gsk-2126458 and Neoplasms

Aberrant activation of the phosphoinositide 3-kinase (PI3K) signaling network is a key event in many human cancers and therefore enormous efforts have been made in the development of PI3K inhibitors. However, due to intrinsic and acquired resistance as well as poor drug tolerance, limited therapeutic efficacy has been achieved with these agents. In view of the fact that PI3K inhibitors can show synergistic antitumor effects with other cancer agents, namely mammalian target of rapamycin (mTOR) inhibitors, histone deacetylase (HDAC) inhibitors and mitogen-activated protein kinase (MEK) inhibitors, dual inhibition of both targets by a single-molecule is regarded as a promising complementary or alternative therapeutic strategy to overcome the drawbacks of just PI3K monotherapy. In this review, we discuss the theoretical foundation for designing PI3K-based dual-target inhibitors and summarize the structure-activity relationships and clinical progress of these dual-binding agents.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Drug Design; Humans; Molecular Structure; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors

GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, and δ), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors.. Patients received oral GSK458 once or twice daily in a dose-escalation design to define the maximum tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clinical activity in histologically and molecularly defined cohorts.. One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea,n= 4; fatigue and rash,n= 1) occurred in 5 patients (n= 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated withPIK3CAmutations (OR rate: 5% wild-type vs. 6% mutant).. Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however,PIK3CAmutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Class I Phosphatidylinositol 3-Kinases; Drug Monitoring; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Pyridazines; Quinolines; Risk Factors; Sulfonamides; Treatment Outcome; Young Adult

Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

Topics: Adult; Aged; Biomarkers, Tumor; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; MAP Kinase Kinase 1; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Prognosis; Protein Kinase Inhibitors; Pyridazines; Pyridones; Pyrimidinones; Quinolines; Sulfonamides; Survival Rate; Tissue Distribution; TOR Serine-Threonine Kinases; Young Adult

A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for GSK2126458, a dual PI3K/mTOR inhibitor, was developed and validated. Plasma and tumor homogenate samples were pre-treated using protein precipitation with acetonitrile containing dabrafenib as internal standard. After dilution with water, the extract was directly injected into the reversed-phase liquid chromatographic system. The eluate was transferred into the electrospray interface with positive ionization and compounds were detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was completely validated for plasma in a 4-4000 ng/ml calibration range with r(2)=0.9996±0.0003 using double logarithmic calibration (n=5). Within-run precisions (n=6) were 2.0-5.3% and between-run (3 runs; n=18) precisions 2.7-5.8%. Accuracies were between 101 and 105% for the whole calibration range. The drug was sufficiently stable under all relevant analytical conditions. Finally, the assay was successfully applied to determine plasma and tumor drug levels after oral administration of GSK2126458 to mice with AMC711T neuroblastoma xenografts.

Topics: Animals; Calibration; Chromatography, Liquid; Female; Mice; Neoplasms; Neuroblastoma; Phosphoinositide-3 Kinase Inhibitors; Plasma; Protein Kinase Inhibitors; Pyridazines; Quinolines; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Sulfonamides; Tandem Mass Spectrometry; TOR Serine-Threonine Kinases

GSK2126458 is a highly potent inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with low picomolar to subnanomolar activity. [(11)C]GSK2126458 and [(18)F]GSK2126458, new potential PET agents for imaging of PI3K and mTOR in cancer, were first designed and synthesized in 40-50% and 20-30% decay corrected radiochemical yield, and 370-740 and 37-222GBq/μmol specific activity at end of bombardment (EOB), respectively.

Topics: Carbon Radioisotopes; Fluorodeoxyglucose F18; Humans; Molecular Structure; Neoplasms; Phosphatidylinositol 3-Kinases; Positron-Emission Tomography; Pyridazines; Quinolines; Radiopharmaceuticals; Sulfonamides; TOR Serine-Threonine Kinases