Clinical Shared Resource

Dana-Farber Cancer Inst, Boston MA

Investigators

Linked publications, trials & patents

Abstract

Project Summary Core 3 The Clinical Research Support Core 3 is dedicated to two major efforts: biobanking and translating preclinical data into studies. First, we are responsible for consenting and collecting biospecimens from patients with MDS/AML at times of diagnostic procedures and at scheduled timepoints in clinical trials for ancillary studies. We will obtain samples at diagnosis, remission, and relapse and transfer them to Biospecimen Core 1 for clinical annotation and availability for scientists in the projects. Project 1 focuses on identifying the potential therapeutic role for another anti-apoptotic protein BFL-1 (also known as A1), which has been understudied in AML. This Letai-led project requires human leukemic blasts for routine and dynamic BH3 profiling to reveal functional and pharmacologic dependencies based on mitochondrial apoptotic response. Ebert-led Project 2 focuses on the biology of MYB degradation in response to microtubule destabilization and its implications on MYB-dependent leukemia. Recently, menin inhibitors have demonstrated clinically meaningful activity among distinct AML subsets with preclinical groundwork laid by the Armstrong lab. The immediate next step to advance the field is to prevent single-agent resistance. The Armstrong and Fischer labs (Project 3) will examine the role of menin in maintaining KMT2A complex stability and chromatin conformation, and preclinically evaluate new menin degraders. Project 4 focuses on R-loop regulation and the therapeutic implications of targeting cGAS and STING pathways to resolve R loops in cohesin-mutated MDS/AML. Second, Core 3 will design and execute clinical trials emanating from the science described in the projects. We anticipate at least one clinical trial during the funding period, including a menin and KAT6A inhibitor study in AML. After the funding period we anticipate additional development of a proof-of-concept study in cohesin-mutated MDS/AML once a therapeutic cGAS/STING modulator is identified. The overarching goal of the clinical trials is to improve the outcome of patients with leukemia. Clinical trial designs including dose scheduling, pharmacodynamic analysis, and correlative studies to confirm target engagement, will be informed by Biostatistical Core 2. Biostatistical Core 2 will also assist in the analysis of clinical and correlative data for publication. Rigorous biobanking with clinical annotation will provide opportunity for sample use in assays within the projects, which will inform leukemia biology, and potentially reveal additional targets that can be exploited. Collaboration directly facilitated by this grant will accelerate translation of these findings into scientifically driven clinical studies.