他的培训差距。 具有非重叠技术专长的淋巴瘤和CLL的世界知名专家 与Soumerai博士提议的K08研究计划和职业目标有关，并包括Jeremy Abramson MD，Timothy Graubert MD和Andrew Zelenetz MD博士。 Soumerai博士的K08职业生涯 开发计划将为翻译的生物标志物测定开发提供必要的培训， 生物标志物研究，监管要求/程序的先进生物统计技术 和临床公用事业评估，以开发经过验证的临床使用的生物标志物。研究。经过验证 需要进行响应的预测标记来开发个性化疗法，最终需要 改善CLL的人的健康和生存。他的核心目标是在临床上识别 经过验证的响应预测标记，有助于指导个性化CLL的开发 疗法。为了实现这一目标，他将使用他的Co-Ementor对BCL2抑制剂（BCL2I）的试验 疗法，根据ΔMRD400状态修改治疗持续时间（400倍最小残留 疾病（MRD）在4个月内部署）以验证ΔMRD400作为指导的预测标记 治疗持续时间以实现无法检测到的MRD（UMRD）并识别高危患者（AIM 1）。 接下来，他将使用他的同事试验中的BCL2I撤退效率数据来确定是否是否 Δmrd400先验疗法，生存的球危险因素（B2-微球蛋白，， 贫血，LDH，最后疗法的时间）或TP53突变/17p缺失可以预测BCl2i 撤退成功/失败（目标2）。最后，他将对串行基线/治疗患者进行串行 从他的同事的试验中示例到分阶段/capp-seq，以识别基因组特征 预测未能达到UMRD，这可能会确定导致的治疗脆弱性 新型热方法（AIM 3）。该提案/培训计划的完成将定位。 Soumerai具有必要的经验和技能，成为R01资助的独立 研究人员领导淋巴瘤/CLL的临床试验/转化生物标志物研究计划。