Dataset Information

RES-529: a PI3K/AKT/mTOR pathway inhibitor that dissociates the mTORC1 and mTORC2 complexes.

ABSTRACT: RES-529 (previously named Palomid 529, P529) is a phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway inhibitor that interferes with the pathway through both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) dissociation. This compound is currently being developed in oncology and ophthalmology. The oncology focus is for the treatment of glioblastoma, where it has received orphan designation by the US Food and Drug Administration, and prostate cancer. We present a review of the PI3K/AKT/mTOR pathway, its role in tumorigenesis, and the potential of RES-529 in cancer treatment. RES-529 inhibits mTORC1/mTORC2 activity in various cancer cell lines, as noted by decreased phosphorylation of substrates including ribosomal protein S6, 4E-BP1, and AKT, leading to cell growth inhibition and death, with activity generally in the range of 5-15??mol/l. In animal tumor models where the PI3K/AKT/mTOR pathway is abnormally activated (i.e. glioblastoma, prostate cancer, and breast cancer), RES-529 reduces tumor growth by as much as 78%. RES-529 treatment is synergistic with radiation therapy, chemotherapy, and hormonal therapy in reducing tumor growth, potentially by preventing PI3K/AKT/mTOR pathway activation associated with these treatments. Furthermore, this compound has shown antiangiogenic activity in several animal models. mTORC1 and mTORC2 have redundant and distinct activities that contribute toward oncogenesis. Current inhibitors of this pathway have primarily targeted mTORC1, but have shown limited clinical efficacy. Inhibitors of mTORC1 and mTORC2 such as RES-529 may therefore have the potential to overcome the deficiencies found in targeting only mTORC1.

SUBMITTER: Weinberg MA

PROVIDER: S-EPMC4881730 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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RES-529: a PI3K/AKT/mTOR pathway inhibitor that dissociates the mTORC1 and mTORC2 complexes.

Weinberg Mark A MA

Anti-cancer drugs 20160701 6

RES-529 (previously named Palomid 529, P529) is a phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway inhibitor that interferes with the pathway through both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) dissociation. This compound is currently being developed in oncology and ophthalmology. The oncology focus is for the treatment of glioblastoma, where it has received orphan designation by the US Food and Drug Administration, and prostate cancer. We present ...[more]

PMID: 26918392

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Project description:The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.

Project description:BackgroundSapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of 5'-AMP-activated protein kinase (AMPK) suggesting combination therapy may enhance antitumor activity of sapanisertib. We report preliminary safety, tolerability, and efficacy from the dose-escalation study of sapanisertib in combination with metformin in patients with advanced solid tumors.MethodsPatients with advanced metastatic solid tumors resistant or refractory to standard treatment, with and without mTOR/AKT/PI3K pathway alterations, received sapanisertib 3 or 4 mg daily together with metformin once to three times daily (500-1,500 mg). All patients underwent 14-day titration period for metformin in cycle 1. Tumor measurements were performed following cycle 2 and subsequently every 8 weeks.ResultsA total of 30 patients were enrolled across four cohorts (3 mg/500 mg; 3 mg/1,000 mg, 4 mg/1,000 mg; 4 mg/1,500 mg). 19 were female (63%), median age was 57 (range: 30-77), all were Eastern Cooperative Oncology Group performance status 1. Tumor types included sarcoma (6), breast (4), ovarian (4), head and neck (3), colorectal (2), lung (2), renal cell (2), endometrial (2), gastroesophageal junction (1), prostate (1), stomach (1), urachus (1), and cervical cancer (1). Median number of prior lines of therapy was 4. Most common genomic alterations included PIK3CA (27%), PTEN (17%), AKT1/2 (10%), mTOR (10%). Of 30 patients evaluable for response, 4 patients achieved partial response (PR); 15 patients achieved stable disease (SD) as best response. Disease control rate (PR+SD) was 63%. Of the responders in PR, 3 of 4 patients had documented PTEN mutations (3/5 patients enrolled with PTEN mutations had PR); 2 of 4 of patients in PR had comutations (patient with leiomyosarcoma had both PTEN and TSC; patient with breast cancer had both PTEN and STK11); 1 of 4 patients in PR had AKT and mTOR mutation; tumor types included leiomyosarcoma (n = 2), breast (n = 1), and endometrial cancer (n = 1). Most common treatment-emergent adverse events included nausea, anorexia, diarrhea, and rash. Grade (G) 3-5 treatment-related adverse events included hyperglycemia (4/30; 13%), fatigue (2/30; 7%), hypertriglyceridemia (1/30; 3%), rash (2/20; 7%), diarrhea (2/30; 7%), creatinine increase (1/30; 3%), acidosis (1/30; 3%). No dose-limiting toxicities (DLT) were reported in the 3 mg/500 mg cohort. One of 6 patient had DLT in the 3 mg/1,000 mg cohort (G3 diarrhea) and 2 of 11 patients had DLTs in the 4 mg/1,500 mg cohort (G3 fatigue, G3 rash). 4 mg/1,000 mg was defined as the MTD.ConclusionsThe safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with antitumor activity observed in patients with advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations.SignificanceSapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, next-generation dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of AMPK suggesting combination therapy may enhance antitumor activity of sapanisertib. This dose-escalation study of sapanisertib and metformin in advanced solid tumors and mTOR/AKT/PI3K pathway alterations, demonstrates safety, tolerability, and early clinical activity in advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations.Clinical trial information: NCT03017833.

Dataset Information

RES-529: a PI3K/AKT/mTOR pathway inhibitor that dissociates the mTORC1 and mTORC2 complexes.

Publications

RES-529: a PI3K/AKT/mTOR pathway inhibitor that dissociates the mTORC1 and mTORC2 complexes.

Similar Datasets

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