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Research in Michael Green’s Lab

Discovery of Therapeutically Targetable Pathways in Cancer and Other Diseases

Identification of New Factors and Regulatory Pathways that Promote or Prevent Cancer

My laboratory has used transcription-based approaches, functional screens (such as genome-wide loss-of-function RNAi- and CRISPR-based screens) and genomic methods to identify new genes and regulatory pathways that contribute to cancer. These studies are intended to enhance our understanding of the molecular basis of cancer and reveal potential new targets for therapeutic intervention. These approaches have enabled us to discover new oncogenes, such as the H2A ubiquitin ligase TRIM37 (Bhatnagar et al. 2014), tumor suppressor genes, such as the CREB coactivator CRTC2 (Fang et al. 2015) and repressors of FGFR signaling (Lin et al. 2014), and metastasis suppressor genes, such as GAS1 (Gobeil et al. 2008) and the histone H3K9 demethylase KDM3A (Pedanou et al. 2016). We have also identified two therapeutically targetable mechanisms that render chronic myeloid leukemia (CML) stem cells resistant to the drug imatinib mesylate (also known as Gleevec), the first-line treatment for CML (Ma et al. 2014; Ma et al. 2019). We are currently conducting functional screens to identify new factors involved in various aspects of cancer biology including transformation, cancer stem cell formation and maintenance, regulation of the epithelial-to-mesenchymal transition, and cancer drug resistance.

Alterations in pre-mRNA splicing lead to numerous diseases, including cancer. We have a long-standing interest in regulation of gene expression at the level of RNA processing, in particular pre-mRNA splicing. The essential splicing factor U2AF, which initiates spliceosome assembly by binding to the intronic polypyrimidine tract/3’ splice site, was originally discovered in our laboratory. Subsequent cancer genome sequencing studies revealed driver mutations in the U2AF 35 kDa subunit (U2AF35). We have shown that oncogenic U2AF35 mutants promote transformation through mis-regulation of both splicing and mRNA 3’ end formation (Park et al. 2016). We are continuing to investigate the role of aberrant RNA processing in cancer as well as other diseases.

Modulating Gene Expression as a Therapeutic Approach

Factors that drive cancer progression are often not druggable and thus their therapeutic inhibition is challenging. We are taking a novel approach to identify inhibitors of these “undruggable” cancer-promoting factors. First, we have developed and carried out reporter-based CRISPR screening strategies to identify factors and pathways required for expression of a cancer-promoting gene. Based upon this information, we then identify biological or small molecule inhibitors of these factors and pathways, which abrogate expression of the cancer-promoting gene and suppress tumor growth. We have used this approach to identify inhibitors of expression of oncogenes and other genes that affect tumor development such as suppressors of anti-tumor immunity. This approach can also be used to identify antagonists of proteins that cause diseases other than cancer, such as neurodegenerative diseases.

Cancer and other diseases can also arise due to the inappropriate transcriptional inactivation of specific genes. My lab has developed and successfully used functional genomic and proteomic approaches to identify factors and pathways involved in epigenetic silencing of tumor suppressor genes. Biological or small molecule inhibitors of these factors and pathways can reactivate expression of the tumor suppressor gene, which is a therapeutic approach that can be used to treat cancer. For example, we have delineated two independent oncoprotein-directed pathways that lead to widespread DNA hypermethylation and epigenetic silencing (known as the CpG island methylator phenotype; CIMP) in colorectal cancers, and shown that genetic or pharmacological inhibition of the pathways can reactivate expression of the silenced genes (Serra et al. 2014; Fang et al. 2014). The epigenetic silencing pathways we have identified are directly linked to cellular transformation, have enhanced our understanding of how normal cells become cancerous, and have revealed new therapeutic targets.

We are taking a similar approach to identify small molecule inhibitors that will reactivate genes whose aberrant epigenetic silencing causes rare monogenic disorders such as Fragile X Syndrome and Friedreich ataxia. We also work on X-linked dominant disorders, such as Rett Syndrome and CDKL5 Deficiency, which are caused by heterozygous mutations in the X-linked genes MECP2 and CDKL5, respectively, and for which reactivation of the wild-type gene on the inactive X chromosome (Xi) is a potential therapeutic approach. For example, we have identified a number of cellular factors that are required for silencing of the Xi (Bhatnagar et al. 2014). Small molecule inhibitors of these factors can reactivate expression of the wild-type Xi-linked MECP2 gene in cultured cells and cerebral cortical neurons of adult living mice (Bhatnagar et al. 2014; Przanowski et al., 2018).

Development of New Gene Therapy Approaches

We have previously identified IGFBP7 (insulin-like growth factor binding protein 7) as a secreted tumor suppressor protein and shown in mouse models that systemic administration of recombinant IGFBP7 can suppress tumor growth of human melanoma and colorectal cancer xenografts expressing oncogenic BRAF or RAS (Wajapeyee et al. 2008, 2009). More recently, in collaboration with Dr. Guangping Gao (Director, UMMS Gene Therapy Center) we have shown that IGFBP7 can also be effectively delivered into mice using an adeno-associated virus (AAV) vector. Intramuscular injection of an AAV9-IGFBP7 vector results in the expression and secretion of IGFBP7 and markedly reduces growth of human melanoma and colorectal cancer xenografts. We have confirmed the generality of this approach using another secreted tumor suppressor protein. Our results indicate that AAV9 delivery of secreted tumor suppressors is a new and promising anti-cancer treatment.

In collaboration with Guangping Gao and Miguel Sena-Esteves (UMMS Gene Therapy Center), we are developing a novel AAV-based gene therapy approach for Rett Syndrome. Several lines of evidence indicate that MECP2 expression levels must be tightly regulated to maintain normal neuronal function and development. We are therefore developing self-regulating AAV vectors that can express MECP2 within a narrow range of levels compatible with normal development and neuronal function.