Research
We are interested in molecular mechanisms that make cancers “tick” and how we can exploit these alterations for cancer therapies. Our overarching goal is to leverage our novel understanding of these processes to develop innovative and effective therapeutic strategies for cancer patients. To achieve these goals, we combine multi-omics approaches including genomics, transcriptomics, proteomics, and functional genomic approaches across cell lines, patient-derived organoid, and mouse models. These strategies allow us to interrogate vulnerabilities in a genome-scale and unbiased manner, revealing how cancers survive despite the multitude of stressors associated with malignancy. Below are a few examples of ongoing efforts in our lab.
Unraveling WRN: a synthetic lethal helicase in MSI-H cancer
Integrating large scale functional genomics and genomics, we identified the WRN RecQ helicase as a synthetic lethal target in cancers characterized as microsatellite instability-high(MSI). Our work has elucidated the molecular mechanisms underlying this synthetic lethal phenomenon and spurred ongoing clinical trials testing WRN inhibition for the treatment of MSI-H cancers. This body of work has spurred several key questions including (1) the mechanisms of resistance to WRN inhibition, (2) features that best predict WRN inhibition, and (3) strategies to potentiate WRN inhibition.
Stalled & stranded: PELO–HBS1L ribosome rescue
Protein translation and ribosomal homeostasis have largely been under-recognized as a vulnerability in cancer cells. We identified the PELO-HBS1L ribosome rescue complex as a synthetic lethal target that exploits dysregulated ribosomal homeostasis in specific molecular subtypes of cancer. This finding emphasizes ribosomal dysfunction as an important feature in cancer and underscores the growing recognition of ribosomes as therapeutic targets. These observations suggest that further exploration of ribosomal dysregulation could facilitate our ability to design therapies tailored to these fundamental cancer dependencies, opening the door to a new generation of precision oncology drugs and mechanistic interrogation of fundamental ribosomal processes.
Unbiased dissection of tumor microenvironmental modulators
The importance of the tumor microenvironment in cancer therapeutics has become increasingly recognized. We are leveraging multi-omic approaches in immunocompetent models to uncover targets that modulate responses to immunotherapy and uncover targets harnessing the immune system. These efforts have led to functional genomic screening approaches in murine models and in patient-derived organoid cancer models co-cultured with autologous tumor resident immune cells, with ongoing efforts to define modulators of immune response and mechanistic inquiry.