EGFR, a critical activator of PI3K signaling is amplified and/or mutated in nearly 50% of GBMs, in collaboration with other altered signaling cascades, has been shown to play a critical role in the development and progression of glioblastoma (GBM), suggesting that it is a compelling molecular target. However, attempts to target EGFR in the clinic with the small molecule inhibitors erlotinib and gefitinb have failed, resulting in relatively few clinical responses of very short duration. Attempts to target the pathway downstream at the level of mTOR have also failed due to feedback activation of PI3K signaling. Thus, new approaches towards targeting EGFR-activated GBMs are needed. Recent work suggests that some of the critical oncogenic properties of EGFR are mediated through their effect on cellular metabolism. We have recently uncovered a previously unsuspected result by which EGFR signaling promotes tumor survival by altering cellular metabolism. By studying GBM patient samples, including patients treated with EGFR tyrosine kinase inhibitors, cell lines and a mouse model, we have demonstrated that EGFR/PI3K/Akt signaling promotes fatty acid synthesis through the master transcriptional regulator of lipogenesis, SREBP-1. More importantly, we have shown that EGFR-activated GBMs are highly dependent upon SREBP-1-medaited fatty acid synthesis, so that preventing SREBP-1 activation promotes massive apoptosis of GBMs bearing mutated EGFR. This paper suggests a powerful new strategy for treating GBMs bearing amplified or constitutively activated EGFR. We provide compelling molecular evidence that genetic inhibition of SREBP-1 cleavage kills EGFR-activated GBMs. To move these findings into the clinic, it is essential to identify the optimal points in the fatty acid synthesis pathway to target, and that we select and test pharmacological inhibitors that can potentially be used in the clinic. In this proposal, we will use genetic and pharmacological approaches to identify the most effective molecular target and inhibitor within the SREBP-1 mediated fatty acid synthesis pathway. In preliminary data, SREBP-1 inhibitor fatostatin was shown to significantly inhibit cell proliferation of prostate cancer cell line and of GBM cell line. Excitingly, fatostatin treatment markedly leads to GBM cell death in dose-dependent manner. Importantly, the key enzymes ACL, ACC and FAS in SREBP-1 regulated fatty acid synthesis pathway have already been shown to play an important role in cancer growth, the inhibitors radicicol (ACL inhibitor), TOFA (ACC inhibitor) and C75 (FAS inhibitor) were shown potent in inhibition of cancer cell growth. Our preliminary data indicated TOFA and C75 were potent to inhibit GBM cell growth and induce cell death, particularly in EGFR activated cells. So it is promising to determine the anti-cancer effect of these inhibitors for GBM treatment, to open a promising new avenue to target the deadly cancer. Completion of this study is likely to provide necessary pre-clinical data to support a phase I clinical trial.
Glioblastoma (GBM) is one of the most deadly cancers, with patient survival averaging 12-18 months, despite surgery, radiation, and chemotherapy. We have recently uncovered a previously undescribed result by which EGFR signaling promotes tumor survival by activating SREBP-1 regulated fatty acid synthesis pathway. We identified SREBP-1 as a potential molecular target in GBM therapies;therefore, to move these findings into the clinic, it is essential to identify the optimal target points in the fatty acid synthesis pathway and to select and test pharmacological inhibitors that can potentially be used in the clinic. Completion of this study is likely to provide necessary pre-clinical data to support a phase I clinical trial in GBM and probably other cancers with activated EGFR signaling, and to promote developing potential drugs to treat cancer patients and to improve patient survival.
|Guo, Deliang; Bell, Erica Hlavin; Mischel, Paul et al. (2014) Targeting SREBP-1-driven Lipid Metabolism to Treat Cancer. Curr Pharm Des 20:2619-26|
|Guo, Deliang; Bell, Erica Hlavin; Chakravarti, Arnab (2013) Lipid metabolism emerges as a promising target for malignant glioma therapy. CNS Oncol 2:289-299|
|Guo, Deliang; Reinitz, Felicia; Youssef, Mary et al. (2011) An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov 1:442-56|