Wednesday, April 2, 2025
4/2/2025
Modeling and targeting intrinsic and extrinsic features of Myc-driven Osteosarcoma - Osteosarcoma (OS) is the most common bone tumor in pediatric patients. While defining genetic mutations are rare for OS, somatic DNA copy number alterations (SCNA) are a hallmark of OS and are becoming a means towards categorizing this complex, heterogeneous disease. One such SCNA is amplification of chromosome 8q24, which harbors the oncogene c-MYC, occurs in approximately 30% of OS patients. This molecular subgroup of patients has a high-risk of relapse and overall poor prognosis when treated with the current standard of care. However, targeting oncogenic transcription factors such as Myc through direct protein inhibition has been a tremendous challenge, thus signifying the need to gain a comprehensive understanding of the complete tumor biology in order to identify effective and actionable therapeutic regimens. Recent studies indicate that oncogenes not only cause tumor-intrinsic molecular aberrations, but these intrinsic molecular defining traits can cause extrinsic ramifications on the tumor microenvironment (TME), including regulating immune infiltrations. The central hypothesis is that the Myc-amplified OS tumors confer unique intrinsic molecular signatures that dictate extrinsic microenvironmental dynamics on OS cells. These unique molecular and cellular distinctions will result in therapeutic vulnerabilities that can selectively inhibit Myc-amplified OS cells. Our proposal uses complementary resources, including publically available databases and cross-species analysis of homologous OS patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM) we have garnered, generated, and characterized towards dissecting and targeting the defining intrinsic and extrinsic Myc-amplified molecular signatures. While the approaches are innovative, they are rational and achievable, with well-defined OS resources, including immunocompetent models are readily available, thus demonstrating feasibility. AIM1: Comprehensively characterize and genetically perturb cross-species molecular features of Myc-hyperactivated human and murine OS tumors. We will define intrinsic and extrinsic single cell proteo-transcriptomic signatures and cell-cell communications present in our murine and human primary and metastatic patient tumors. We will also perform proof-of-concept genetic perturbation to disrupt candidate metastatic-associated cell-cell communications. Subsequent bioinformatic analysis will provide additional candidate therapeutic avenues to be streamlined into Aim3. AIM2: Determine the role of Myc in the reprogramming of immune suppressive TME in OS. We will employ our dTAG-MYC to characterize Myc-dependent intrinsic and extrinsic effects on OS. We will investigate the role of identified Myc-mediated immune modulators, specifically CCL9 (MIP-1ϒ) on T cell and myeloid activity. AIM3: Novel combinatorial therapeutic approaches targeting Myc-hyperactivated tumors that remodels the immune TME and consequently enhances targeted therapeutic efficacy. The long-term goal will change the treatment paradigm by enabling early risk stratification, upfront targeted therapy, and enhanced patient outcomes for this high-risk SCNA subgroup of OS patients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).