The central hypothesis of this research proposal is that new targets and compounds for cancer therapy can be coordinately revealed by a high throughput screen for genes and small molecules that mimic the effects of the molecular scaffold Kinase Suppressor of Ras 1 (KSR1). KSR1-/- mice and cells derived from those mice grow and develop normally but are resistant to tumorigenesis and transformation by oncogenic Ras. These observations suggest that KSR1, gene products downstream of KSR1, or gene products with functional characteristics similar to KSR1, may serve as targets for therapeutic manipulation in tumors bearing oncogenic Ras, but with reduced or minimal toxicity to normal tissue. We developed a Gene Expression High Throughput Screen (GE-HTS) that can coordinately identify effectors mimicking KSR1 function and small molecule inhibitors of those targets that selectively inhibit tumor cell growth, but not growth of normal colonic epithelium. Subsequent analysis demonstrated that human colon tumor cell lines expressing mutated, activated Ras exhibit KSR1-dependent expression of transcriptional regulators essential for maintenance of the transformed phenotype. Immortalized normal human colonic epithelial cells did not express these regulators. These data identify a previously unrecognized signaling network that promotes colon tumor cell survival. RNAi based GE- HTS will be used to define that network and test its potential as a therapeutic target by characterizing the role of transcriptional regulators and the identification of additional network effectors regulating KSR1-dependent tumorigenic potential. GE-HTS using a natural products library will be used to identify small molecule inhibitors of network effectors. These effectors and small molecules will be tested in vitro and in in vivo orthotopic tumor models to validate their ability to regulate tumor development and maintenance.
When mutated and activated, the protein product of the Ras gene contributes to 30% of human cancer including 50% of colon cancers. We previously identified a scaffold protein that is critical to the complete formation of tumors by activated Ras protein, but seemingly dispensable to normal cells. We used this observation to develop an assay that would detect similarly acting proteins and chemical compounds that might inhibit their function. The goal of this research is to identify and validate those proteins and compounds as targets and potential therapeutics, respectively, for the treatment of cancer.
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|Neilsen, Beth K; Frodyma, Danielle E; Lewis, Robert E et al. (2017) KSR as a therapeutic target for Ras-dependent cancers. Expert Opin Ther Targets 21:499-509|
|Guo, Lili; Costanzo-Garvey, Diane L; Smith, Deandra R et al. (2017) Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis. Mol Metab 6:194-205|
|Guo, Lili; Costanzo-Garvey, Diane L; Smith, Deandra R et al. (2016) Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2). Sci Rep 6:32093|
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|Fisher, Kurt W; Das, Binita; Kim, Hyun Seok et al. (2015) AMPK Promotes Aberrant PGC1? Expression To Support Human Colon Tumor Cell Survival. Mol Cell Biol 35:3866-79|
|Bohovych, Iryna; Fernandez, Mario R; Rahn, Jennifer J et al. (2015) Metalloprotease OMA1 Fine-tunes Mitochondrial Bioenergetic Function and Respiratory Supercomplex Stability. Sci Rep 5:13989|
|Kortum, Robert L; Fernandez, Mario R; Costanzo-Garvey, Diane L et al. (2014) Caveolin-1 is required for kinase suppressor of Ras 1 (KSR1)-mediated extracellular signal-regulated kinase 1/2 activation, H-RasV12-induced senescence, and transformation. Mol Cell Biol 34:3461-72|
|Guo, Lili; Volle, Deanna J; Lewis, Robert E (2014) Identification of a truncated kinase suppressor of Ras 2 mRNA in sperm. FEBS Open Bio 4:420-5|
|Henry, MaLinda D; Costanzo-Garvey, Diane L; Klutho, Paula J et al. (2014) Obesity-dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2-/- mice. Physiol Rep 2:|
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