Abstract B04: Novel Methods to Target RB Pathway Disruption in Osteosarcoma

Abstract

Abstract Osteosarcoma, prevalently a pediatric disease, is the most common primary non-hematologic bone tumor. The five-year survival rates range from 24-62% depending on age. A deeper understanding of the disease and new therapeutic approaches are crucial to reducing osteosarcoma's morbidity and mortality. Data from our and other laboratories point to interconnections between bone development and cancer. Specifically, RB1 gene mutation (encoding retinoblastoma protein or pRB) is observed in 60% of sporadic osteosarcomas, and the pRB pathway is altered in osteosarcomas that retain pRB function. Mouse data suggests that loss of pRB can change osteoprogenitor function and increase osteosarcoma formation. Our work shows that: pRB loss leads to the expansion of bipotent (adipogenic/osteogenic) progenitor cells, properties also found in osteosarcomas; pRB binds to and activates the transcriptional regulator of osteogenesis Runx2, suggesting that pRB could alter promoter binding by chromatin modifying enzymes and regulate osteoblast differentiation; pRB can act as a transcriptional coactivator with Runx2 inducing Indian hedgehog (Ihh) expression late in osteoblast differentiation (Ihh can drive osteoprogenitor cells to the osteoblast lineage, potentially mediating the pRB phenotype loss in osteoblasts). Our studies also show a role for CDK6 in Runx2 activation and bone development, and a requirement for CDK6 activity in p53-dependent osteosarcoma. Thus, here we (a) analyze the role of pRB in fate specification of osteoblasts; (b) test the function of Ihh as a mediator of altered differentiation and tumorigenesis in pRB-null cells; and (c) test the role of CDK6 as a therapeutic target in osteosarcoma. Citation Format: Philip W. Hinds, Miriam Enos, Elizabeth Kong, Elisabeth Dignan, Volkan Gunduz, Jodie Pietruska. Novel Methods to Target RB Pathway Disruption in Osteosarcoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B04.