James M. Kelvin
BME PhD Defense Presentation
Date: 2023-03-15
Time: 3:00 PM - 5:00 PM
Location / Meeting Link: HSRB E260; https://jamesmichaelkelvin-935.my.webex.com/meet/jkelvin
Committee Members:
Erik C. Dreaden, Ph.D. (Advisor); Deborah DeRyckere, Ph.D.; Melissa L. Kemp, Ph.D.; Yuhong Du, Ph.D.; Younan Xia, Ph.D.
Title: Discovery and Development Strategies of Combination Nanomedicines for Childhood Blood Cancers
Abstract:
Blood cancers are the most frequently diagnosed and the second deadliest of malignancies in children. Despite advances in multiagent chemotherapy that have contributed to improved survival rates, nearly half of patients who survive will suffer from treatment associated long-term toxicities, and a considerable number of patients eventually relapse with poor survival prognoses thereafter. Thus, there is an urgent and unmet clinical need to develop novel therapies that improve treatment outcomes in pediatric patients with leukemia. Conventional therapeutic regimens often ignore ratio-dependent effects between drugs in combination that can amplify tumor cell killing (synergy) or provoke a sub-optimal response (additivity or antagonism). In this Dissertation, we describe the discovery and development of nanoscale combination therapeutics based on the principle of ratio-dependent multidrug synergy. We approach our task via three specific aims: (i) develop synergistic nanomedicines through the high-dimensional, combinatorial discovery of ratiometric drug interactions; (ii) use computational and transcriptomic tools to guide the selection, prediction, and mechanistic interpretation of ratiometric synergy in pairwise drug combinations; and (iii) evaluate treatment outcomes in primary patient samples and mouse models of leukemia using engineered liposomal formulations of defined drug ratios. We divided our investigations between two types of pediatric leukemia: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). We first developed a novel, combinatorial high-throughput drug screen that measured tyrosine kinase inhibition in combination with frontline chemotherapy and anti-apoptotic inhibitors. Then, using computational models we identified strong, lineage-conserved ratiometric synergy in T-cell ALL (T-ALL) and AML, and subsequently developed a clinical-scale manufacturing method to encapsulate synergistic ratios of pairwise combinations in nanoparticles. We demonstrated conditional delivery into the intracellular compartment and observed clinically relevant synergistic responses in patient-derived specimens. Finally, we compared synergistic, additive, and antagonistic nanoformulations in a mouse model of T-cell leukemia. We observed significant delays in disease progression and extensions in survival mediated by the synergistic and additive nanoformulations. In sum, we present a systematic approach to discovery and development that maximizes the therapeutic potential of ratiometric nanomedicines for the treatment of childhood blood cancers.