Tissue Repository and Animal Models Core

  • Claxton, David F. (PI)
  • Claxton, David D.F (PI)

Project: Research project

Project Details

Description

PROJECT SUMMARY AML is a highly lethal neoplasm, which is increasing in incidence, and in spite of advances in our understanding of AML pathogenesis, it is still largely incurable. AML is heterogeneous, with subtypes defined by clinical, morphologic, cytogenetic, and molecular characteristics. This core provides viable, clinically annotated, and moleculary characterized primary human AML samples and animal models for mechanism- based therapeutic studies. Numerous examples of progress from grant years 1-5 have employed these resources. This Core will pursue the following Specific Aims: Aim 1) Expand, maintain, and characterize leukemia tissue banks. Data from the Penn State Cancer Institute (PSCI) Bank form much of the progress described in this application. The Core will be strengthened by the addition of preclinical/clinical isolates from Memorial Sloan Kettering Cancer Center (MSKCC). Our bank will be expanded through inclusion of clinical trial specimens acquired from Project 1 (CAV trial) and ECOG. Molecularly profiled samples will be made available to Projects and Cores for in vitro study and PDX construction (Aim 3). Aim 2) Assess the toxicities and determine the Maximum Tolerated Dose (MTD) and pharmacokinetics (PK) of agents in vivo. Animal models for preclinical toxicity (dose escalation, MTD and pharmacokinetics) assessment are in place at PSCI. Results from this Aim are critical for continued clinical development of therapeutics. Aim 3) Develop and maintain animal models for testing program-derived therapies. This application and our published studies demonstrate promising preclinical data acquired in a number of such models. Transplantable human AML cell line models labelled with luciferase and YFP/RFP grown as NRG xenografts allow in vivo tumor monitoring and provide rapid readout of anti-AML efficacy (PSCI). Considerable data are provided with these models in this application. Pre-clinical efficacy data in such models underscore the premise of evaluating ceramide nano- liposome (CNL), AraC and venetoclax in a phase Ib/IIa clinical trial (Project 1, pre-IND #142902, UVA Protocol Review Committee Approval #5414, CAV trial). Dr. Levine's (co-investigator; MSKCC) novel genetically accurate AML models provide state-of-the-art models of molecularly defined AML subtypes. These models will be critical in defining genetically-driven alterations in sphingolipid metabolism and for testing the efficacy of Program therapeutic regimens in all Projects (MSKCC). Finally, PDX models with well-defined primary AMLs will be used to validate findings in NRGS hosts (PSCI and MSKCC). Efficacy of Program therapeutics will be compared to and combined with clinically relevant standard-of-care (SOC) chemotherapy regimens. In aggregate, the Animal Modeling and Clinical Resources Core is a unique and state-of-the-art resource which provides all Projects with animal models and the clinical material needed to translate novel biologic insights and therapeutics into clinical studies.
StatusActive
Effective start/end date5/1/205/31/24

Funding

  • National Cancer Institute: $346,774.00
  • National Cancer Institute: $337,280.00

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