On June 24, 2021 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage precision oncology company focused on developing targeted therapies to inhibit frontier targets in RAS-addicted cancers, reported the publication of an original scientific paper in Nature Chemical Biology describing anti-tumor effects of bi-steric mTORC1-selective inhibitors that potently suppress phosphorylation of 4EBP1, a key translational regulator of oncogene expression (Press release, Revolution Medicines, JUN 24, 2021, View Source [SID1234584348]). In preclinical models of cancers with mutations that drive mTORC1 hyperactivation, a series of bi-steric inhibitors demonstrated the favorable anti-tumor effects and tolerability of deeply and selectively inhibiting mTORC1 compared to earlier generations of mTOR inhibitors. Mutations that cause hyperactive mTORC1 signaling are found in tumors with and without co-existent RAS mutations. This original research was led by scientists at Revolution Medicines and conducted in collaboration with the Neal Rosen Lab at the Memorial Sloan Kettering Cancer Center, as well as researchers from McGill University and The Karolinska Institute.
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Revolution Medicines recently advanced RMC-5552, the company’s investigational first-in-class bi-steric mTORC1 inhibitor, into clinical development. RMC-5552 is a potent and selective inhibitor of mTORC1 that is being developed as an anti-cancer therapeutic for patients with solid tumors that exhibit hyperactivation of the mTOR pathway, including certain RAS-addicted cancers. The compound is designed to inhibit mTORC1 and thereby protect the natural tumor suppressor activity of 4EBP1, without the undesirable inhibition of mTORC2. RMC-5552 has demonstrated anti-tumor activity in a wide variety of preclinical models. Revolution Medicines has also reported in vivo data demonstrating that RMC-5552 may increase anti-tumor activity in combination with KRASG12C inhibitors in lung and colon cancers harboring both KRAS mutations and co-mutations in the mTOR signaling pathway that can cause resistance to single agent RAS inhibition.
"The paper published in Nature Chemical Biology highlights the therapeutic promise of mTORC1-selective bi-steric inhibitors in the treatment of tumors driven by the genomic activation of the mTORC1 pathway. Specifically, the published research details the manner in which these selective inhibitors of mTORC1 potently inhibit tumor growth while causing less toxicity and receptor reactivation, a potential mechanism of adaptive resistance, as compared to conventional mTOR inhibitors," said Steve Kelsey, M.D., president, research and development at Revolution Medicines. "These study results offer compelling rationale for our recently initiated clinical development program for RMC-5552."
The company recently initiated a multicenter, open-label dose-escalation and dose-expansion Phase 1/1b clinical trial designed to evaluate the safety, tolerability, preliminary efficacy and pharmacokinetics of RMC-5552 in patients with advanced relapsed/refractory solid tumors. Results from this study will inform identification of the maximum tolerated dose (MTD) and selection of recommended Phase 2 dose and schedule (RP2DS) for further evaluation of the compound.
The paper published in Nature Chemical Biology is titled, "Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth," and can be accessed at: View Source
About mTORC1
The mTOR Complex 1 (mTORC1) is a central node within the mTOR signaling pathway and a critical regulator of metabolism, growth and proliferation in cancer cells. Oncogenic mutations of genes encoding proteins that lie upstream of mTOR, including PI3K, PTEN, and STK11, can drive abnormal activation of mTORC1 and subsequent inactivation of the tumor suppressor 4EBP1. Selective inhibition of mTORC1 to reactivate 4EBP1 is a potential therapeutic strategy for patients with tumors bearing such mutations. These mutations are often co-occurring with RAS mutations in RAS-addicted tumors and combinations of mTORC1 and RAS-targeted inhibitors may be of particular benefit in this context.