Kendall Williams

BME PhD Proposal Presentation

Date:2021-11-30

Time: 1:00 PM - 3:00 PM

Location / Meeting Link: https://bluejeans.com/453401445/2784

Committee Members:

Wilbur Lam, MD, PhD (Advisor) Andrés García, PhD Melissa Kemp, PhD David Myers, PhD Christopher Porter, MD

Title: Microfluidic Multi-Drug Functional Profiling Towards Personalized Clinical Predictions in Pediatric Leukemia

Abstract: Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has seen dramatic improvements over the last several decades, leading to overall survival rates of over 85%. However, for patients with relapsed/refractory disease, achieving complete remission remains extremely challenging. Improving treatment outcomes for these patients will require increasingly personalized treatment strategies that make use of functional screens in addition to molecular profiling technologies. Given the past success of combination chemotherapy in cancer treatment and recent promise for newly developed targeted agents, functional assays that are able to evaluate patient response to combinations of therapies will likely be most effective in identifying clinically actionable treatment protocols. Moreover, those that can achieve this with minimal patient sample and reduced experimental workload will have the greatest chance of clinical translation and integration into clinical workflows. To that end, this work aims to develop a multi-dose, multi-drug functional response assay, enabled by overlapping stable gradients, to directly test up to three drug combinations in patient derived T-ALL cells and further aims to identify candidate biomarkers of combination response. Specifically, we will first develop, optimize, and validate our system for combination screening in primary samples (Aim 1). With this system, we will then seek to provide a better understanding of patient T-ALL response to standard combination therapies as well as combinations with targeted agents (Aim 2). We will specifically evaluate clinically relevant combinations consisting of agents FDA approved for either T-ALL or other malignancies, as well as combinations currently used in frontline T-ALL treatment. With these results, we will seek to clarify the prognostic value of specific clinical variables and our developed assay, and identify candidate biomarkers of combination response. In sum, the results of this work will provide a new methodology for three drug combination screening in limited sample settings, establish the prognostic value of drug combination response profiling in the context of available clinical data, and finally, evaluate the validity of potential markers as predictors of response to combinations with targeted agents in pediatric T-ALL.