Stearoyl CoA Desaturase: A Therapeutic Target in Glioblastoma
By Mohamed El-Abtah
Glioblastoma (GBM), a brain cancer characterized by high mortality and resistance to therapy, is considered to be the most malignant and common form of primary central nervous system tumor. Emerging evidence suggests that in addition to glucose, a main fuel source for brain tumors, other metabolites such as acetate1 and fatty acids (FAs)2 may drive brain cancer growth (Figure 1). Indeed, increased lipid synthesis is a major hallmark of GBM, but it is still unclear whether these tumor cells take up freely circulating FAs or synthesize them de-novo using their own cellular machinery.3 Either way, blocking FA synthesis may present a new therapy for GBM.
GBM tumors are similar to other types of brain cancer in that both follow a model of tumor growth in which glioma stem cells (GSC), a self-renewing subpopulation of cells, initiate and drive the growth of the tumor. One paper recently characterized a subpopulation of these GSCs which exhibits enhanced tumor potential and an aggressive phenotype that results in the resistance to chemotherapy and radiation. These characteristics are often associated with the onset of GBM.4
Upon completion of a drug screening test, it was shown that these cells are extremely vulnerable to Stearoyl CoA Desaturase 1 (SCD1) inhibitors. SCD1 is a key enzyme responsible for the conversion of saturated fatty acids to unsaturated fatty acids and has been shown to play a major role in the proliferation of many cancers, including GBM5 (Figure 2). In particular, SCD1 promotes the conversion of the saturated fatty acid, Palmitic Acid (PA) to an unsaturated fatty acid (UFA). This conversion results in the release of energy that may be used to fuel the growth of GBM tumors. Ergo, the hypothesis of the research was that due to its role in converting SFA to UFA, SCD1 promotes a stem-cell phenotype in GBM and increases the tumor initiating properties of GBM. And if SFA-like PA promotes tumor growth such that through the inhibition of SCD1, it is possible that a targeted therapy to GBM may be developed.
Genetic silencing of the SCD1 enzyme is possible through the pharmacological agent CAY10566 (CAY). To test the efficacy of CAY as a potential therapeutic, rodent studies were implemented to see if mice implanted with brain tumors would have an improved prognosis post CAY treatment. The first phase of the research was to test the effect of fatty acids on tumor growth in a GSC xenograft model. A xenograft model refers to the transplantation of cancerous cells from a human patient to the brains of the mice through a surgical procedure so that the mice rapidly develop GBM. As a proof of concept, the mice were administered PA and, as expected, there was a twofold increase in tumor growth (Figure 3b) compared to the control (Figure 3a). More importantly, this increase in tumor growth could be reversed by CAY treatment, confirming that saturated FAs are essential for the observed increase in tumor growth and suggesting that PA is taken up by the tumor cells and processed through SCD1. Notably, the CAY-treated group showed a significant decrease in tumor growth , confirming its therapeutic efficacy. These results were visualized using BODIPY staining, a fluorescent dye that is used to stain lipids. Increasing redness of a brain section indicates a larger tumor; in this case, there is no observable tumor in the CAY+PA group which may suggest potential therapeutic efficacy (Figure 3c).
We are far from a cure for GBM. Nonetheless, through the emergence of metabolomics, it is now possible to gain a profound understanding of the dynamics of how tumor cells initiate and maintain their tumorigenic properties. Fatty acid synthesis may very well be an ‘Achilles heel’ that can be exploited in order to impact cells at the apex of the brain tumor hierarchy and hopefully find a cure for GBM in the near future.
References
1. Mashimo, T., et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603-1614 (2014).
2. Lin, H., et al. Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells. Neuro-oncology 19, 43-54 (2017).
3. Beloribi-Djefaflia, S., Vasseur, S. & Guillaumond, F. Lipid metabolic reprogramming in cancer cells. Oncogenesis 5, e189 (2016).
4. Badr, C., et al. Dissecting inherent heterogeneity in patient-derived glioblastoma models. Nat Commun 17, 67-75 (2016).
5. Igal, R.A. Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer. Carcinogenesis 31, 1509-1515 (2010).
Glioblastoma (GBM), a brain cancer characterized by high mortality and resistance to therapy, is considered to be the most malignant and common form of primary central nervous system tumor. Emerging evidence suggests that in addition to glucose, a main fuel source for brain tumors, other metabolites such as acetate1 and fatty acids (FAs)2 may drive brain cancer growth (Figure 1). Indeed, increased lipid synthesis is a major hallmark of GBM, but it is still unclear whether these tumor cells take up freely circulating FAs or synthesize them de-novo using their own cellular machinery.3 Either way, blocking FA synthesis may present a new therapy for GBM.
GBM tumors are similar to other types of brain cancer in that both follow a model of tumor growth in which glioma stem cells (GSC), a self-renewing subpopulation of cells, initiate and drive the growth of the tumor. One paper recently characterized a subpopulation of these GSCs which exhibits enhanced tumor potential and an aggressive phenotype that results in the resistance to chemotherapy and radiation. These characteristics are often associated with the onset of GBM.4
Upon completion of a drug screening test, it was shown that these cells are extremely vulnerable to Stearoyl CoA Desaturase 1 (SCD1) inhibitors. SCD1 is a key enzyme responsible for the conversion of saturated fatty acids to unsaturated fatty acids and has been shown to play a major role in the proliferation of many cancers, including GBM5 (Figure 2). In particular, SCD1 promotes the conversion of the saturated fatty acid, Palmitic Acid (PA) to an unsaturated fatty acid (UFA). This conversion results in the release of energy that may be used to fuel the growth of GBM tumors. Ergo, the hypothesis of the research was that due to its role in converting SFA to UFA, SCD1 promotes a stem-cell phenotype in GBM and increases the tumor initiating properties of GBM. And if SFA-like PA promotes tumor growth such that through the inhibition of SCD1, it is possible that a targeted therapy to GBM may be developed.
Genetic silencing of the SCD1 enzyme is possible through the pharmacological agent CAY10566 (CAY). To test the efficacy of CAY as a potential therapeutic, rodent studies were implemented to see if mice implanted with brain tumors would have an improved prognosis post CAY treatment. The first phase of the research was to test the effect of fatty acids on tumor growth in a GSC xenograft model. A xenograft model refers to the transplantation of cancerous cells from a human patient to the brains of the mice through a surgical procedure so that the mice rapidly develop GBM. As a proof of concept, the mice were administered PA and, as expected, there was a twofold increase in tumor growth (Figure 3b) compared to the control (Figure 3a). More importantly, this increase in tumor growth could be reversed by CAY treatment, confirming that saturated FAs are essential for the observed increase in tumor growth and suggesting that PA is taken up by the tumor cells and processed through SCD1. Notably, the CAY-treated group showed a significant decrease in tumor growth , confirming its therapeutic efficacy. These results were visualized using BODIPY staining, a fluorescent dye that is used to stain lipids. Increasing redness of a brain section indicates a larger tumor; in this case, there is no observable tumor in the CAY+PA group which may suggest potential therapeutic efficacy (Figure 3c).
We are far from a cure for GBM. Nonetheless, through the emergence of metabolomics, it is now possible to gain a profound understanding of the dynamics of how tumor cells initiate and maintain their tumorigenic properties. Fatty acid synthesis may very well be an ‘Achilles heel’ that can be exploited in order to impact cells at the apex of the brain tumor hierarchy and hopefully find a cure for GBM in the near future.
References
1. Mashimo, T., et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603-1614 (2014).
2. Lin, H., et al. Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells. Neuro-oncology 19, 43-54 (2017).
3. Beloribi-Djefaflia, S., Vasseur, S. & Guillaumond, F. Lipid metabolic reprogramming in cancer cells. Oncogenesis 5, e189 (2016).
4. Badr, C., et al. Dissecting inherent heterogeneity in patient-derived glioblastoma models. Nat Commun 17, 67-75 (2016).
5. Igal, R.A. Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer. Carcinogenesis 31, 1509-1515 (2010).
