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。雅各布·D·索梅莱，医学博士，哈佛医学院医学助理教授 麻省总医院(MGH)学校(HMS)和血液学家/内科肿瘤学家(MGH) 世卫组织在淋巴瘤和慢性淋巴细胞白血病(CLL)方面进行有指导的临床研究。 他的目标是在未来5年内过渡到由R01资助的独立调查员 促进患者护理的临床试验和翻译生物标记物研究计划 淋巴瘤/慢性淋巴细胞性白血病。指导、职业发展和培训活动。以确保他的 成功过渡到独立后，索梅莱博士制定了强有力的职业发展计划 通过有重点的培训/课程作业和指导来弥补他的培训差距。他的导师是 世界知名的淋巴瘤和慢性淋巴细胞性白血病专家，直接拥有不重叠的技术专长 与Soumerai博士提出的K08研究计划和职业目标相关，包括Jeremy 艾布拉姆森医学博士、蒂莫西·格劳伯特医学博士和安德鲁·泽勒内茨医学博士。苏梅莱博士的K08职业生涯 发展计划将提供必要的翻译生物标记物分析开发培训， 生物标记物研究的先进生物统计技术、法规要求/程序 和临床效用评估，以开发临床使用的有效生物标记物。研究。经过验证 需要反应的预测性标记物来开发个性化治疗，并最终 改善慢性淋巴细胞性白血病患者的健康和生存。他的中心目标是在临床上识别 经过验证的响应预测性标记，有助于指导个性化CLL的开发 治疗。为了实现这一目标，他将使用他的合作导师对基于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 疾病耗竭超过4个月)以验证ΔMRD400作为预测标记物来指导 治疗持续时间以实现无法检测的MRD(UMRD)并识别高危患者(目标1)。 接下来，他将使用他的合作导师试验中的BCL2i再治疗疗效数据来确定 曾接受BCL2i治疗的ΔMRD400状态，生存的球类危险因素(B2-微球蛋白， 贫血、乳酸脱氢酶、最后治疗时间)或TP53突变/17p缺失可预测BCL2i 再治疗成功/失败(目标2)。最后，他将让连续基线/正在治疗的患者 从他的同事导师的试验到分阶段序列/CAPP-Seq的样本，以确定 预测未能实现uMRD，这可能会识别导致以下疾病的治疗漏洞 新的治疗方法(目标3)。该提案/培训计划的完成将使Dr。 索梅莱拥有成为R01资助的独立公司所需的经验和技能 领导淋巴瘤/CLL临床试验/翻译生物标记物研究计划的研究员。