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

In this OsteoBites webinar, Dr. Karen E. Pollok and Dr. Pankita H. Pandya from the Indiana University School of Medicine discuss their research on novel therapeutic strategies for pediatric osteosarcoma (OS). They explore the use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, particularly when combined with BET inhibition, as a promising treatment approach for pediatric OS, regardless of retinoblastoma (RB) status.

Hyperactivation of CDK4/6 is an actionable molecular signature in pediatric and AYA OS patients. While CDK4/6 inhibition shows promise in reducing tumor progression, overcoming resistance remains a challenge. Their research aims to identify rational drug combinations that enhance the efficacy of CDK4/6 inhibition. This is crucial given that over 70% of OS patients have an RB deficiency, which can impact treatment response in other cancers. Their findings support further exploration of CDK4/6 inhibitors, especially alongside BET inhibition, as a viable therapeutic option for pediatric OS, regardless of RB status.

Dr. Pollok, Associate Director of Basic Science and Director of the Preclinical Modeling and Therapeutics Shared Resource Facility for the IU Simon Comprehensive Cancer Center (IUSCCC), leads a research program focused on finding cures for aggressive cancers like sarcomas and brain tumors. Her team uses multi-omics data to prioritize testing novel combination therapies and has developed over 60 tumor models from pediatric and adolescent patients.

Dr. Pandya, an Assistant Research Professor and Genomics Data Scientist, works in partnership with the Pediatric Precision Genomics Program. Her research tests novel targeted therapies to improve outcomes and minimize toxicity in pediatric and young adult solid cancers. She has extensive expertise in in-vivo modeling of aggressive pediatric sarcomas and uses multi-omics data to identify risk signatures, biomarkers, and therapeutic vulnerabilities.


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0:00 - Introduction: Osteobytes and Guest Speakers
0:44 - About Dr. Karen Pollock
1:59 - About Dr. Pinka Pandia
3:08 - Announcements: Childhood Cancer Awareness Month & FACTOR Conference
4:25 - Presentation: Landscape of Pediatric Cancer & Precision Genomics
7:16 - The Utility of Preclinical Models
8:06 - Patient-Derived Xenograft (PDX) Pipeline
10:15 - Unmet Clinical Need in Osteosarcoma
10:47 - Genomic Instability in Osteosarcoma & Therapeutic Strategy
11:39 - Scientific Vignette 1: Targeting BET Proteins
13:05 - Validating PDX Models' Fidelity
15:34 - BET Inhibition & Chemotherapy Combination
19:08 - BET Inhibitor Efficacy & Biomarkers
20:07 - Kinome Profiling & Pathway Analysis
22:18 - Interpreting TXNIP, GLI1, and AXL Data
23:21 - Salvage Agent and BET Inhibitor Combination
25:18 - Scientific Vignette 2: CDK4/6 Hyperactivation
27:29 - CDK4/6 Inhibitors: Palbociclib & Abemaciclib
28:57 - Palbociclib Monotherapy Efficacy
29:55 - Resistance Mechanisms to CDK4/6 Inhibition
31:31 - Maximizing Clinical Benefit: PI3K/mTOR & CDK4/6 Combination
35:17 - In Vivo & In Vitro Combination Studies
38:53 - Lung Colonization Model Results
40:15 - RB Deficiency & Genomic Instability
41:10 - Scientific Vignette 3: BET & CDK4/6 in RB Proficient/Deficient Sarcomas
43:16 - Combination Therapy in TT2 Model
44:30 - Future Studies & Ongoing Research
46:54 - Concluding Remarks & Acknowledgments
47:27 - Q&A: Genomic Sequencing and Biomarkers
49:01 - Q&A: Selecting PI3K/mTOR Inhibitors
50:19 - Q&A: Challenges in Grant Writing & Drug Prioritization
50:52 - Q&A: Heterogeneity and Spatial Transcriptomics
52:34 - Q&A: Combining Three Inhibitors & Sequential Dosing
54:34 - Q&A: Earlier Intervention & MAP Combination
56:30 - Q&A: PDX Model Passaging and Maintenance
58:18 - Closing Remarks

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