September 16, 2011 — Blocking the uptake of large amounts of cholesterol into glioblastoma cells could be a new therapeutic strategy for this deadly brain cancer, according to the results of a basic science study published online September 15 in Cancer Discovery.
The mutated epidermal growth-factor receptor (EGFRvIII), an oncogene overexpressed in glioblastoma, facilitates the entry of cholesterol into cancer cells by upregulating its cellular receptor — the low-density lipoprotein (LDL) receptor — thereby enhancing rapid tumor growth and survival.
"Our study found that the mutant EGFR hijacks this system, enabling cancer cells to import large amounts of cholesterol through the LDL receptor," senior author Paul Mischel, MD, professor of pathology and laboratory medicine and molecular and medical pharmacology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, said in a news release. "This study identifies the LDL receptor as a key regulator of cancer cell growth and survival, and as a potential drug target."
The investigators' hypothesis was that targeting the LDL receptor for destruction would achieve strong activity against glioblastoma cells. Using cell lines, mouse models, and analysis of tissue from trial participants with glioblastoma, Dr. Mischel and colleagues found potent antitumor activity of the liver X receptor (LXR) agonist GW3965. By activating the nuclear LXR, which plays a vital role in regulating intracellular cholesterol to ensure appropriately balanced levels, GW3965 degraded the LDL receptor in glioblastoma cells carrying the EGFRvIII mutations.
Because approximately 45% of human glioblastomas are positive for EGFRvIII, this therapeutic target is potentially appropriate for nearly half of patients with these highly aggressive brain tumors. In addition, EGFR mutations in various other malignancies suggest the possible application of this strategy to these cancers.
"This study suggests a potential therapeutic strategy to treat glioblastoma, and potentially a broader range of cancer types," Dr. Mischel said. "This study uncovers a novel and potentially therapeutically targetable tumor cell growth and survival pathway, which could result in more effective treatments for patients."
Earlier research by Dr. Mischel's group demonstrated the potential utility of inhibiting fatty acid synthesis in brain cancer cells with EGFR mutations. The same cell signaling pathway appears to be operative in fatty acid synthesis and in the importing of cholesterol into cancer cells.
"That was a surprise here, this ghastly trick of the cancer cells," Dr. Mischel said. "The same mutation is coordinately regulating both the cholesterol and fatty acid synthesis mechanisms."
"This study reveals that [glioblastoma] cells have devised a mechanism to subvert the normal pathways for feedback inhibition of cholesterol homeostasis via EGFRvIII and [phosphoinositide 3-kinase]–dependent activation of [sterol regulatory element-binding protein 1]," the study authors conclude. "We show that an LXR agonist causes IDOL [inducible degrader of LDL receptor]-mediated [LDL receptor] degradation and increases expression of the ABCA1 cholesterol efflux transporter, potently promoting [glioblastoma] cell death in vivo. These results suggest a role for LXR agonists in the treatment of [glioblastoma] patients."
This study was supported by the Rose DeGangi American Brain Tumor Association Translational Grant, the National Institutes of Health, the California Institute of Regenerative Medicine, Accelerate Brain Cancer Cure, STOP Cancer, the John W. Carson Foundation, the Lya and Harrison Latter endowed chair, and the Ziering Family Foundation. Some of the study authors report various financial relationships with the Howard Hughes Medical Institute, Adnexus, Bayer, Genentech, Merck, Schering Plough, Tomotherapy, Pharmacyclics, Stemina, Apogenix, Colby, and/or Procertus.
Cancer Discov. Published online September 15, 2011. Abstract
The mutated epidermal growth-factor receptor (EGFRvIII), an oncogene overexpressed in glioblastoma, facilitates the entry of cholesterol into cancer cells by upregulating its cellular receptor — the low-density lipoprotein (LDL) receptor — thereby enhancing rapid tumor growth and survival.
"Our study found that the mutant EGFR hijacks this system, enabling cancer cells to import large amounts of cholesterol through the LDL receptor," senior author Paul Mischel, MD, professor of pathology and laboratory medicine and molecular and medical pharmacology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, said in a news release. "This study identifies the LDL receptor as a key regulator of cancer cell growth and survival, and as a potential drug target."
The investigators' hypothesis was that targeting the LDL receptor for destruction would achieve strong activity against glioblastoma cells. Using cell lines, mouse models, and analysis of tissue from trial participants with glioblastoma, Dr. Mischel and colleagues found potent antitumor activity of the liver X receptor (LXR) agonist GW3965. By activating the nuclear LXR, which plays a vital role in regulating intracellular cholesterol to ensure appropriately balanced levels, GW3965 degraded the LDL receptor in glioblastoma cells carrying the EGFRvIII mutations.
Because approximately 45% of human glioblastomas are positive for EGFRvIII, this therapeutic target is potentially appropriate for nearly half of patients with these highly aggressive brain tumors. In addition, EGFR mutations in various other malignancies suggest the possible application of this strategy to these cancers.
"This study suggests a potential therapeutic strategy to treat glioblastoma, and potentially a broader range of cancer types," Dr. Mischel said. "This study uncovers a novel and potentially therapeutically targetable tumor cell growth and survival pathway, which could result in more effective treatments for patients."
Earlier research by Dr. Mischel's group demonstrated the potential utility of inhibiting fatty acid synthesis in brain cancer cells with EGFR mutations. The same cell signaling pathway appears to be operative in fatty acid synthesis and in the importing of cholesterol into cancer cells.
"That was a surprise here, this ghastly trick of the cancer cells," Dr. Mischel said. "The same mutation is coordinately regulating both the cholesterol and fatty acid synthesis mechanisms."
"This study reveals that [glioblastoma] cells have devised a mechanism to subvert the normal pathways for feedback inhibition of cholesterol homeostasis via EGFRvIII and [phosphoinositide 3-kinase]–dependent activation of [sterol regulatory element-binding protein 1]," the study authors conclude. "We show that an LXR agonist causes IDOL [inducible degrader of LDL receptor]-mediated [LDL receptor] degradation and increases expression of the ABCA1 cholesterol efflux transporter, potently promoting [glioblastoma] cell death in vivo. These results suggest a role for LXR agonists in the treatment of [glioblastoma] patients."
This study was supported by the Rose DeGangi American Brain Tumor Association Translational Grant, the National Institutes of Health, the California Institute of Regenerative Medicine, Accelerate Brain Cancer Cure, STOP Cancer, the John W. Carson Foundation, the Lya and Harrison Latter endowed chair, and the Ziering Family Foundation. Some of the study authors report various financial relationships with the Howard Hughes Medical Institute, Adnexus, Bayer, Genentech, Merck, Schering Plough, Tomotherapy, Pharmacyclics, Stemina, Apogenix, Colby, and/or Procertus.
Cancer Discov. Published online September 15, 2011. Abstract
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