Wednesday, April 24, 2024
4/24/2024
Project Summary/ Abstract Survival outcomes for patients with osteosarcoma have not changed since the advent of modern chemotherapy four decades ago and it has been challenging to develop new effective therapies in this disease. Our lab’s long- term mission is to identify novel molecular targets in osteosarcoma via comprehensive genomic and proteomic profiling of patient-derived cell lines and xenografts as well as human tumors with the ultimate goal of identifying and/or developing and testing therapeutics against these targets. To achieve this goal, we have a) built a robust profiling platform to identify novel targets; b) expanded our repertoire of osteosarcoma patient derived xenograft (PDX) models to reflect disease heterogeneity; and c) conducted high-throughput in vivo testing of 8-10 new agents each year both as part of Pediatric Preclinical Testing Consortium (PPTC) as well as independent of it. All of these efforts form the basis of our current research proposal and place us strongly poised to successfully achieve our goals. Our overall objective is to efficiently evaluate the efficacy of new agents with high potential to have activity in osteosarcoma based on target data from our genomic and proteomic profiling both as single agents and in rational combinations, with the vision of moving effective agents into clinical trials through the Children’s Oncology Group. We have three specific aims- 1) to select and test agents in vivo against surface targets identified by comprehensive proteomic profiling of osteosarcoma xenografts and patient tumors; 2) to select and test agents in vivo against targets identified by comprehensive genomic profiling of osteosarcoma xenografts and patient tumors; and 3) to perform testing of rationally combined agents based on target, toxicity and efficacy data of single agents. Agents from the PPTC pipeline will be selected based on either the proteomic target or genomic alteration being present in at least a subset of available osteosarcoma PDX models. The agent will be tested in selected cohorts of low/ high expressing protein target or present/ absent genomic alteration. In cases with multiple models with target expression, 3-5 mice per model will be used and in cases with few models available, 8-10 mice per model will be used for control and experiment groups with an overall n per arm per experiment of approximately 30 mice. Standard PPTC procedures will be used for tumor implantation and treatment. Tumor dimensions will be measured twice a week and response quantified as per standard PPTC definitions of complete response, maintained complete response, partial response, stable disease and progressive disease. For combination studies, three potential types of combinations will be considered based on efficacy and toxicity data- a) two surface protein targeted agents such as two antibody-drug conjugates; 2) two molecularly targeted agents and 3) a surface protein targeted agent and a molecularly targeted agent. Our results will guide the development of the next generation of clinical trials in osteosarcoma.
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