Combined mTORC1 and MEK Inhibition Leads to Regression of NF1-Mutant Cancers
Posted May 4, 2016
Karen Cichowski, Ph.D., Brigham and Women's Hospital, Boston, Massachusetts
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is primarily characterized by tumorigenic manifestation in the nervous system. Although most of the tumors associated with NF1, known as neurofibromas, are benign (non-cancerous), some develop into malignant tumors known as malignant peripheral nerve sheath tumors (MPNSTs). MPNST are the most clinically aggressive tumors associated with NF1 and are the leading cause of mortality for patients suffering from the disease. Hence, the identification of potential therapeutic targets is imperative for effective treatment against these tumors. NF1 is caused by a mutation in the NF1 gene that normally codes for a tumor suppressor protein known as neurofibromin. Defects in neurofibromin result in unregulated cell proliferation and differentiation. Dr. Karen Cichowski, of Brigham and Women's Hospital, was awarded a 2012 Investigator-Initiated Research Award by the Neurofibromatosis Research Program (NFRP) for the development of effective targeted therapies for MPNSTs.
Currently, there are a large number of available therapeutics that target specific components of the signaling pathways known to be associated with NF1 tumorigenesis. Dr. Cichowski and her research team proposed to utilize a mouse model of MPNSTs to dissect these signaling pathways in an effort to identify the most promising therapeutic targets. In addition, she aimed to explore the efficacy of combination-targeted therapies and potential real-time biomarkers of that efficacy. The efforts of Dr. Cichowski and her team led to several key discoveries. Dr. Cichowski previously demonstrated, with support from a 2002 NFRP New Investigor Award, that the PI3K-mTOR Complex 1 (mTORC1) signaling pathway is abnormal in NF1-deficient MPNSTs.  In the current studies, Dr. Cichowski and her colleagues identified that the mTOR Complex 1 (mTORC1) specifically plays a key role in NF1-deficient MPNSTs, and therefore is a potential target for therapy.  They demonstrated that only sustained treatment of combined mTORC1 and MEK inhibition promoted tumor regression. All of the mice treated with MEK inhibitor PD-0325901 and Rapamycin (a fungicide that inhibits mTORC1) responded to treatment. More than half of the tumors exhibited a 50% regression, with several shrinking 75% or more. In addition, Dr. Cichowski and her team discovered the potential use of GLUT1 to develop an imaging biomarker. GLUT1 is a membrane-bound glucose carrier, which is involved in 18F-fluorodeoxyglucose (F18-FDG) uptake, in turn found to be overexpressed in many cancer types. During combined mTORC1-MEK inhibition, but not in response to single agents, GLUT1 levels dramatically decreased. Since PET scans can be used to quantify F18-FDG uptake, FDG-PET imaging represents a potential method of quantifying combined mTORC1-MEK inhibition, providing a means to determine effective doses of both drugs and minimize toxicity during treatment. The information obtained from these studies - the identification of optimal therapeutic targets and a noninvasive means for measuring mTORC1-MEK inhibition - can be translated into clinical trials for MPNST patients.
Johannessen CM, Reczek EE, James MF, Brems H, Legius E, and Cichowski K. 2005. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A 102(24):8573-8578. http://www.pnas.org/content/102/24/8573.long
Malone CF, Fromm JA, Maertens O, DeRaedt T, Ingraham R, and Cichowski K. 2014. Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers. Cancer Discov 4(9):1062-1073. http://cancerdiscovery.aacrjournals.org/content/4/9/1062.long
Last updated Wednesday, August 31, 2016