Research Program
The Stegmaier lab uses state-of-the-art genomic, chromatin, and chemical biology approaches to dissect the mechanisms underlying pediatric cancer, identify new therapeutic targets, and evaluate new candidate therapies, including biomarkers of response and resistance.
Despite tremendous progress in the treatment of pediatric malignancies, cancer remains the leading cause of death from disease in children in high-income countries. Improved treatment for children with cancer remains an urgent unmet clinical need.
Over the last decades, several important themes have emerged in childhood cancers based in part on our work and that of many researchers in the community:
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Pediatric cancers have fewer point mutations than adult.
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Fusion oncoproteins are common in childhood malignancies and typically involve a transcription factor or chromatin regulator.
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Pediatric cancers are far less responsive to immune checkpoint inhibitors than adult cancers.
Dissecting and Targeting Fusion Oncoprotein Driven Cancers
Fusion oncoproteins are dominant oncogenic drivers in many childhood cancers, which makes them favorable therapeutic targets. Indeed, some of the most impactful responses to targeted inhibitors have been in the context of fusions, for example, imatinib for the BCR-ABL fusion. However, childhood cancers typically involve transcription factor fusions, which have been difficult to target due to the lack of structural enzymatic pockets.
Our laboratory is taking a multi-pronged approach to studying fusion-driven pediatric sarcomas, including Ewing sarcoma and alveolar rhabdomyosarcoma, as well as fusion-driven pediatric acute myeloid leukemias. First, we are applying a suite of innovative assays to evaluate the impact of deletion/degradation and overexpression (activation lethality) of the fusions to understand their biology. Second, we are exploring strategies to target the fusion directly by hijacking the cell’s protein degradation machinery. Third, we are using functional genomic and other -omic strategies to identify new lethal dependencies in the context of the fusion, and are working closely with chemists to target these Achilles heels.
Mechanisms of Response and Resistance to Cancer Therapies
While most children with cancer will achieve a complete remission with standard therapies, many of them will relapse. In some cases, we have learned a lot about the mechanisms underlying response and resistance, particularly for drugs that target kinases. In other cases, the mechanisms of response and resistance to therapies have remained elusive.
A major effort in our laboratory applies an integrative approach to identify biomarkers of drug response and resistance, including to immunotherapies. These efforts reveal previously unknown biology that can be used to identify novel drug combinations. Here, CRISPR-Cas and drug-drug screening, the development of drug-resistant models, and massively parallel sequencing approaches serve as key strategies toward achieving these goals.
Toward a Comprehensive Pediatric Cancer Dependency Map
Because of the difficulty in directly targeting the oncogenic drivers in many childhood cancers, an alternative approach is to identify other collaborating liabilities in these malignancies. Toward this end, our lab collaboratively led the creation of the first Pediatric Cancer Dependency Map with the Broad Institute. Our vision was to apply genome-wide CRISPR-Cas screening to systematically survey every gene in the genome, in over 100 genomically characterized pediatric cancer models. Our goals were two-fold: 1) to identify new candidate therapeutic targets in childhood cancers and 2) to develop a deeper mechanistic understanding of pediatric malignancies. To increase our power to identify selective gene dependencies and associated biomarkers, we integrated our pediatric with the adult cancer data generated through the Broad’s Dependency Map and made the data publicly available. We discovered that pediatric cancers have a similar complexity of genetic dependencies to adult cancers despite having fewer mutations. The vulnerabilities observed in pediatric cancers, however, were often distinct from those observed in adult cancers, highlighting the critical importance of functional genomic efforts focused specifically on childhood cancers.
The success of this initial effort has led to an unprecedented collaboration with the Broad Institute, St. Jude Children’s Research Hospital, and Dana-Farber Cancer Institute to dramatically accelerate the depth and breadth of the Pediatric Cancer Dependency Map. We expect this project will reveal a treasure trove of new targets and improved mechanistic understanding of these malignancies.
