Diverse Approaches to Developing Combination Therapies for NF1-Mutant Cancers
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CitationMalone, Clare Felicity. 2015. Diverse Approaches to Developing Combination Therapies for NF1-Mutant Cancers. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractThe NF1 tumor suppressor is lost or mutated in a variety of sporadic cancers, as well as in the hereditary cancer predisposition syndrome neurofibromatosis type 1 (NF1). NF1 patients have an 8–13% risk of developing a malignant peripheral nerve sheath tumor (MPNST), which are lethal when they cannot be surgically resected. There are currently no effective therapies for NF1-mutant cancers. As such, developing treatments for NF1-mutant malignancies represents a huge unmet clinical need. This dissertation focuses on the development of combination therapies using two distinct approaches: inhibiting specific oncogenic signaling pathways activated by NF1 mutation (or loss), and exploiting cellular stresses in cancer cells.
NF1 encodes a RAS GTPase activating protein. Therefore, when NF1 is lost, RAS pathway signaling is hyper-activated. However, the signaling node or nodes most critical for tumor growth were not known. Here, we report that p110α and mTORC1 are essential for NF1-deficient proliferation, while AKT and mTORC2 are dispensable. Moreover, we demonstrate that sustained inhibition of both the mTORC1 and MEK/ERK pathways promotes MPNST regression. To identify molecular biomarkers of combined target inhibition we performed transcriptional profiling. GLUT1, which encodes a glucose transporter, is significantly repressed when both mTORC1 and MEK are inhibited. 18F-FDG uptake is also suppressed, indicating that FDG-PET imaging could be a useful biomarker. A clinical trial based on these findings is being developed.
We have previously found that the combination of ER-stress inducing agents and the mTOR inhibitor rapamycin causes MPNST regression. Here, we show that the combination of the histone deacetylase inhibitor vorinostat with rapamycin exploits this same vulnerability and promotes tumor regression. This therapeutic effect is dependent on activation of the unfolded protein response and production of reactive oxygen species. Expression profiling identified that the gene encoding thioredoxin interacting protein, TXNIP, is transcriptionally upregulated by combined treatment and TXNIP appears to be a driver of cell death in this context. Regardless, these studies suggest that the combination of two FDA-approved drugs, rapamycin and vorinostat, could be rapidly translated to clinical trials.
In summary, we have identified two promising combination therapies for NF1-mutant cancers. These studies highlight the therapeutic utility of exploiting both signaling and stress vulnerabilities in cancer. These findings have promising clinical applications, and provide a framework for future therapeutic and mechanistic exploration.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17467360
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