Research Abstract
Metabolomics is the quantitative measurement of the metabolic response to external stimuli or genetic alterations and can detect and quantify low-molecular weight metabolites produced by living cells. The metabolites of living cells are seen as the end products of the biological hierarchy starting with activated genes (genome) and extending over the collection of gene transcripts (transcriptome) and proteins (proteome). Metabolic alterations can occur as a consequence of genetic events (e.g. Akt activation results in increased glycolysis). Alternatively, metabolic alterations are primary events in cancer but require genetic alterations in critical pathways for oncogenesis to occur (e.g. isocitrate dehydrogenase mutations). Either way, our hypothesis is that genetic alterations and altered metabolic pathways go hand in hand in a tumor cell-specific manner. Thus, simultaneous targeting of selected metabolic enzymes and “driving” oncogenes may be a cancer cell-selective therapeutic approach.
Our group discovered that USP2a binds to and stabilizes fatty acid synthase (FASN) by preventing its degradation (Graner et al Cancer Cell, 2004). This prompted us to initiate a research program focused on FASN. Specifically, investigated the expression of FASN in prostate cancer by immunohistochemistry as well as gene expression profiling demonstrating that it is overexpressed in aggressive prostate carcinomas (Rossi et al Mol Cancer Res 2003). Since FASN expression is highest in androgen-independent bone metastatic disease, we set out to determine whether it confers a growth advantage to prostate cancer. Using genetically engineered human prostate epithelial cells infected with FASN, transgenic mice expressing FASN in the murine prostate and well characterized human databases, we established that FASN can act as a prostate cancer oncogene in the presence of AR (Migita et al J Natl Cancer Inst 2009). Subsequently, we showed that FASN germline polymorphisms are significantly associated with risk of lethal PCa. Significant interactions of BMI with FASN polymorphisms and FASN tumor expression suggest FASN as a potential link between obesity and poor PCa outcome and raise the possibility that FASN inhibition could reduce PCa-specific mortality, particularly in overweight men (Nguyen, J Clin Oncol, 2011).
We recently expanded the analysis of metabolism in prostate cancer to assess the global metabolic profile by GS/MS in immortalized prostate epithelial cells and transgenic mice comparing Akt and Myc as the driving oncogenes. The results were then applied to human tumors previously categorized as to the status of these oncogenes. Results show starkly different metabolic profiles resulting from these oncogenes and signatures that could be applied to human tumors and exploited as imaging tools (Priolo, Cancer Res, 2014). We also show that inhibition of de novo lipogenesis is the predominant downstream effector of AMPK-mediated inhibition over mTORC1 (EMBO Mol Med, 2014).
We recently showed that the inhibition of fatty acid synthesis arrested the cells at G2/M despite the presence of abundant fatty acids in the media. Our results suggest that de novo lipogenesis is essential for cell cycle completion. This “lipogenic checkpoint” at G2/M may be therapeutically exploited for hyperproliferative diseases such as cancer (Scaglia et all, Cell Cycle, 2014).
As co-chair of the prostate cancer TCGA effort we reported the first comprehensive molecular taxonomy of localized prostate cancer (Schultz et al, Cell, 2015).
