Simultaneous targeting of CDK4/6 and BETs is independent of RB status in osteosarcoma

Osteosarcoma Webinar Series: Karen E. Pollok, PhD, and Pankita H. Pandya, PhD, from the Indiana University School of Medicine, join us on OsteoBites to discuss their work exploring CDK4/6i, particularly in the context of BET inhibition, as a therapeutic option for pediatric OS, regardless of RB status.Hyperactivation of cyclin-dependent kinases 4 and 6 (CDK4/6) has been identified as an actionable molecular signature in pediatric and AYA OS patients at the Indiana University School of Medicine and others. While targeting CDK4/6 has shown promise in significantly reducing tumor progression in many cancers, resistance to CDK4/6 inhibition remains a challenge. To maximize CDK4/6 inhibitor (CDK4/6i) efficacy, a combination therapy will likely be required to mitigate emergence of resistance. Moreover, retinoblastoma proficiency (RB+) has been used as a biomarker to predict response and stratify patients for treatment with CDK4/6 inhibitors in other cancers. This is concerning in the context of OS, since over 70% of OS patients harbor a retinoblastoma deficiency (RB-). Therefore, validation of RB as a biomarker of therapeutic response to CDK4/6 inhibition in OS is needed. The lab's objective in these investigations is to identify rational drug combinations that enhance efficacy of CDK4/6 inhibition, and test prioritized combinations in both RB+ and RB- OS models. Their findings support further exploration of CDK4/6i, particularly in the context of BET inhibition, as a therapeutic option for pediatric OS, regardless of RB status.Dr. Pollok is the Associate Director of Basic Science and Director of the Preclinical Modeling and Therapeutics Shared Resource Facility for the IU Simon Comprehensive Cancer Center (IUSCCC). Dr. Pollok works with cancer research laboratories in the IUSCCC to enhance programmatic science focused on translation to the clinic. In her own lab, she leads a team-oriented research program that brings together basic scientists and clinicians focused on finding cures for aggressive cancers such as sarcomas and brain tumors. Her team utilizes multi-omics data to prioritize the testing of novel combination therapies and has developed over 60 tumor models from pediatric and adolescent patients treated at the Riley Hospital for Children IU Health. In collaboration with Dr. Pankita Pandya and the Pediatric Precision Genomics Program, they employ multi-omics data from these models to focus on testing new molecularly-guided targeted therapies. Their goal is to understand the mechanisms behind therapy-mediated tumor efficacy and emerging resistance.Dr. Pandya is heavily involved in translational team science, where she works in partnership with the Pediatric Precision Genomics Program at the Riley Hospital for Children at IU Health, as well as under the mentorship of Dr. Karen E. Pollok at the Herman B Wells Center. Her research initiatives involve testing novel targeted therapies for improving therapeutic outcomes while minimizing toxicity in pediatric and young adult solid cancers like sarcomas. As a genomics data scientist, she has training in multi-omics data management and mining. Additionally, Dr. Pandya has extensive expertise in in-vivo modeling of aggressive pediatric sarcomas. Such skillsets have enabled Dr. Pandya to identify risk signatures, biomarkers of therapeutic response, and other clinically-relevant therapeutic vulnerabilities in pediatric sarcoma patients for functional validation using molecularly characterized preclinical models that our translational team has developed.