Preclinical evaluation of the third-generation, bi-steric mechanistic target of rapamycin complex 1-selective
Srirupa Bhattacharyya1, Janet L Oblinger2, Roberta L Beauchamp1
1Department of Neurology and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Background:
NF2-associated meningiomas are progressive, highly morbid, and nonresponsive to chemotherapies, highlighting the need for improved treatments. We have established aberrant activation of the mechanistic target of rapamycin (mTOR) signaling in NF2-deficient tumors, leading to clinical trials with first- and second-generation mTOR inhibitors. However, results have been mixed, showing stabilized tumor growth without shrinkage offset by adverse side effects. To address these limitations, here we explored the potential of third-generation, bi-steric mTOR complex 1 (mTORC1) inhibitors using the preclinical tool compound RMC-6272.
Methods:
Employing human NF2-deficient meningioma lines, we compared mTOR inhibitors rapamycin (first-generation), INK128 (second-generation), and RMC-6272 (third-generation) using in vitro dose-response testing, cell-cycle analysis, and immunoblotting. Furthermore, the efficacy of RMC-6272 was assessed in NF2-null 3D-spheroid meningioma models, and its in vivo potential was evaluated in 2 orthotopic meningioma mouse models.
Results:
Treatment of meningioma cells revealed that, unlike rapamycin, RMC-6272 demonstrated superior growth inhibitory effects, cell-cycle arrest, and complete inhibition of phosphorylated 4E-BP1 (mTORC1 readout). Moreover, RMC-6272 had a longer retention time than INK128 and inhibited the expression of several eIF4E-sensitive targets on the protein level. RMC-6272 treatment of NF2 spheroids showed significant shrinkage in size as well as reduced proliferation. Furthermore, in vivo studies in mice revealed effective blockage of meningioma growth by RMC-6272, compared with vehicle controls.
Conclusions:
Our study in preclinical models of NF2 supports possible future clinical evaluation of third-generation, investigational mTORC1 inhibitors, such as RMC-5552, as a potential treatment strategy for NF2.
Insights
Third-generation mTORC1 inhibitors like RMC-6272 show promise for treating NF2-associated meningiomas, effectively inhibiting tumor growth in preclinical models. This offers a potential new therapeutic avenue for these aggressive brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- NF2-associated meningiomas are aggressive, difficult-to-treat tumors requiring novel therapeutic strategies.
- Aberrant mechanistic target of rapamycin (mTOR) signaling is implicated in NF2-deficient tumors, prompting clinical trials with existing mTOR inhibitors.
- First- and second-generation mTOR inhibitors have shown limited efficacy and significant side effects in meningioma treatment.
Purpose of the Study:
- To investigate the efficacy of third-generation, bi-steric mTOR complex 1 (mTORC1) inhibitors, specifically RMC-6272, against NF2-associated meningiomas.
- To compare the effects of RMC-6272 with first-generation (rapamycin) and second-generation (INK128) mTOR inhibitors in preclinical meningioma models.
Main Methods:
- Utilized human NF2-deficient meningioma cell lines for in vitro dose-response, cell-cycle, and immunoblotting analyses.
- Assessed RMC-6272 efficacy in NF2-null 3D-spheroid meningioma models.
- Evaluated the in vivo potential of RMC-6272 in orthotopic meningioma mouse models.
Main Results:
- RMC-6272 demonstrated superior growth inhibition and cell-cycle arrest compared to rapamycin in meningioma cells.
- RMC-6272 effectively inhibited mTORC1 signaling, showed longer retention than INK128, and reduced expression of eIF4E-sensitive targets.
- Treatment with RMC-6272 led to significant shrinkage and reduced proliferation in NF2 spheroids and blocked tumor growth in vivo.
Conclusions:
- Third-generation mTORC1 inhibitors like RMC-6272 show significant preclinical efficacy against NF2-associated meningiomas.
- These findings support the potential clinical evaluation of investigational mTORC1 inhibitors for NF2 treatment.
- Further research into agents like RMC-5552 may offer improved therapeutic options for patients with NF2.
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