The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma.
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ABSTRACT:
SUBMITTER: Huynh C
PROVIDER: S-EPMC3182998 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aberrant Notch activation confers a proliferative advantage to many human tumors, including melanoma. This phase 2 trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of patients with advanced melanoma.Chemotherapy-naive patients with metastatic melanoma of cutaneous or unknown origin were treated orally with RO4929097 at a dose of 20 mg daily 3 consecutive days per week. A 2-step accrual design was used with an interim analysis of the first 32 patients and with continuation of enrollment if 4 or more of the 32 patients responded.Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and there were 8 patients with stable disease lasting at least through week 12, with 1 of these continuing for 31 months. The 6-month progression-free survival rate was 9% (95% confidence interval [CI], 2%-22%), and the 1-year overall survival rate was 50% (95% CI, 32%-66%). Peripheral blood T-cell assays showed no significant inhibition of the production of interleukin-2, a surrogate pharmacodynamic marker of Notch inhibition, and this suggested that the drug levels were insufficient to achieve Notch target inhibition.RO4929097 showed minimal clinical activity against metastatic melanoma in this phase 2 trial, possibly because of inadequate exposure to therapeutic drug levels. Although Notch inhibition remains a compelling target in melanoma, the results do not support further investigation of RO4929097 with this dose and schedule.
| S-EPMC4304973 | biostudies-literature
Project description:Interest continues to build around the early application of patient selection markers to prospectively identify patients likely to show clinical benefit from cancer therapies. Hypothesis generation and clinical strategies often begin at the preclinical stage where responder and nonresponder tumor cell lines are first identified and characterized. In the present study, we investigate the drivers of in vivo resistance to the γ-secretase inhibitor RO4929097. Beginning at the tissue culture level, we identified apparent IL6 and IL8 expression differences that characterized tumor cell line response to RO4929097. We validated this molecular signature at the preclinical efficacy level identifying additional xenograft models resistant to the in vivo effects of RO4929097. Our data suggest that for IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts. These preclinical data provide a rationale for preselecting patients possessing low levels of IL6 and IL8 prior to RO4929097 dosing. Extending this hypothesis into the clinic, we monitored patient IL6 and IL8 serum levels prior to dosing with RO4929097 during Phase I. Interestingly, the small group of patients deriving some type of clinical benefit from RO4929097 presented with low baseline levels of IL6 and IL8. Our data support the continued investigation of this patient selection marker for RO4929097 and other types of Notch inhibitors undergoing early clinical evaluation.
| S-EPMC5528291 | biostudies-other
Project description:Glioblastomas (GBM) are poorly differentiated astrocytic tumors arising in the Central Nervous System (CNS), which despite aggressive treatments are still characterized by a fatal outcome. Several studies have shown the existence of a subpopulation of cells within glioma tumors displaying cancer stem cells properties. As the term “tumor initiating cells” (TICs) is frequentely used to describe cells as these with cancer stem cells capacity. Because TICs promotes the tumor chemo- and radio-resistance and angiogenesis it is conceivable that finding a mean to kill these cells would lead to a better therapy for GBM. The NOTCH gene has an important role during the CNS development, in the maintenance of dividing cells in promoting neural lineage entry of Embryonic Stem Cells and the differentiation of astroglia from the rat adult hippocampus-derived multipotent progenitors. The activation of the NOTCH signaling requires the proteolytic processing of this type I integral membrane protein by a two step process catalyzed first by a metalloprotease and then by the gamma-secretase. An increased activation of the NOTCH signaling has been implicated in several tumors types. Recently some studies showed that this pathway induces the survival/proliferation in GBM and glioma cells, and the expression of stem cell properties in glioma cells. Accordingly to these findings, the inhibition of this pathway leads to depletion of stem-like cells and blocks the engraftment in embryonal brain tumors. Furthermore, enhanced NOTCH signaling may lead to one of the tumor resistance mechanisms deployed by GBM. Targeting the NOTCH pathway specifically in GBM TICs appears therefore as a rational approach for exploring novel and hopefully more effective therapeutic strategies for the management of this malignancy. Several molecular tools are available for targeting the Notch pathway such as specific siRNAs, shRNAs or drugs such as gamma-secretase inhibitors. Among these tools, the latter are small peptides/molecules able to inhibit the gamma-secretase by distinct mechanisms. In this study we used two drugs known as gamma-secretase inhibitors, to investigate by gene expression profiling, their ability to interfere specifically with the proliferative properties of GBM TICs previously obtained in our laboratory. Our data show that one of these two drugs, LLNle, is effective in killing these cells in vitro by activating protein catabolic process mediated by the proteasome, suggesting that preclinical studies should definitely be carried on to evaluate whether LLNle is able to significantly improve the survival in hybrid human GBM-animal models. Gamma-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. In this study we employed two of such inhibitors, namely the z-Leu-leu-Nle-CHO (LLNle) and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to verify whether they were effective in vitro in the killing of human GBM tumor initiating cells (TICs). We first established that of the two drugs only LLNle reduces the viability of GBM TICs obtained from three different patients in the low micromolar range. Cells were treated with 7.5 μM LLNle or DAPT or vehicle alone (DMSO 0.1%) and kept in a humidified 5% CO2 atmosphere at 37°C for the indicated time period (24 or 48 hours). To establish which cellular processes are activated in GBM TICs by LLNle we generated and analyzed the gene expression profile after treatment with this compound and with DAPT and DMSO (vehicle). Our data show that LLNle induces upregulation of genes coding for proteasome subunits and subsequently mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activation of genes acting as mitotic inhibitors. Our data are consistent with proteasome inhibition by LLNle, subsequent upregulation of proteasome activity and subsequent unleash of the apoptotic process in GBM TICs.
| S-ECPF-GEOD-14581 | biostudies-other
Project description:Glioblastomas (GBM) are poorly differentiated astrocytic tumors arising in the Central Nervous System (CNS), which despite aggressive treatments are still characterized by a fatal outcome. Several studies have shown the existence of a subpopulation of cells within glioma tumors displaying cancer stem cells properties. As the term “tumor initiating cells” (TICs) is frequentely used to describe cells as these with cancer stem cells capacity. Because TICs promotes the tumor chemo- and radio-resistance and angiogenesis it is conceivable that finding a mean to kill these cells would lead to a better therapy for GBM. The NOTCH gene has an important role during the CNS development, in the maintenance of dividing cells in promoting neural lineage entry of Embryonic Stem Cells and the differentiation of astroglia from the rat adult hippocampus-derived multipotent progenitors. The activation of the NOTCH signaling requires the proteolytic processing of this type I integral membrane protein by a two step process catalyzed first by a metalloprotease and then by the gamma-secretase. An increased activation of the NOTCH signaling has been implicated in several tumors types. Recently some studies showed that this pathway induces the survival/proliferation in GBM and glioma cells, and the expression of stem cell properties in glioma cells. Accordingly to these findings, the inhibition of this pathway leads to depletion of stem-like cells and blocks the engraftment in embryonal brain tumors. Furthermore, enhanced NOTCH signaling may lead to one of the tumor resistance mechanisms deployed by GBM. Targeting the NOTCH pathway specifically in GBM TICs appears therefore as a rational approach for exploring novel and hopefully more effective therapeutic strategies for the management of this malignancy. Several molecular tools are available for targeting the Notch pathway such as specific siRNAs, shRNAs or drugs such as gamma-secretase inhibitors. Among these tools, the latter are small peptides/molecules able to inhibit the gamma-secretase by distinct mechanisms. In this study we used two drugs known as gamma-secretase inhibitors, to investigate by gene expression profiling, their ability to interfere specifically with the proliferative properties of GBM TICs previously obtained in our laboratory. Our data show that one of these two drugs, LLNle, is effective in killing these cells in vitro by activating protein catabolic process mediated by the proteasome, suggesting that preclinical studies should definitely be carried on to evaluate whether LLNle is able to significantly improve the survival in hybrid human GBM-animal models.
2009-12-21 | GSE14581 | GEO
Project description:Glioblastomas (GBM) are poorly differentiated astrocytic tumors arising in the Central Nervous System (CNS), which despite aggressive treatments are still characterized by a fatal outcome. Several studies have shown the existence of a subpopulation of cells within glioma tumors displaying cancer stem cells properties. As the term âtumor initiating cellsâ (TICs) is frequentely used to describe cells as these with cancer stem cells capacity. Because TICs promotes the tumor chemo- and radio-resistance and angiogenesis it is conceivable that finding a mean to kill these cells would lead to a better therapy for GBM. The NOTCH gene has an important role during the CNS development, in the maintenance of dividing cells in promoting neural lineage entry of Embryonic Stem Cells and the differentiation of astroglia from the rat adult hippocampus-derived multipotent progenitors. The activation of the NOTCH signaling requires the proteolytic processing of this type I integral membrane protein by a two step process catalyzed first by a metalloprotease and then by the gamma-secretase. An increased activation of the NOTCH signaling has been implicated in several tumors types. Recently some studies showed that this pathway induces the survival/proliferation in GBM and glioma cells, and the expression of stem cell properties in glioma cells. Accordingly to these findings, the inhibition of this pathway leads to depletion of stem-like cells and blocks the engraftment in embryonal brain tumors. Furthermore, enhanced NOTCH signaling may lead to one of the tumor resistance mechanisms deployed by GBM. Targeting the NOTCH pathway specifically in GBM TICs appears therefore as a rational approach for exploring novel and hopefully more effective therapeutic strategies for the management of this malignancy. Several molecular tools are available for targeting the Notch pathway such as specific siRNAs, shRNAs or drugs such as gamma-secretase inhibitors. Among these tools, the latter are small peptides/molecules able to inhibit the gamma-secretase by distinct mechanisms. In this study we used two drugs known as gamma-secretase inhibitors, to investigate by gene expression profiling, their ability to interfere specifically with the proliferative properties of GBM TICs previously obtained in our laboratory. Our data show that one of these two drugs, LLNle, is effective in killing these cells in vitro by activating protein catabolic process mediated by the proteasome, suggesting that preclinical studies should definitely be carried on to evaluate whether LLNle is able to significantly improve the survival in hybrid human GBM-animal models. Gamma-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. In this study we employed two of such inhibitors, namely the z-Leu-leu-Nle-CHO (LLNle) and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to verify whether they were effective in vitro in the killing of human GBM tumor initiating cells (TICs). We first established that of the two drugs only LLNle reduces the viability of GBM TICs obtained from three different patients in the low micromolar range. Cells were treated with 7.5 μM LLNle or DAPT or vehicle alone (DMSO 0.1%) and kept in a humidified 5% CO2 atmosphere at 37°C for the indicated time period (24 or 48 hours). To establish which cellular processes are activated in GBM TICs by LLNle we generated and analyzed the gene expression profile after treatment with this compound and with DAPT and DMSO (vehicle). Our data show that LLNle induces upregulation of genes coding for proteasome subunits and subsequently mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activation of genes acting as mitotic inhibitors. Our data are consistent with proteasome inhibition by LLNle, subsequent upregulation of proteasome activity and subsequent unleash of the apoptotic process in GBM TICs.
2010-04-09 | E-GEOD-14581 | biostudies-arrayexpress
Project description:The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the ?-secretase enzyme has been safely given as a single agent in patients with advanced solid tumors. We aimed to evaluate the efficacy of RO4929097 in patients with pancreatic adenocarcinoma (PDA).A two-stage, single-arm Phase II trial was conducted in patients with previously treated metastatic PDA. RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles. The primary endpoint was survival at 6 months. Secondary endpoints included overall survival (OS), response rate, toxicities, pharmacokinetic and pharmacodynamic analyses.Eighteen patients were recruited, 17 in the first stage and one in the 2nd stage. It was decided to stop further enrollment after RO4929097 was discontinued by the sponsor and was no longer a development candidate. Three (25 %) of 12 evaluable patients achieved stable disease. The 6-month survival rate was 27.8 % (95 % CI 9.7-53.5). The median OS was 4.1 months (95 % CI 2.7-5.8 months) and median progression-free survival was 1.5 months (95 % CI 1.3-1.6 months). Pharmacokinetic properties of RO4929097 in patients (n?=?5) with PDA was similar to that previously reported in other patient populations. There was a trend towards a decrease in HeyL (p?=?0.08) gene expression in three patients following study drug administration.RO4929097 was well-tolerated in patients with previously treated PDA. Development of RO4929097 has been discontinued, but development of other notch-targeting agents in pancreatic cancer is continuing.
| S-EPMC4292847 | biostudies-literature
Project description:BackgroundTo determine the recommended phase II dose (RP2D) and assess the safety, pharmacokinetics (PKs) and pharmacodynamics of RO4929097in combination with temsirolimus.MethodsEscalating doses of RO4929097 and temsirolimus were administered at three dose levels. Patients received once daily oral RO4929097 on a 3 days on/4 days off schedule every week, and weekly intravenous temsirolimus. Blood samples were collected for PK analysis. Archival tissue specimens were collected for Notch pathway biomarker analysis and genotyping of frequent oncogenic mutations.ResultsSeventeen patients with refractory advanced solid tumors were enrolled in three dose levels (DLs): DL1 (RO4929097 10 mg; Temsirolimus 25 mg), DL2 (RO4929097 20 mg; Temsirolimus 25 mg), and DL3 (RO4929097 20 mg; Temsirolimus 37.5 mg). The most common toxicities related to the study drug combination included: fatigue (82 %; grade 3 6 %), mucositis, (71 %; grade 3 6 %), neutropenia (59 %; grade 3 12 %), anemia (59 %; grade 3 0 %), and hypertriglyceridemia (59 %; grade 3 0 %). Two dose-limiting toxicities, grade 3 rash and grade 3 mucositis, were observed in the same patient in the first dose level prompting dose expansion. Eleven patients (73 %) had stable disease as their best response. Co-administration of RO4929097 was associated with increased clearance and reduced exposure to temsirolimus, suggestive of drug-drug interaction via CYP3A4 induction. No correlation between the expression of Notch pathway biomarkers or genotype and time to progression was noted.ConclusionsRO4929097 can be safely combined with temsirolimus in patients with advanced solid tumors. The RP2D was established at 20 mg of RO4929097 combined with 37.5 mg of temsirolimus.
| S-EPMC3771370 | biostudies-literature
Project description:This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.
| 2091475 | ecrin-mdr-crc
Project description:PurposeBecause the Hedgehog and Notch pathways are often overexpressed in mesenchymal malignancies, we evaluated the efficacy of concurrent inhibition of Notch and Hedgehog signaling using the gamma-secretase inhibitor (GSI) RO4929097 and the smoothened antagonist vismodegib in unresectable or metastatic sarcoma.Patients and methodsIn this investigator-initiated trial, phase Ib used standard 3+3 dose escalation in which patients first received vismodegib once daily for 21 days, followed by the combination of RO4929097 concurrently with vismodegib in 21-day cycles. In phase II, patients were randomized to RO4929097 alone or in combination with vismodegib.ResultsNine patients were treated in phase Ib with no dose-limiting toxicities. RO4929097 at 15 mg daily in combination with 150 mg daily of vismodegib was declared the recommended phase II dose. Most adverse events were grade ≤ 2. In phase II (closed early due to discontinuation of RO4929097 evaluation), 34 patients were randomized to RO4929097 alone and 33 to RO4929097 plus vismodegib. RO4929097 did not interfere with the steady-state concentration of vismodegib, while vismodegib reduced the plasma concentration of RO492909. No patients had an objective response. Neither progression-free nor overall survival differed significantly between treatment arms. Paired tumor biopsies from a subset of patients demonstrated inhibition of cleaved Notch.ConclusionsThe combination of RO4929097 plus vismodegib was generally well tolerated. Although accrual to this study was not completed, vismodegib did not meaningfully enhance the clinical efficacy of RO4929097 in an unplanned analysis. GSIs and GSIs plus vismodegib can inhibit intratumoral Notch and downstream phosphorylated Akt signaling.
| S-EPMC9187109 | biostudies-literature
Project description:PurposeThis study aimed to explore whether RO4929097 (RO), a specific γ-secretase inhibitor, could inhibit the subretinal fibrosis in laser-induced mouse model and the relevant molecular mechanisms.MethodsMale C57BL/6J mice were used to produce choroidal neovascularization (CNV) and subretinal fibrosis by laser photocoagulation, and RO was administered intravitreally 1 day after laser induction. The sizes of CNV and subretinal fibrosis were measured and quantified in both 2D and 3D constructions. The ARPE-19 cell line and primary human RPE (phRPE) cells were treated with TGFβ1, in combination with or without RO, to examine Notch related molecules, epithelial mesenchymal transition (EMT), cell viability, migration, and contractile function, as well as the crosstalk between Notch and other EMT relevant signaling pathways.ResultsIntravitreal injection of RO reduced the sizes of both CNV and subretinal fibrosis in laser-induced young and old mice at day 7 and day 14 after laser induction. Moreover, EMT and Notch activation in RPE-choroid complexes from laser-induced mice were significantly attenuated by RO. In vitro, TGFβ1 activated Notch signaling and induced EMT in ARPE-19 cells, accompanied by enhanced EMT-related function, which were inhibited by RO. The inhibition of RO on EMT was further confirmed in TGFβ1-treated phRPE cells. Blockage of Notch signaling by RO could inhibit ERK1/2 signaling; whereas ERK1/2 inhibition had no effect on Notch. The action of RO was independent of Smad2/3 or p38, and co-inhibition of Notch and Smad2/3 showed synergistic effect on EMT inhibition.ConclusionsRO exerts its antifibrotic effect by directly inhibiting Notch signaling and indirectly suppressing ERK1/2 signaling. Targeting Notch signaling might provide a therapeutic strategy in prevention and treatment of subretinal fibrosis in neovascular age-related macular degeneration (nAMD).
| S-EPMC9526367 | biostudies-literature