The anticancer mTOR-inhibitor temsirolimus induces cardiac dysfunction in mice
Carlo G. TocchettiCarmela CoppolaCristina QuintavalleAnna BarbieriDaniel ReaGiuseppe PalmaMaria Carmen Álamo de la GalaAmelia K. LucianoAldo GiudiceImmacolata CapassoC. ArraR.V. IaffaioliGerolama CondorelliNicola Maurea
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Temsirolimus
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8508 Background: Preclinical models suggested synergistic antineoplastic activity of HDAC and mTOR inhibitors in Hodgkin lymphoma by reducing the activity of AKT, mTOR and HDAC. Methods: We designed a phase I study to determine the safety of the mTOR inhibitor sirolimus (1mg-5mg PO daily q 28 days) and HDAC inhibitor vorinostat (100mg-400mg PO daily q 28 days) in advanced cancers with an expansion cohort at the recommended phase 2 dose (RP2D) of sirolimus 4mg and vorinostat 300mg for patients with refractory classical Hodgkin lymphoma. The expansion cohort included optional pre- and post-treatment tumor biopsies, peripheral blood mononuclear cells (PBMCs), plasma/serum collections for pharmacodynamic (PD) and pharmacokinetic (PK) endpoints. Upon identification of R2PD patients were allowed to be treated and registered off label if protocol spots were not available. Results: A total of 28 patients (men, n=15; women, n=13), median age 34 years, median of 6 prior therapies (including autologous SCT [n=23], autologous and allogeneic SCT [n=6]) were enrolled in dose escalation (n=1), RP2D (n=19) or registered off label (n=8). Per Cheson 2007 criteria the overall response rate was 57% with 9 CRs (32%) and 7 PRs (25%). At the median follow-up of 5.4 months, the median progression-free survival has not been reached. Also given successful induction of remissions 5 (18%) patients were referred for allogeneic SCT. Major grade 3-4 treatment-related toxicities included grade 3 thrombocytopenia (9 patients, 32%), grade 4 thrombocytopenia (8, 29%), grade 3 anemia (4, 14%), and grade 3 transaminitis (3, 11%). Treatment interruptions and/or dose modifications were needed in 19 (68%) patients. Ten (36%) patients had archival tissue available for targeted next-generation sequencing and one patient had a loss of TSC2, an abnormality that putatively activates mTOR (PR -56% for 8.4+ months). PD studies in pre- and post-treatment tumor biopsies, PBMCs and plasma as well as PK analysis are pending. Conclusions: The combination of sirolimus and vorinostat is well tolerated with encouraging activity in very heavily pretreated patients with Hodgkin lymphoma refractory to standard therapies. Clinical trial information: NCT01087554.
Sirolimus
Vorinostat
Refractory (planetary science)
Pharmacodynamics
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5113 Background: Everolimus, an oral mTOR inhibitor, affects tumor growth by blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. mTOR inhibitors and agents with primarily antiangiogenic activity have shown efficacy in renal cell cancer (RCC). Reported at ASCO 2007, everolimus has promising anti-tumor activity in patients with MRCC demonstrated by 32% partial response (PR) and stable disease (SD) for >6 months in 38% of patients. This phase II study assessed the efficacy of daily oral dosing with everolimus in MRCC patients who have failed no more than 2 prior therapies one of which was a tyrosine kinase inhibitor (sorafenib or sunitinib). Methods: Patients had confirmed predominantly clear cell RCC, progressive measurable metastatic disease, adequate organ/marrow function, good performance status and no active CNS involvement. Everolimus was given (10 mg daily, p.o.) without an interruption (28-day cycle), with dose modifications for toxicity per NCI-CTC, version 3.0. Patients were evaluated every 2 cycles (8 weeks) using RECIST. Results: Among the first 22 enrolled patients, 22 were treated and evaluable for safety, 19 for response after withdrawal of 2 patients following the first 4 weeks of therapy, and 1 too early. Patients were mostly male (68%) with a median age 57 years, 100% Zubrod Performance Status 0–1. PR were seen in 3(16%) and SD for ≥ 3 months in 14 (74%). Median PFS was 5.5+ months (1–12+ months), median OS was 8+ months (1–14+). The most common treatment related adverse events were Grade 1/2: hypertriglyceridemia (73%), hyperglycemia (59%). hypercholesterolemia (64%), stomatitis (45%), rash (32%), nausea (27%), and diarrhea (18%); Grade 3/4 adverse events included pneumonitis (27%). Conclusions: Everolimus shows encouraging anti-tumor activity against MRCC patients who have had prior exposure to sorafenib or sunitinib as indicated by the tumor responses and progression free survival. Anti-tumor activity and toxicity will be presented in addition an update of the ASCO 2007 data. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis
Everolimus
Temsirolimus
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Pazopanib
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mTORC2
Everolimus
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Mammalian target of rapamycin(mTOR) is a serine / threonine protein kinase,and it plays an important role in the occurrence and development of renal cell carcinoma(RCC).mTOR inhibitors can inhibit cancer gene transformation caused by abnormal mTOR signaling pathway,tumor growth and tumor angiogenesis.Temsirolimus and everolimus are approved in clinical application,and bring new hope for the prognosis of advanced renal cell carcinoma.
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mTORC2
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Context: Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor anticancer agent whose clinical use is often limited by cardiovascular complications. Trimetazidine (TMZ) is an anti-angina agent that has been demonstrated cardioprotective effects in numerous cardiovascular conditions, but its potential effects in SU-induced cardiotoxicity have not been investigated. Objective: This study investigates the effect of TMZ in sunitinib-induced cardiotoxicity in vivo and in vitro and molecular mechanisms. Materials and methods: Male 129S1/SvImJ mice were treated with vehicle, SU (40 mg/kg/d) or SU and TMZ (20 mg/kg/d) via oral gavage for 28 days, and cardiovascular functions and cardiac protein expressions were examined. H9c2 cardiomyocytes were treated with vehicle, SU (2-10 μM) or SU and TMZ (40-120 μM) for 48 h, and cell viability, apoptosis, autophagy, and protein expression was tested. Results: SU induces hypertension (systolic blood pressure [SBP] + 28.33 ± 5.00 mmHg) and left ventricular dysfunction (left ventricular ejection fraction [LVEF] - 11.16 ± 2.53%) in mice. In H9c2 cardiomyocytes, SU reduces cell viability (IC50 4.07 μM) and inhibits the AMPK/mTOR/autophagy pathway (p < 0.05). TMZ co-administration with SU reverses SU-induced cardiotoxicity in mice (SBP - 23.75 ± 4.69 mmHg, LVEF + 10.95 ± 3.317%), alleviates cell viability loss in H9c2 cardiomyocytes (p < 0.01) and activates the AMPK/mTOR/autophagy pathway in vivo (p < 0.001) and in vitro (p < 0.05). Discussion and conclusions: Our results suggest TMZ as a potential cardioprotective approach for cardiovascular complications during SU regimen, and potentially for cardiotoxicity of other anticancer chemotherapies associated with cardiomyocyte autophagic pathways.
Cardiotoxicity
Viability assay
Cardioprotection
Trimetazidine
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Temsirolimus
Everolimus
Sirolimus
Targeted Therapy
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AbstractThe mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG ), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.
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mTORC2
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Background: The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-Kinase (PI3K)/AKT signalling pathway with a central role in the control of cell growth, survival and angiogenesis. Multiple and frequent dysregulations of this pathway in human tumors make it a central target in the development of new anticancer treatments. Objective: To review the most significant data on mTOR pathway, role of mTOR inhibitors in cancer treatment, preclinical and clinical data of the three first generation mTOR inhibitors (temsirolimus, everolimus and deferolimus), rationales, preclinical and clinical data of second generation mTOR inhibitors. Methods: Review of published literature on mTOR and related pathways, rapalogs and novel mTOR inhibitors. Results/conclusions: Temsirolimus and everolimus have been approved for the treatment of metastatic Renal Cell Carcinoma (RCC), temsirolimus also for Mantle Cell Lymphoma (MCL) and everolimus will be approved for pancreatic neuroendocrine tumors; all three rapalogs are currently evaluated in phase III studies in several tumors. Only limited published data are available on new mTOR inhibitors; however, in vitro and in vivo in preclinical studies they have shown a significant antiproliferative activity against a broad panel of tumors and a favourable safety profile, with disease stabilization or even tumor regression, either as single agent or in combination. Keywords: Mammalian target of rapamycin, temsirolimus, everolimus, deforolimus, renal cell carcinoma, mantle cell lymphoma, mTORC1/mTORC2-inhibitors, dual-kinase PI3K/mTOR-Inhibitors, tumor regression, receptor tyrosine kinases (RTKs)
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2585 Background: ABTL0812 is a novel drug with reported preclinical activity in several tumor types. In vitro and in vivo assays have shown that ABTL0812 is an inhibitor of the Akt/mTOR pathway by a novel mechanism of action. Methods: A Phase I/Ib First in Human (FiH) clinical trial started on February 2014 (NCT02201823) in which patients with solid tumors and no standard treatment were enrolled. ABTL0812 was administered daily, by the oral route in 28-day cycles. The primary objective of the trial was to obtain a maximum tolerated dose and a recommended phase II dose (RP2D). The secondary objectives of the trial were assessment of dose-limiting toxicity (DLT), response rate, progression-free survival and overall survival. Pharmacokinetic (days 1 and 29) and pharmacodynamic (inhibition of the phosphorylation of Akt in platelets at day 29 vs. predose, as biomarker) end-points were also introduced. The study design consisted in a 3+3 dose escalation with up to five cohorts. An expansion phase with 12 patients is planned. Results: The dose-escalation, in which 15 patients were recruited, started at 500 mg/day and was completed in December 2014 at 4,000 mg/day. ABTL0812 showed overall a good safety profile. Grade 1-2 adverse events included swallowing disturbance, asthenia, increase of hepatic enzymes, hyperglycemia and nausea; grade > 2 adverse events were rare and included anemia and asthenia. No DLTs were observed and therefore, RP2D has been determined as 1,300 mg tid by pharmacokinetic-pharmacodynamic modeling of drug plasma concentrations at steady state vs. platelet pAkt inhibition. One patient with endometrial cancer and one patient with sigmoid colon cancer currently show stable disease (SD) after 10 and 5 months of treatment, respectively. Conclusions: RP2D of ABTL0812 has been determined. ABTL0812 has demonstrated a good safety profile, with only mild adverse events. Additionally, ABTL0812 has shown activity on biomarkers, and hints of activity in two patients presenting prolonged SD. Clinical trial information: NCT02201823.
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