buparlisib and Glioblastoma

To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D) for combined INC280 and buparlisib in patients with recurrent glioblastoma with homozygous phosphatase and tensin homolog (PTEN) deletion, mutation or protein loss.. This multicenter, open-label, Phase Ib/II study included adult patients with glioblastoma with mesenchymal-epithelial transcription factor (c-Met) amplification. In Phase Ib, patients received INC280 as capsules or tablets in combination with buparlisib. In Phase II, patients received INC280 only. Response was assessed centrally using Response Assessment in Neuro-Oncology response criteria for high-grade gliomas. All adverse events (AEs) were recorded and graded.. 33 patients entered Phase Ib, 32 with altered PTEN. RP2D was not declared due to potential drug-drug interactions, which may have resulted in lack of efficacy; thus, Phase II, including 10 patients, was continued with INC280 monotherapy only. Best response was stable disease in 30% of patients. In the selected patient population, enrollment was halted due to limited activity with INC280 monotherapy. In Phase Ib, the most common treatment-related AEs were fatigue (36.4%), nausea (30.3%) and increased alanine aminotransferase (30.3%). MTD was identified at INC280 Tab 300 mg twice daily + buparlisib 80 mg once daily. In Phase II, the most common AEs were headache (40.0%), constipation (30.0%), fatigue (30.0%) and increased lipase (30.0%).. The combination of INC280/buparlisib resulted in no clear activity in patients with recurrent PTEN-deficient glioblastoma. More stringent molecular selection strategies might produce better outcomes.. NCT01870726.

Topics: Adult; Aged; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Brain Neoplasms; Female; Follow-Up Studies; Glioblastoma; Humans; Imidazoles; Male; Maximum Tolerated Dose; Middle Aged; Morpholines; Neoplasm Recurrence, Local; Prognosis; Proto-Oncogene Proteins c-met; PTEN Phosphohydrolase; Tissue Distribution; Triazines

Most glioblastoma tumours exhibit intrinsic phosphatidylinositol 3-kinase (PI3K) pathway activation. Preclinical in vitro and in vivo models suggest that buparlisib (an oral pan-PI3K inhibitor) can have an effect on glioblastoma directly and by enhancing the activity of radiation and of temozolomide.. This was a phase I, two-stage, multicentre, open-label, dose-escalation study of buparlisib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. In stage I, patients who completed the concomitant phase of combination of temozolomide and radiation prior to study entry received buparlisib in combination with temozolomide. In stage II, patients received buparlisib in combination with temozolomide and radiotherapy in the concomitant phase and temozolomide in the adjuvant treatment phase. The primary objective was to estimate the maximum tolerated dose (MTD) of buparlisib when combined with the approved first-line treatment of temozolomide and radiotherapy.. The MTD of buparlisib in combination with temozolomide at stage I (adjuvant phase only) was 80 mg/day, which was used as the starting dose in stage II. The MTD of buparlisib in combination with temozolomide and radiotherapy in stage II (concomitant + adjuvant phase) was not determined due to the observed dose-limiting toxicities and treatment discontinuations due to adverse events (AEs). In stage I, the most commonly reported AEs were nausea (72.7%) and fatigue (59.1%). In stage II, the most commonly reported AEs were fatigue and nausea (56.3% each). No on-treatment deaths were reported during the study.. Considering that the primary objective of estimating the MTD was not achieved in addition to the observed challenging safety profile of buparlisib in combination with radiotherapy and temozolomide, Novartis decided not to pursue the development of buparlisib in newly diagnosed glioblastoma.

Topics: Adult; Aged; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Female; Glioblastoma; Humans; Male; Middle Aged; Morpholines; Phosphatidylinositol 3-Kinases; Temozolomide

Glioblastoma relapse is associated with activation of phosphatidylinositol 3-kinase (PI3K) signalling pathway. In preclinical studies, the pan-PI3K inhibitor buparlisib showed antitumour activity in glioma models.. Between 28 February 2014 and 7 July 2016, 35 patients were enrolled and treated with buparlisib plus carboplatin (n=17; buparlisib (80 mg) plus carboplatin, n=3; and buparlisib (100 mg) plus carboplatin, n=14), or buparlisib (60 mg) plus lomustine (n=18). The MTD of buparlisib was determined to be 100 mg per day in combination with carboplatin at an AUC of 5 every 3 weeks. The MTD of buparlisib in combination with lomustine could not be determined as it did not satisfy the MTD criteria per the Bayesian logistic regression model.. The overall safety profile of buparlisib remained unchanged, and no new or unexpected safety findings were reported in this study. Preliminary assessment for both combinations did not demonstrate sufficient antitumour activity compared with historical data on single-agent carboplatin or lomustine.. NCT01934361.

Topics: Aged; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Carboplatin; Female; Glioblastoma; Humans; Lomustine; Male; Middle Aged; Morpholines; Phosphatidylinositol 3-Kinases; Recurrence

Current bevacizumab-based regimens have failed to improve survival in patients with recurrent glioblastoma. To improve treatment efficacy, we evaluated bevacizumab + BKM120, an oral pan-class I PI3K inhibitor, in this patient population.. A brief phase I study established the optimal BKM120 dose to administer with standard-dose bevacizumab. BKM120 60 mg PO daily + bevacizumab 10 mg/kg IV every 2 weeks in 28-day cycles was then administered to patients with relapsed/refractory glioblastoma in the phase II portion.. Eighty-eight patients enrolled (phase I, 12; phase II, 76). In phase I, BKM120 80 mg PO daily produced dose limiting toxicity in 3 of 6 patients; a BKM120 dose of 60 mg PO daily was established as the maximum tolerated dose. In phase II, the median progression-free survival (PFS) was 4.0 months (95% CI 3.4, 5.4), PFS at 6 months was 36.5%, and the overall response rate was 26%. Forty-two patients (57%) experienced one or more serious treatment related toxicities. The most common CNS toxicities included mood alteration (17%) and confusion (12%); however, these were often difficult to classify as treatment- versus tumor-related.. The efficacy seen in this study is similar to the efficacy previously reported with single-agent bevacizumab. This regimen was poorly tolerated, despite the low daily dose of BKM120. Further development of this combination for the treatment of glioblastoma is not recommended.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Middle Aged; Morpholines; Neoplasm Recurrence, Local; Neoplasms; Phosphatidylinositol 3-Kinases; Prognosis; Salvage Therapy; Survival Rate

Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.. This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.. Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKT. Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Antineoplastic Agents; Brain Neoplasms; Chemotherapy, Adjuvant; Disease Progression; Enzyme Activation; Female; Glioblastoma; Humans; Male; Middle Aged; Morpholines; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Progression-Free Survival; Time Factors

PARP inhibitors have been approved for the therapy of cancers with homologous recombination (HR) deficiency based on the concept of "synthetic lethality". However, glioblastoma (GBM) patients have gained little benefit from PARP inhibitors due to a lack of BRCA mutations. Herein, we demonstrated that concurrent treatment with the PARP inhibitor rucaparib and the PI3K inhibitor BKM120 showed synergetic anticancer effects on GBM U251 and U87MG cells. Mechanistically, BKM120 decreased expression of HR molecules, including RAD51 and BRCA1/2, and reduced HR repair efficiency in GBM cells, therefore increasing levels of apoptosis induced by rucaparib. Furthermore, we discovered that the two compounds complemented each other in DNA damage response and drug accumulation. Notably, in the zebrafish U87MG-RFP orthotopic xenograft model, nude mouse U87MG subcutaneous xenograft model and U87MG-Luc orthotopic xenograft model, combination showed obviously increased antitumor efficacy compared to each monotherapy. Immunohistochemical analysis of tumor tissues indicated that the combination obviously reduced expression of HR repair molecules and increased the DNA damage biomarker γ-H2AX, consistent with the in vitro results. Collectively, our findings provide new insight into combined blockade of PI3K and PARP, which might represent a promising therapeutic approach for GBM.

Topics: Aminopyridines; Animals; Female; Glioblastoma; Humans; Indoles; Mice; Morpholines; Poly(ADP-ribose) Polymerase Inhibitors; Recombinational DNA Repair; Zebrafish

Glioblastoma is an aggressive, invasive tumor of the central nervous system (CNS). There is a widely acknowledged need for anti-invasive therapeutics to limit glioblastoma invasion. BKM-120 is a CNS-penetrant pan-class I phosphatidyl-inositol-3 kinase (PI3K) inhibitor in clinical trials for solid tumors, including glioblastoma. We observed that BKM-120 has potent anti-invasive effects in glioblastoma cell lines and patient-derived glioma cells in vitro. These anti-migratory effects were clearly distinguishable from cytostatic and cytotoxic effects at higher drug concentrations and longer durations of drug exposure. The effects were reversible and accompanied by changes in cell morphology and pronounced reduction in both cell/cell and cell/substrate adhesion. In vivo studies showed that a short period of treatment with BKM-120 slowed tumor spread in an intracranial xenografts. GDC-0941, a similar potent and selective PI3K inhibitor, only caused a moderate reduction in glioblastoma cell migration. The effects of BKM-120 and GDC-0941 were indistinguishable by in vitro kinase selectivity screening and phospho-protein arrays. BKM-120 reduced the numbers of focal adhesions and the velocity of microtubule treadmilling compared with GDC-0941, suggesting that mechanisms in addition to PI3K inhibition contribute to the anti-invasive effects of BKM-120. Our data suggest the CNS-penetrant PI3K inhibitor BKM-120 may have anti-invasive properties in glioblastoma.

Topics: Aminopyridines; Animals; Blood-Brain Barrier; Brain Neoplasms; Cell Adhesion; Cell Culture Techniques; Cell Line, Tumor; Cell Movement; Cell Proliferation; Enzyme Inhibitors; Glioblastoma; Humans; Mice; Mice, Nude; Microtubules; Morpholines; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Spheroids, Cellular; Transplantation, Heterologous; Vimentin

Glioblastomas (GBMs) are aggressive brain tumours with a dismal prognosis, despite combined surgery, radio- and chemotherapy. Close to 90 % of all GBMs harbour a deregulated PI3K pathway, which is essential in regulating central cellular functions such as proliferation, cell growth, motility and survival. Thus, PI3K represents a potential target for molecular therapy in GBM. We investigated the anti-tumour efficacy of the PI3K inhibitor buparlisib (NVP-BKM120) in GBM cell lines in vitro and in vivo, when treatment was initiated after MRI-confirmed tumour engraftment. We found that buparlisib inhibited glioma cell proliferation in a dose dependent manner, demonstrated by MTS assay, manual cell count and BrdU incorporation. A dose dependent increase in apoptosis was observed through flow cytometric analysis. Furthermore, by immunocytochemistry and western blot, we found a dose dependent inhibition of Akt phosphorylation. Moreover, buparlisib prolonged survival of nude rats harboring human GBM xenografts in three independent studies and reduced the tumours' volumetric increase, as determined by MRI. In addition, histological analyses of xenograft rat brains showed necrotic areas and change in tumour cell nuclei in buparlisib-treated animals. The rats receiving buparlisib maintained their weight, activity level and food- and water intake. In conclusion, buparlisib effectively inhibits glioma cell proliferation in vitro and growth of human GBM xenografts in nude rats. Moreover, the compound is well tolerated when administered at doses providing anti-tumour efficacy. Thus, buparlisib may have a future role in glioma therapy, and further studies are warranted to validate this compound for human use.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Glioblastoma; Humans; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Nude; Survival Analysis; Xenograft Model Antitumor Assays

Objective To investigate the effect of phosphatidylinositide 3-kinase (PI3K) inhibitor BKM120 on the proliferation and apoptosis of human glioma U251 cells. Methods U251 cells were treated with different concentrations of BKM120 (final concentrations were 1, 5, 20 μmol/L) for 48 hours. The effect of BKM120 on cell proliferation was detected by CCK-8 assay. The apoptosis was detected by annexin V-FITC/PI staining. The protein expressions of Bax and Bcl-2 were detected by Western blotting. Results CCK-8 assay showed that BKM120 inhibited U251 proliferation in a concentration-dependent manner and the maximum inhibitory rate was 78.3%. Flow cytometry showed that BKM120 induced cell aopotosis in a concentration-dependent manner. Western blotting revealed that the expression of Bax was elevated by BKM120, but the expression of Bcl-2 had a reverse trend. Conclusion BKM120 can inhibit the proliferation and induce the apoptosis of U251 cells.

Topics: Aminopyridines; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Flow Cytometry; Glioblastoma; Humans; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2

Combined targeting with a PI3-kinase inhibitor, BKM120, and an Hsp90 inhibitor, HSP990, was investigated as a multi-targeted approach to potentiate cell death in glioblastoma (GBM). Additionally, the effect of dual drug treatment combined with cytotoxic stress (radiation therapy) was examined.. Four human GBM cell lines containing wild-type or mutated PTEN and/or p53 were studied. The effects of drug treatments on cell viability, apoptosis induction, pAKt activity, cell cycle arrest, clonogenicity, and tumor growth delay were studied.. Combined concurrent treatment with both drugs produced more cell killing in cell viability and apoptosis assays than either drug alone. BKM120 plus HSP990 induced suppression of baseline Akt signaling as well as radiation (RT)-induced pAkt signaling in all cell lines. Cell cycle analysis revealed that HSP990 and BKM120, singly or combined, induced G2/M arrest leading to apoptosis/necrosis and polyploidy. Additionally, the drugs radiosensitized GBM cells in clonogenic assays. In vivo tumor growth delay studies demonstrated the effectiveness of combined drug treatment with HSP990 and BKM120 over single drug treatment, as well as the effectiveness of combined drug treatment in enhancing the effectiveness of radiation therapy.. In conclusion, HSP990 and BKM120, with and without RT, are active agents against glioma tumors. The sensitivity to these agents does not appear to depend on PTEN/p53status in the cell lines tested. We suggest that the combined action of both drugs is a viable multi-targeted strategy with the potential to improve clinical outcome for patients with high-grade glioma.

Topics: Aminopyridines; Animals; Apoptosis; Blotting, Western; Brain Neoplasms; Cell Proliferation; Flow Cytometry; Gene Expression Regulation, Neoplastic; Glioblastoma; HSP90 Heat-Shock Proteins; Humans; Mice; Mice, Nude; Morpholines; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Radiation Tolerance; Radiation-Sensitizing Agents; Tumor Cells, Cultured

Identification of therapeutic strategies that might enhance the efficacy of B-cell lymphoma-2 (Bcl-2) inhibitor ABT-737 [N-{4-[4-(4-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-4-(3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-3-nitro-benzenesulfonamide] is of great interest in many cancers, including glioma. Our recent study suggested that Akt is a crucial mediator of apoptosis sensitivity in response to ABT-737 in glioma cell lines. Inhibitors of phosphatidylinositol 3-kinase (PI3K)/Akt are currently being assessed clinically in patients with glioma. Because PI3K/Akt inhibition would be expected to have many proapoptotic effects, we hypothesized that there may be unique synergy between PI3K inhibitors and Bcl-2 homology 3 mimetics. Toward this end, we assessed the combination of the PI3K/Akt inhibitor NVP-BKM120 [5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine] and the Bcl-2 family inhibitor ABT-737 in established and primary cultured glioma cells. We found that the combined treatment with these agents led to a significant activation of caspase-8 and -3, PARP, and cell death, irrespective of PTEN status. The enhanced lethality observed with this combination also appears dependent on the loss of mitochondrial membrane potential and release of cytochrome c, smac/DIABLO, and apoptosis-inducing factor to the cytosol. Further study revealed that the upregulation of Noxa, truncation of Bid, and activation of Bax and Bak caused by these inhibitors were the key factors for the synergy. In addition, we demonstrated the release of proapoptotic proteins Bim and Bak from Mcl-1. We found defects in chromosome segregation leading to multinuclear cells and loss of colony-forming ability, suggesting the potential use of NVP-BKM120 as a promising agent to improve the anticancer activities of ABT-737.

Topics: Aminopyridines; Antineoplastic Agents; Apoptosis Inducing Factor; Apoptosis Regulatory Proteins; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; Bcl-2-Like Protein 11; Biphenyl Compounds; Caspase 3; Caspase 8; Caspases; Cell Death; Cell Line, Tumor; Chromosome Segregation; Cytochromes c; DNA Damage; Drug Synergism; Glioblastoma; Humans; Intracellular Signaling Peptides and Proteins; Membrane Potential, Mitochondrial; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Morpholines; Nitrophenols; Phosphoinositide-3 Kinase Inhibitors; Piperazines; Poly(ADP-ribose) Polymerases; Primary Cell Culture; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides

In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma.

Topics: Aminopyridines; Animals; Biphenyl Compounds; Brain Neoplasms; Cell Line, Tumor; Enzyme Inhibitors; Glioblastoma; Hedgehog Proteins; Humans; Mice; Mice, Nude; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; PTEN Phosphohydrolase; Pyridines; Ribosomal Protein S6 Kinases; Signal Transduction; Xenograft Model Antitumor Assays