Research at the George Lab

We investigate how normal developmental programs are disrupted in cancer, with an emphasis on transcriptional and chromatin regulation. Using genome-wide approaches, first-in-class small molecule inhibitors, and functional models, we aim to define oncogenic mechanisms and uncover new therapeutic strategies.
 

ALK Kinase Mutations in Neuroblastoma

Our lab discovered activating mutations in the ALK tyrosine kinase, the first targetable genetic abnormality in neuroblastoma, leading to clinical trials of ALK inhibitors and their incorporation into standard therapy (George et al, Nature, 2008; Berry et al, Cancer Cell, 2012). We continue to study ALK biology, including how extracellular domain shedding influences metastasis and therapy response (Huang et al., Cell Rep, 2021). 

MYC/MYCN Amplification in Neuroblastoma and Osteosarcoma

We investigate how MYC family oncogenes drive tumor growth by altering chromatin architecture and transcription. Our studies revealed that MYCN amplification creates super-enhancers and transcriptional amplification, opening opportunities for therapeutic targeting (Chipumuro et al, Cell, 2012). Current efforts focus on disrupting oncogenic transcription and translation through CDK inhibitors, eIF4A inhibition, and rational drug combinations (Volegova et al, Cell Rep, 2024; ). 

CDK12 as a Therapeutic Target in Osteosarcoma

We identified CDK12 as a key regulator of DNA repair and genomic stability in osteosarcoma, demonstrating its therapeutic potential in preclinical models (Krajewska et al, Nat Commun, 2019; Bayles et al, J Clin Invest, 2019). Ongoing studies explore CDK12/13 inhibitors and degraders, the role of CDK12 in maintaining chromatin architecture, and novel factors such as CDC5L that safeguard genome integrity.

Mechanisms of Therapy Resistance

A central challenge in cancer treatment is resistance to targeted therapies. We have shown that resistance in neuroblastoma can arise through transcriptional reprogramming, lineage plasticity, epigenetic remodeling or upregulation of multidrug transporters (Debruyne et al, Nature, 2019; Debruyne et al, Oncogene, 2016; Gao et al, Cell Chem Bio, 2018). Our current work focuses on drug-tolerant persister cells, aiming to identify early adaptive pathways and eliminate them before resistance becomes established.

Immune Response Regulation

We study how tumor cell lineage state influences immune recognition and immunotherapy response. Our research revealed that mesenchymal neuroblastomas are more immunogenic than adrenergic tumors, providing biomarkers for therapy selection (Sengupta et al, Nat Cancer, 2022). Current projects include:
•    Defining immunogenic vulnerabilities in mesenchymal tumors
•    Harnessing ALK as an immunotherapy target
•    Restoring innate immune signaling to convert “cold” tumors into “hot,” immunotherapy-responsive states