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Elisabeth M. Storck - One of the best experts on this subject based on the ideXlab platform.
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Tipifarnib prevents development of hypoxia-induced pulmonary hypertension.
Cardiovascular research, 2017Co-Authors: Lucie Duluc, Blerina Ahmetaj-shala, Jane A. Mitchell, Vahitha B. Abdul-salam, Abdul S. Mahomed, Lulwah Aldabbous, Eduardo Oliver, Lucio Iannone, Olivier Dubois, Elisabeth M. StorckAbstract:Aims RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated whether inhibition of protein farnesylation will have a protective effect. Methods and results The analysis of lung tissues from rodent models and pulmonary hypertensive patients showed increased levels of protein farnesylation. Oral farnesyltransferase inhibitor Tipifarnib prevented development of hypoxia-induced pulmonary hypertension in mice. Tipifarnib reduced hypoxia-induced vascular cell proliferation, increased endothelium-dependent vasodilatation and reduced vasoconstriction of intrapulmonary arteries without affecting cell viability. Protective effects of Tipifarnib were associated with inhibition of Ras and RhoB, actin depolymerization and increased eNOS expression in vitro and in vivo. Farnesylated-only RhoB (F-RhoB) increased proliferative responses in cultured pulmonary vascular cells, mimicking the effects of hypoxia, while both geranylgeranylated-only RhoB (GG-RhoB), and Tipifarnib had an inhibitory effect. Label-free proteomics linked F-RhoB with cell survival, activation of cell cycle and mitochondrial biogenesis. Hypoxia increased and Tipifarnib reduced the levels of F-RhoB-regulated proteins in the lung, reinforcing the importance of RhoB as a signalling mediator. Unlike simvastatin, Tipifarnib did not increase the expression levels of Rho proteins. Conclusions Our study demonstrates the importance of protein farnesylation in pulmonary vascular remodelling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.
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Abstract 230: Protein Farnesylation Inhibitor Tipifarnib Prevents Development of Chronic Hypoxia-induced Pulmonary Hypertension
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Lucie Duluc, Blerina Ahmetaj-shala, Jane A. Mitchell, Vahitha B. Abdul-salam, Lulwah Aldabbous, Lucio Iannone, Olivier Dubois, Elisabeth M. Storck, Robert Edwards, Edward W. TateAbstract:Study objectives: Small GTPase RhoB contributes to pulmonary vascular remodelling in pulmonary hypertension. Farnesylation of RhoB augments cell proliferation while geranylgeranylation of RhoB is believed to be pro-apoptotic. We hypothesized that farnesyltransferase inhibitors may prevent vascular pathology in pulmonary hypertension. We studied the effects of farnesyltransferase inhibitor Tipifarnib on pulmonary vascular remodelling and vasoreactivity in chronically hypoxic pulmonary hypertensive mice and cultured human pulmonary artery endothelial cells (HPAECs). Chemical proteomics was used to characterise Tipifarnib-induced changes in protein prenylation while label- free quantitative proteomics was used to characterise changes induced by overexpression of RhoB prenylation mutants: farnesylated-only or geranlygeranylated-only RhoB in HPAECs. The effects of Tipifarnib on Ras and Rho GTPases expression and activity, filamentous and globular actin levels and eNOS pathway, were also studied. Results: Oral ...
Nigel H Russell - One of the best experts on this subject based on the ideXlab platform.
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low dose ara c versus low dose ara c and Tipifarnib result of the uk ncri aml16 pick a winner comparison abstract
Blood, 2008Co-Authors: Alan Kenneth Burnett, Robert Kerrin Hills, Donald Milligan, William J Kell, Keith Wheatley, Andres E Virchis, Nigel H RussellAbstract:Novel treatments are needed for older patients with AML who are not thought likely to benefit from standard chemotherapy. A recent randomised trial demonstrated that Low Dose Ara-C (LD Ara-C) was superior to best supportive care (BSC) (Burnett et al Cancer 2007: 109: 1114–1124). The Farnesyl Transferase inhibitor, Tipifarnib, has produced encouraging responses in this patient group (Lancet 109; 1387–1394) although in a subsequent randomised comparison vs BSC it was not superior (Haroussea et al Blood 1997:110,135a) The UK NCRI AML16 trial aims to test novel agents or combinations in untreated older patients with AML or high risk MDS (marrow blasts >10%) following a “pick a winner” design. The intention is to randomise up to 50 patients per arm with the expectation that a “winner” will achieve a remission rate in excess of 30%, compared with 15–20% with LD Ara-C. If that is achieved randomisation will continue with OS and DFS as endpoints. We report our experience of LD Ara-C (20mg bd days 1–10 for 4 courses versus LD Ara-C combined with Tipifarnib (300mg bd days 1–21) for 4 courses at 6–8 week intervals. Patient Details: Sixty-five patients were randomised between December 2006 and October 2007. The median age was 74.4 years with 82% of patients over 70 years. There were no differences between the treatment arms with respect to age distribution, gender, performance status, de novo/secondary AML, high risk MDS presenting WBC or cytogenetic risk group. Because of concerns about excess deaths in the Tipifarnib arm and therefore the low probability that LD Ara-C + Tipifarnib would be superior to LD Ara-C alone, the DMEC recommended premature closure of the Tipifarnib arm. Conclusions: While other agents combined with Tipifarnib may continue to show promise, the combination with LD-Ara-C in this patient population was not beneficial.
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Low dose Ara-C versus low Dose Ara-C and Tipifarnib: result of the UK NCRI AML16 "Pick a Winner" comparison [Abstract]
Blood, 2008Co-Authors: Alan Kenneth Burnett, Robert Kerrin Hills, Donald Milligan, William J Kell, Keith Wheatley, Andres E Virchis, Nigel H RussellAbstract:Novel treatments are needed for older patients with AML who are not thought likely to benefit from standard chemotherapy. A recent randomised trial demonstrated that Low Dose Ara-C (LD Ara-C) was superior to best supportive care (BSC) (Burnett et al Cancer 2007: 109: 1114–1124). The Farnesyl Transferase inhibitor, Tipifarnib, has produced encouraging responses in this patient group (Lancet 109; 1387–1394) although in a subsequent randomised comparison vs BSC it was not superior (Haroussea et al Blood 1997:110,135a) The UK NCRI AML16 trial aims to test novel agents or combinations in untreated older patients with AML or high risk MDS (marrow blasts >10%) following a “pick a winner” design. The intention is to randomise up to 50 patients per arm with the expectation that a “winner” will achieve a remission rate in excess of 30%, compared with 15–20% with LD Ara-C. If that is achieved randomisation will continue with OS and DFS as endpoints. We report our experience of LD Ara-C (20mg bd days 1–10 for 4 courses versus LD Ara-C combined with Tipifarnib (300mg bd days 1–21) for 4 courses at 6–8 week intervals. Patient Details: Sixty-five patients were randomised between December 2006 and October 2007. The median age was 74.4 years with 82% of patients over 70 years. There were no differences between the treatment arms with respect to age distribution, gender, performance status, de novo/secondary AML, high risk MDS presenting WBC or cytogenetic risk group. Because of concerns about excess deaths in the Tipifarnib arm and therefore the low probability that LD Ara-C + Tipifarnib would be superior to LD Ara-C alone, the DMEC recommended premature closure of the Tipifarnib arm. Conclusions: While other agents combined with Tipifarnib may continue to show promise, the combination with LD-Ara-C in this patient population was not beneficial.
Brian R Untch - One of the best experts on this subject based on the ideXlab platform.
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Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers.
Cancer research, 2018Co-Authors: Brian R Untch, Vanessa Dos Anjos, Jeffrey A Knauf, Maria E.r. Garcia-rendueles, Gnana P. Krishnamoorthy, Mahesh Saqcena, Umeshkumar K. Bhanot, Nicholas D. Socci, Ronald GhosseinAbstract:Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers (Tpo-Cre/HrasG12V/p53flox/flox) with the FTI Tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS-MAPK signaling was abrogated in vitro by selective RTK (i.e. EGFR, FGFR) inhibitors, but responses were ineffective in vivo, whereas combination of Tipifarnib with the MEK inhibitor AZD6244 improved outcomes. A subset of tumor-bearing mice treated with Tipifarnib developed acquired resistance. Whole-exome sequencing of resistant tumors identified a Nf1 nonsense mutation and an activating mutation in Gnas at high allelic frequency, supporting the on-target effects of the drug. Cell lines modified with these genetic lesions recapitulated Tipifarnib resistance in vivo. This study demonstrates the feasibility of targeting Ras membrane association in cancers in vivo and predicts combination therapies that confer additional benefit.
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abstract 2063 the farnesyltransferase inhibitor Tipifarnib causes dramatic tumor regression and increases survival in murine hrasg12vdriven aggressive thyroid cancers consequent adaptive and acquired resistance mechanisms inform combination treatment
Cancer Research, 2017Co-Authors: Brian R Untch, Vanessa Dos Anjos, Maria E R Garciarendueles, Jeffrey A Knauf, James A FaginAbstract:Of the three RAS oncoproteins, only HRAS is delocalized and functionally inactivated by farnesyltransferase inhibition (FTI), an approach that has yet to be exploited clinically. We treated a murine model of poorly differentiated and anaplastic thyroid cancer (Tpo-cre/HrasG12V/p53flox/flox; Hras;p53) with the FTI Tipifarnib, and observed sustained tumor regression and increased survival; however, tumors eventually recurred. Following HRAS delocalization by Tipifarnib in vitro, ERK phosphorylation was only inhibited transiently in HRAS-mutant cell lines, which was associated with increased GTP loading of wild-type RAS proteins in the setting of RTK ligand stimulation. This adaptive reactivation of RAS-MAPK signaling was abrogated by selective RTK (i.e. EGFR, FGFR) inhibitors, or by MEK inhibitors. Importantly, Tipifarnib combined with the MEK inhibitor AZD6244 led to improved responses in Hras;p53 mouse tumors, whereas combination with the EGFR/FGFR inhibitors erlotinib and ponatinib did not, suggesting heterogeneity of upstream inputs. In order to identify acquired resistance mechanisms, tumor-bearing Hras;p53 mice were treated with Tipifarnib until resistance developed (6 months). Whole exome sequencing of resistant tumors identified a truncating NF1 mutation and an activating mutation in GNAS at high allelic frequency. Upon NF1 knockdown in the human HRAS- mutant cell line C643, Tipifarnib failed to inhibit pERK in vitro and caused resistance to Tipifarnib in xenografts. By contrast, activating GNAS mutations transduced into Hras;p53 mouse tumor cell lines produced Tipifarnib-resistant xenografts that activated the GNAS-cAMP-CREB pathway and demonstrated signs of redifferentiation. These data show that pharmacological targeting of RAS in a genetically accurate, mouse model of a RAS-driven virulent cancer leads to objective major responses and improved survival. We identified adaptive and acquired resistance mechanisms, and show that combined treatment with selective MEK inhibitors are beneficial. These data should also inform a currently enrolling clinical trial of Tipifarnib for HRAS-mutant malignancies. Citation Format: Brian R. Untch, Vanessa Dos Anjos, Maria ER Garcia-Rendueles, Jeff A. Knauf, Alan L. Ho, James A. Fagin. The farnesyltransferase inhibitor Tipifarnib causes dramatic tumor regression and increases survival in murine HrasG12V driven aggressive thyroid cancers: Consequent adaptive and acquired resistance mechanisms inform combination treatments with improved responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2063. doi:10.1158/1538-7445.AM2017-2063
Lucie Duluc - One of the best experts on this subject based on the ideXlab platform.
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Tipifarnib prevents development of hypoxia-induced pulmonary hypertension.
Cardiovascular research, 2017Co-Authors: Lucie Duluc, Blerina Ahmetaj-shala, Jane A. Mitchell, Vahitha B. Abdul-salam, Abdul S. Mahomed, Lulwah Aldabbous, Eduardo Oliver, Lucio Iannone, Olivier Dubois, Elisabeth M. StorckAbstract:Aims RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated whether inhibition of protein farnesylation will have a protective effect. Methods and results The analysis of lung tissues from rodent models and pulmonary hypertensive patients showed increased levels of protein farnesylation. Oral farnesyltransferase inhibitor Tipifarnib prevented development of hypoxia-induced pulmonary hypertension in mice. Tipifarnib reduced hypoxia-induced vascular cell proliferation, increased endothelium-dependent vasodilatation and reduced vasoconstriction of intrapulmonary arteries without affecting cell viability. Protective effects of Tipifarnib were associated with inhibition of Ras and RhoB, actin depolymerization and increased eNOS expression in vitro and in vivo. Farnesylated-only RhoB (F-RhoB) increased proliferative responses in cultured pulmonary vascular cells, mimicking the effects of hypoxia, while both geranylgeranylated-only RhoB (GG-RhoB), and Tipifarnib had an inhibitory effect. Label-free proteomics linked F-RhoB with cell survival, activation of cell cycle and mitochondrial biogenesis. Hypoxia increased and Tipifarnib reduced the levels of F-RhoB-regulated proteins in the lung, reinforcing the importance of RhoB as a signalling mediator. Unlike simvastatin, Tipifarnib did not increase the expression levels of Rho proteins. Conclusions Our study demonstrates the importance of protein farnesylation in pulmonary vascular remodelling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.
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Abstract 230: Protein Farnesylation Inhibitor Tipifarnib Prevents Development of Chronic Hypoxia-induced Pulmonary Hypertension
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Lucie Duluc, Blerina Ahmetaj-shala, Jane A. Mitchell, Vahitha B. Abdul-salam, Lulwah Aldabbous, Lucio Iannone, Olivier Dubois, Elisabeth M. Storck, Robert Edwards, Edward W. TateAbstract:Study objectives: Small GTPase RhoB contributes to pulmonary vascular remodelling in pulmonary hypertension. Farnesylation of RhoB augments cell proliferation while geranylgeranylation of RhoB is believed to be pro-apoptotic. We hypothesized that farnesyltransferase inhibitors may prevent vascular pathology in pulmonary hypertension. We studied the effects of farnesyltransferase inhibitor Tipifarnib on pulmonary vascular remodelling and vasoreactivity in chronically hypoxic pulmonary hypertensive mice and cultured human pulmonary artery endothelial cells (HPAECs). Chemical proteomics was used to characterise Tipifarnib-induced changes in protein prenylation while label- free quantitative proteomics was used to characterise changes induced by overexpression of RhoB prenylation mutants: farnesylated-only or geranlygeranylated-only RhoB in HPAECs. The effects of Tipifarnib on Ras and Rho GTPases expression and activity, filamentous and globular actin levels and eNOS pathway, were also studied. Results: Oral ...
Jeffrey E. Lancet - One of the best experts on this subject based on the ideXlab platform.
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Biologics: Targets & Therapy 2008:2(3) 491–500 491
2016Co-Authors: Judith E. Karp, Jeffrey E. Lancet, Johns Hopkins, Sidney Kimmel, Lee Moffitt H. Comprehensive, Correspondence Judith, E KarpAbstract:Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemi
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311 PUBLICATIONS 12,432 CITATIONS
2016Co-Authors: Jeffrey E. Lancet, Judith E. Karp, Johns Hopkins, Sidney Kimmel, Lee Moffitt H. Comprehensive, Correspondence Judith, E Karp, See Profile, Division Of Hematologic MalignanciesAbstract:Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemi
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Phase II trial of Tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2008Co-Authors: Judith E. Karp, Jeffrey E. Lancet, Ivana Gojo, Lawrence E. Morris, Jacqueline Greer, B. Douglas Smith, Maureen Klein, Mark J. Levis, Steven D. Gore, John J. WrightAbstract:Purpose: Acute myelogenous leukemia (AML) does not have a high cure rate, particularly in patients with poor-risk features. Such patients might benefit from additional therapy in complete remission (CR). Tipifarnib is an oral farnesyltransferase inhibitor with activity in AML. We conducted a phase II trial of maintenance Tipifarnib monotherapy for 48 adults with poor-risk AML in first CR. Experimental Design: Tipifarnib 400 mg twice daily for 14 of 21 days was initiated after recovery from consolidation chemotherapy, for a maximum of 16 cycles (48 weeks). Results: Twenty (42%) patients completed 16 cycles, 24 (50%) were removed from study for relapse, and 4 (8%) discontinued drug prematurely for intolerance. Nonhematologic toxicities were rare, but Tipifarnib dose was reduced in 58% for myelosuppression. Median disease-free survival (DFS) was 13.5 months (range, 3.5-59+ months), with 30% having DFS >2 years. Comparison of CR durations for 25 patients who received two-cycle timed sequential therapy followed by Tipifarnib maintenance with 23 historically similar patients who did not receive Tipifarnib showed that Tipifarnib was associated with DFS prolongation for patients with secondary AML and adverse cytogenetics. Conclusions: This study suggests that some patients with poor-risk AML, including patients with secondary AML and adverse cytogenetics, may benefit from Tipifarnib maintenance therapy. Future studies are warranted to examine alternative Tipifarnib dosing and continuation beyond 16 cycles.
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Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia.
Biologics : targets & therapy, 2008Co-Authors: Judith E. Karp, Jeffrey E. LancetAbstract:Farnesyltransferase inhibitors (FTIs) represent a new class of signal transduction inhibitors that block the processing of cellular polypeptides that have cysteine terminal residues and, by so doing, interdict multiple pathways involved in proliferation and survival of diverse malignant cell types. Tipifarnib is an orally bioavailable, nonpeptidomimetic methylquinolone FTI that has exhibited clinical activity in patients with myeloid malignancies including elderly adults with acute myelogenous leukemia (AML) who are not candidates for traditional cytotoxic chemotherapy, patients with high-risk myelodysplasia, myeloproliferative disorders, and imatinib-resistant chronic myelogenous leukemia. Because of its relatively low toxicity profile, Tipifarnib provides an important alternative to traditional cytotoxic approaches for elderly patients who are not likely to tolerate or even benefit from aggressive chemotherapy. In this review, we will focus on the clinical development of Tipifarnib for treatment of newly diagnosed AML, both as induction therapy for elderly adults with poor-risk AML and as maintenance therapy following achievement of first complete remission following induction and consolidation therapies for poor-risk AML. As with all other malignancies, the optimal approach is likely to lie in rational combinations of Tipifarnib with cytotoxic, biologic and/or immunomodulatory agents with non-cross-resistant mechanisms of action. Gene expression profiling has identified networks of differentially expressed genes and gene combinations capable of predicting response to single agent Tipifarnib. The clinical and correlative laboratory trials in progress and under development will provide the critical foundations for defining the optimal roles of Tipifarnib and in patients with AMl and other hematologic malignancies.
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A 2-gene classifier for predicting response to the farnesyltransferase inhibitor Tipifarnib in acute myeloid leukemia
Blood, 2007Co-Authors: Mitch Raponi, Jeffrey E. Lancet, Lesley Dossey, Ivana Gojo, Eric J. Feldman, Lawrence E. Morris, Jason Gotlib, Peter L. GreenbergAbstract:At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI Tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1 / APTX gene expression ratio was found to predict response to Tipifarnib with the greatest accuracy using a “leave one out” cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to Tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P
