Identification of novel downstream effectors of the mTOR1 pathway
Biomarker and novel substrates of mTORC1
The mTOR pathway is a well-established drug target in cancer and immunosuppressive therapies. The discovery of new mTOR substrates may be important biomarkers as well as a novel approach for drug development:
• Novel biomarker: Novel mTOR substrates may be used as biomarkers for the state of activation of the mTOR pathway. In addition, they may indicate the activation status of potentially dangerous cell survival pathways via inactivation of negative feedback inhibition (mTORC1 to PI3K/Akt feedback inhibition loop). Currently, there are no methods for predicting and monitoring this feedback mechanism. Both protein and phosphorylation levels may be monitored in patient tissue samples to facilitate rapid design of therapeutic strategies to treat patients with altered mTORC1 activation.
• Drug development:
Cancer: Hyperactivation of mTOR signaling has been implicated in tumorigenesis. Activating mutations in the mTOR pathway may occur in as many as 35% of breast cancer cases, and is associated with a poor prognosis. In addition, numerous anti-proliferative and anti-angiogenic mTOR inhibitors are in clinical development as targeted anti-cancer therapies.
Transplantation: mTOR inhibitors, such as rapamycin, are immunosuppressant drugs widely used to prevent organ rejection following transplantation. Modulators of mTOR substrates, used alone or together with already approved immunosuppressants can become a less toxic alternative to current therapies.
Innovations and Advantages
Background: The mammalian target of rapamycin (mTOR) is a kinase that senses the availability of nutrients, energy, amino acids and growth factors to determine cell growth and proliferation. mTOR inhibitors are a class of immunosuppressants widely used to prevent rejection of organ transplants. The pathway has been found to be altered in many human cancers, and numerous mTOR inhibitors are now in clinical development as anticancer agents.
Despite intense interest in developing compounds to inhibit mTOR, relatively little is known about the substrates of this kinase. Identification of novel substrates of mTOR may therefore lead to novel biomarkers for mTOR activation, and a novel approach to drug development.
Novel substrates of mTOR: Using a quantitative phospho-proteomics approach, the Blenis lab discovered a series of novel substrates of mTORC1, including the growth factor receptor-bound protein 10 (Grb10). Using a phosphor-specific antibody developed in the lab, they further show that phosphorylation of two specific serines on Grb10 was strongly inhibited by mTOR kinase inhibitors, including rapamycin. The screen also provided additional mTOR substrates, and one of the most enriched classes of hits in the screen was the receptor protein tyrosine kinase signaling pathway.
Many reports indicate that a feedback inhibition loop exists from mTORC1 to PI3K/Akt and that patients taking mTOR inhibitors may have the secondary effect of activating other pro-survival signals. The inventors demonstrated that Grb10 plays a pivotal role in mediating the feedback inhibition from mTORC1 to PI3K/Akt and suggest a mechanism of action for this regulation based upon their results: upon rapamycin inhibition of mTOR, the mTOR substrate accumulates, and thereby causes a hyperactive state of PI3K.
Intellectual Property Status: Patent(s) pending
This technology is available for worldwide, exclusive licensing.
Gygi, Steven P.
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Reference Harvard Case #3692