Title:
Discovery and Development Strategies of Combination Nanomedicines for Childhood Blood Cancers

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Author(s)
Kelvin, James Michael
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Dreaden, Erik C.
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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 for pediatric patients with leukemia. This Dissertation describes the discovery and development of combination nanomedicines to address this need. We integrate three distinct treatment strategies to maximize the therapeutic potential of novel drug combinations: (i) use tyrosine kinase inhibition to exploit ectopic molecular vulnerabilities; (ii) identify synergistic drug ratios that amplify tumor cell killing; and (iii) formulate therapeutic combinations in liposomal nanocarriers for intracellular delivery of constitutively synergistic drug ratios. Governing our approach is the hypothesis that the conditional delivery of synergistic drug ratios identified in vitro will result in reduced disease burden and prolonged survival in mouse models of leukemia when compared to additive or antagonistic nanoformulations. Our efforts to discover and develop synergistic nanomedicines are mirrored between studies of pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). We begin by describing results from a novel, combinatorial high-throughput drug screen in which we identified ratio-dependent synergy between a dual MERTK/FLT3 inhibitor, MRX-2843, and cytotoxic chemotherapy (vincristine) in T-cell ALL (T-ALL) or BCL-2 inhibition (venetoclax) in AML. We then used computational models to select optimal pairwise drug combinations that exhibited robust inhibition of cell expansion and conserved ratiometric synergy in T-ALL and AML lineages. We characterized pairwise drug synergy by building predictive classifiers of drug responses between MRX-2843 and venetoclax in AML cell lines, and used RNA sequencing to explore functional ontologies that undergird the mechanism of drug synergy between MRX-2843 and vincristine in T-ALL. Next, we developed a clinical-scale manufacturing method that (co-)encapsulated defined drug ratios in liposomal nanoparticles. Nanoformulations delivered intracellular drug ratios at defined stoichiometries and demonstrated synergistic activity in primary patient samples—consistent with high-throughput screens—such that nanoparticles magnified dose-dependent synergy relative to matched free drug ratios. Finally, we directly compared synergistic, additive, and antagonistic nanomedicines in a mouse model of early thymic precursor ALL (ETP-ALL). We found that increasing the dose of MRX-2843 sensitized ETP-ALL cells to vincristine chemotherapy in vivo, and that synergistic and additive nanoformulations reduced disease burden and extended survival relative to liposomal controls. Counter to the hypothesis, the additive nanoformulation most effectively controlled disease and extended survival, a finding that contextualizes the prioritization of ratiometric synergy and therapeutic efficacy in nanomedicine design. In sum, we present a systematic approach to combination drug discovery and development for novel nanomedicines in pediatric leukemias. Our findings underscore the clinical relevance of MRX-2843 in combination with venetoclax in pediatric AML and support the translation of co-formulated MRX-2843 and vincristine nanomedicines for the treatment of pediatric patients with T-ALL. Our generalizable approach may be applied to different drug combinations that treat hematologic neoplasms or other cancers.
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Date Issued
2023-04-17
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Dissertation
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