The Experts below are selected from a list of 375 Experts worldwide ranked by ideXlab platform
Alain Moussy - One of the best experts on this subject based on the ideXlab platform.
-
long term survival analysis of Masitinib in amyotrophic lateral sclerosis
Therapeutic Advances in Neurological Disorders, 2021Co-Authors: Jesus S Mora, Alain Moussy, Colin Mansfield, Josep Gamez, Delia Chaverri, Javier Mascias, Walter G Bradley, Maria Hernandezbarral, Gisella M Gargiulomonachelli, Olivier HermineAbstract:Background:A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered Masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable s...
-
development of Masitinib for the treatment of peripheral t cell lymphoma
Blood, 2015Co-Authors: Olivier Hermine, Patrice Dubreuil, Thiago Trovati Maciel, Douglas H Thamm, Ambroise Marcais, J Bagbor, Darius Jagielski, Nadine Holtermann, Elena Martinez De Merlo, Alain MoussyAbstract:Abstract Increasing resistance to chemotherapy means that approximately 30% of patients afflicted with peripheral T-cell lymphoma will develop a relapsed/refractory form and eventually succumb to the disease. To date there is no clearly established second-line therapy and investigation of new therapies is necessary to address this unmet medical need. Masitinib is an oral tyrosine kinase inhibitor that potently and selectively targets c-Kit and platelet-derived growth factor receptor (PDGFR). Studies in human T-cell lymphoma have identified aberrant expression of PDGFR-alpha and that this kinase fosters peripheral T-cell lymphoma cell proliferation via an autocrine loop. Masitinib may therefore exert an antiproliferative and pro-apoptotic action on abnormal T-cells. In addition to this direct mechanism of action, Masitinib can elicit antitumor effects by acting on mast cells and macrophages. By inhibiting mast cells, Masitinib reduces the release of pro-tumoral M2-polarizing cytokines as well as factors favoring metastasis and angiogenesis. Masitinib can also promote macrophage infiltration into tumors, inducing an anti-tumoral Th1 immune response. Inhibition of cell proliferation was observed following single-agent Masitinib treatment in the OSW canine T-cell lymphoma line, with an IC50 of 0.005 μM, suggesting that it could be used efficiently for the treatment of T-cell lymphoma. This hypothesis was further substantiated by a case study in a companion dog with T-cell lymphoma treated with Masitinib monotherapy 12 mg/kg/day, reporting a complete response following 3 weeks of treatment with increased quality of life. This preliminary observation was repeated in two separate independent studies, each comprised of 11 dogs with T-cell lymphoma. A first study reported an overall response rate (ORR) of 73%, including 3/11 dogs with complete response (CR) and 5/11 dogs with partial response (PR) after 3 months of treatment. A second study reported an ORR of 45%, including 2/11 dogs with CR and 3/11 dogs with PR after 3 months of treatment. Meta-analysis of these data (n=23) showed that Masitinib treatment of canine T-cell lymphoma resulted in a CR in 6/23 dogs (26%) and in a PR 8/23 dogs (35%), resulting in an ORR of 61%. Naturally occurring tumors in dogs have more clinical and biological similarities to human cancers than any other animal cancer model, hence these data provide strong medical plausibility for Masitinib in the treatment of human peripheral T-cell lymphoma. The above in vitro and in vivo data led to initiation of a multicenter, randomized, open-label, three-parallel group, phase 2 study to evaluate the combination of Masitinib plus dexamethasone with or without gemcitabine in patients with relapsed or refractory peripheral T-cell lymphoma. A recent decision to accelerate to a phase 3 study was based on an observed survival benefit for Masitinib treated patients when compared with the control arm, and an acceptable safety profile; passage to phase 3 was validated by the independent Data Safety Monitoring Board with data blinded to sponsor and investigator. Specifically, pooled data from all Masitinib-treated patients in the phase 2 stage (n=34) estimated a median overall survival (OS) of 9.0 months, which compares favorably against the literature benchmark median OS of 5.5 months for documented chemotherapy in this indication. This phase 3 study is currently open for patient recruitment in at least 14 countries and has OS as the primary endpoint. If successful, Masitinib could provide a new treatment option in relapsed or refractory peripheral T-cell lymphoma. Disclosures Off Label Use: Masitinib is a new orally administered tyrosine kinase inhibitor that targets mast cells and macrophages, important cells for immunity, through inhibiting a limited number of kinases. Based on its unique mechanism of action, Masitinib can be developed in a large number of conditions in oncology, in inflammatory diseases, and in certain diseases of the central nervous system. In oncology due to its immunotherapy effect, Masitinib can have an effect on survival, alone or in combination with chemotherapy. Through its activity on mast cells and consequently the inhibition of the activation of the inflammatory process, Masitinib can have an effect on the symptoms associated with some inflammatory and central nervous system diseases and the degeneration of these diseases.. Marcais: AB Science: Consultancy. Dubreuil: AB Science: Consultancy. Moussy: AB Science: Other: CEO.
-
Masitinib plus carboplatin and gemcitabine for treatment of patients with advanced triple negative breast cancer an open label phase ib ii trial
Journal of Clinical Oncology, 2015Co-Authors: Mario Campone, Patrice Dubreuil, Alain Moussy, Colin Mansfield, Jeanmarc Ferrero, K Gunzer, F Priou, Olivier HermineAbstract:1070 Background: Masitinib (MAS) is a selective inhibitor of c-Kit and mast cell function, both of which have been linked to disease progression and poor prognosis in triple negative breast cancer ...
-
Masitinib plus folfiri for second line treatment of metastatic colorectal cancer an open label phase ib ii trial
Journal of Clinical Oncology, 2015Co-Authors: Julien Taieb, Patrice Dubreuil, Alain Moussy, Colin Mansfield, Christophe Borg, Thierry Lecomte, Celine Lepere, Thierry Chatellier, Denis Smith, Olivier HermineAbstract:3526 Background: Masitinib (MAS) is a selective inhibitor of c-Kit and mast cell function. Increased mast cell activity in the tumor microenvironment is linked to poor prognosis and a protumoral im...
-
Masitinib plus irinotecan for second line treatment of esophagogastric adenocarcinoma an open label phase ib ii trial
Journal of Clinical Oncology, 2015Co-Authors: Aziz Zaanan, Colin Mansfield, Olivier Bouche, Thierry Lecomte, Celine Lepere, Jaafar Bennouna, Sandrine Hiret, Jeanyves Douillard, David Tougeron, Alain MoussyAbstract:4027 Background: Masitinib (MAS) is a selective c-Kit inhibitor that efficiently inhibits mast cell function. In vitro studies have shown that MAS could enhance efficacy of 5-fluorouracil (5-FU) an...
Olivier Hermine - One of the best experts on this subject based on the ideXlab platform.
-
long term survival analysis of Masitinib in amyotrophic lateral sclerosis
Therapeutic Advances in Neurological Disorders, 2021Co-Authors: Jesus S Mora, Alain Moussy, Colin Mansfield, Josep Gamez, Delia Chaverri, Javier Mascias, Walter G Bradley, Maria Hernandezbarral, Gisella M Gargiulomonachelli, Olivier HermineAbstract:Background:A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered Masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable s...
-
Masitinib plus gemcitabine as first line treatment of pancreatic cancer with pain results from phase 3 study ab12005
Journal of Clinical Oncology, 2021Co-Authors: Joel Ezenfis, Olivier HermineAbstract:4018Background: Masitinib (MAS) is a small molecule drug targeting mast cell and macrophage activity, innate immune cells that are critical components of the tumor microenvironment. Proof of concep...
-
development of Masitinib for the treatment of peripheral t cell lymphoma
Blood, 2015Co-Authors: Olivier Hermine, Patrice Dubreuil, Thiago Trovati Maciel, Douglas H Thamm, Ambroise Marcais, J Bagbor, Darius Jagielski, Nadine Holtermann, Elena Martinez De Merlo, Alain MoussyAbstract:Abstract Increasing resistance to chemotherapy means that approximately 30% of patients afflicted with peripheral T-cell lymphoma will develop a relapsed/refractory form and eventually succumb to the disease. To date there is no clearly established second-line therapy and investigation of new therapies is necessary to address this unmet medical need. Masitinib is an oral tyrosine kinase inhibitor that potently and selectively targets c-Kit and platelet-derived growth factor receptor (PDGFR). Studies in human T-cell lymphoma have identified aberrant expression of PDGFR-alpha and that this kinase fosters peripheral T-cell lymphoma cell proliferation via an autocrine loop. Masitinib may therefore exert an antiproliferative and pro-apoptotic action on abnormal T-cells. In addition to this direct mechanism of action, Masitinib can elicit antitumor effects by acting on mast cells and macrophages. By inhibiting mast cells, Masitinib reduces the release of pro-tumoral M2-polarizing cytokines as well as factors favoring metastasis and angiogenesis. Masitinib can also promote macrophage infiltration into tumors, inducing an anti-tumoral Th1 immune response. Inhibition of cell proliferation was observed following single-agent Masitinib treatment in the OSW canine T-cell lymphoma line, with an IC50 of 0.005 μM, suggesting that it could be used efficiently for the treatment of T-cell lymphoma. This hypothesis was further substantiated by a case study in a companion dog with T-cell lymphoma treated with Masitinib monotherapy 12 mg/kg/day, reporting a complete response following 3 weeks of treatment with increased quality of life. This preliminary observation was repeated in two separate independent studies, each comprised of 11 dogs with T-cell lymphoma. A first study reported an overall response rate (ORR) of 73%, including 3/11 dogs with complete response (CR) and 5/11 dogs with partial response (PR) after 3 months of treatment. A second study reported an ORR of 45%, including 2/11 dogs with CR and 3/11 dogs with PR after 3 months of treatment. Meta-analysis of these data (n=23) showed that Masitinib treatment of canine T-cell lymphoma resulted in a CR in 6/23 dogs (26%) and in a PR 8/23 dogs (35%), resulting in an ORR of 61%. Naturally occurring tumors in dogs have more clinical and biological similarities to human cancers than any other animal cancer model, hence these data provide strong medical plausibility for Masitinib in the treatment of human peripheral T-cell lymphoma. The above in vitro and in vivo data led to initiation of a multicenter, randomized, open-label, three-parallel group, phase 2 study to evaluate the combination of Masitinib plus dexamethasone with or without gemcitabine in patients with relapsed or refractory peripheral T-cell lymphoma. A recent decision to accelerate to a phase 3 study was based on an observed survival benefit for Masitinib treated patients when compared with the control arm, and an acceptable safety profile; passage to phase 3 was validated by the independent Data Safety Monitoring Board with data blinded to sponsor and investigator. Specifically, pooled data from all Masitinib-treated patients in the phase 2 stage (n=34) estimated a median overall survival (OS) of 9.0 months, which compares favorably against the literature benchmark median OS of 5.5 months for documented chemotherapy in this indication. This phase 3 study is currently open for patient recruitment in at least 14 countries and has OS as the primary endpoint. If successful, Masitinib could provide a new treatment option in relapsed or refractory peripheral T-cell lymphoma. Disclosures Off Label Use: Masitinib is a new orally administered tyrosine kinase inhibitor that targets mast cells and macrophages, important cells for immunity, through inhibiting a limited number of kinases. Based on its unique mechanism of action, Masitinib can be developed in a large number of conditions in oncology, in inflammatory diseases, and in certain diseases of the central nervous system. In oncology due to its immunotherapy effect, Masitinib can have an effect on survival, alone or in combination with chemotherapy. Through its activity on mast cells and consequently the inhibition of the activation of the inflammatory process, Masitinib can have an effect on the symptoms associated with some inflammatory and central nervous system diseases and the degeneration of these diseases.. Marcais: AB Science: Consultancy. Dubreuil: AB Science: Consultancy. Moussy: AB Science: Other: CEO.
-
Masitinib plus carboplatin and gemcitabine for treatment of patients with advanced triple negative breast cancer an open label phase ib ii trial
Journal of Clinical Oncology, 2015Co-Authors: Mario Campone, Patrice Dubreuil, Alain Moussy, Colin Mansfield, Jeanmarc Ferrero, K Gunzer, F Priou, Olivier HermineAbstract:1070 Background: Masitinib (MAS) is a selective inhibitor of c-Kit and mast cell function, both of which have been linked to disease progression and poor prognosis in triple negative breast cancer ...
-
Masitinib plus folfiri for second line treatment of metastatic colorectal cancer an open label phase ib ii trial
Journal of Clinical Oncology, 2015Co-Authors: Julien Taieb, Patrice Dubreuil, Alain Moussy, Colin Mansfield, Christophe Borg, Thierry Lecomte, Celine Lepere, Thierry Chatellier, Denis Smith, Olivier HermineAbstract:3526 Background: Masitinib (MAS) is a selective inhibitor of c-Kit and mast cell function. Increased mast cell activity in the tumor microenvironment is linked to poor prognosis and a protumoral im...
Patrice Dubreuil - One of the best experts on this subject based on the ideXlab platform.
-
O: Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One 2009
2016Co-Authors: Patrice Dubreuil, Laurent Gros, Laurence Borge, Anne Lermet, Marco A Ciufolini, Martine Humbert, Michel Arock, Christian Auclair, Phillip S. Leventhal, Colin D. MansfieldAbstract:Background: The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of Masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT. Methodology/Principal Findings: In vitro, Masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC50) of 200640 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC50 of 150680 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, Masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of Masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, Masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode o
-
post paralysis tyrosine kinase inhibition with Masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis
Journal of Neuroinflammation, 2016Co-Authors: Emiliano Trias, Laurent Gros, Patrice Dubreuil, Sofia Ibarburu, Romina Barretonunez, Joel Babdor, Thiago Trovati Maciel, Matthias Guillo, Pablo Diazamarilla, Patricia CassinaAbstract:In the SOD1G93A mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor Masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS. The cellular effects of pharmacological inhibition of tyrosine kinases with Masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1G93A rats. To determine whether Masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset. We found that Masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1G93A spinal cords, Masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of Masitinib to SOD1G93A rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %. These data show that Masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, Masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.
-
post paralysis tyrosine kinase inhibition with Masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis
Journal of Neuroinflammation, 2016Co-Authors: Emiliano Trias, Laurent Gros, Patrice Dubreuil, Sofia Ibarburu, Romina Barretonunez, Joel Babdor, Thiago Trovati Maciel, Matthias Guillo, Pablo Diazamarilla, Patricia CassinaAbstract:Background In the SOD1G93A mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor Masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS.
-
Additional file 1: of Post-paralysis tyrosine kinase inhibition with Masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis
2016Co-Authors: Emiliano Trias, Laurent Gros, Patrice Dubreuil, Sofia Ibarburu, Joel Babdor, Matthias Guillo, Romina Barreto-núñez, Thiago Maciel, Pablo Díaz-amarilla, Patricia CassinaAbstract:Figures S1. Masitinib inhibited microgliosis along the degenerating spinal cord. Figure S2. Masitinib treatment after paralysis onset increased survival of SOD1G93A female and male rats. (DOCX 700 kb
-
rapid and clinically significant response to Masitinib in the treatment of mucosal primary esophageal melanoma with somatic kit exon 11 mutation involving brain metastases a case report
Biomedical Papers-olomouc, 2015Co-Authors: Jarmila Prosvicova, Patrice Dubreuil, Sarka Lukesova, Jindrich Kopecky, Jiri Grim, Zdenek Papik, Renata Kolarova, Blanka Navratilova, Julie Agopian, Colin MansfieldAbstract:Background: Malignant melanoma in the gastrointestinal tract may be primary or metastatic. Mucosal melanoma is a quite rare and aggressive disease, growing hidden and diagnosed with a certain delay which makes treatment difficult. Case Report: The authors present the first patient with c-kit exon 11 mutated primary esophageal melanoma treated with oral tyrosine kinase inhibitor Masitinib. A 55-year-old-man presented with esophageal melanoma metastising into visceral organs and to the brain. The patient showed objective and clinical significant therapeutic response to Masitinib. After initiation of Masitinib, dysphagia and odynophagia disappeared within 1 week. Following 1 month of treatment, computed tomography showed a regression in the number and size of brain metastatic lesions and regression in visceral lesions. This therapeutic response, despite the aggressive disease on treatment initiation, effectively enabled the patient to have 6 months of quality life. Conclusion: This report corroborates the plausibility of treating advanced melanoma carrying a mutation of KIT with Masitinib. It also raises the question of Masitinib treatment beyond progression. Additionally, the observed Masitinib treatment effect on the brain suggests accumulation of therapeutically relevant concentration of Masitinib in the central nervous system. This observation has possible ramifications for treatment of intracranial neoplasms.
Olivier Bouche - One of the best experts on this subject based on the ideXlab platform.
-
Masitinib plus irinotecan for second line treatment of esophagogastric adenocarcinoma an open label phase ib ii trial
Journal of Clinical Oncology, 2015Co-Authors: Aziz Zaanan, Colin Mansfield, Olivier Bouche, Thierry Lecomte, Celine Lepere, Jaafar Bennouna, Sandrine Hiret, Jeanyves Douillard, David Tougeron, Alain MoussyAbstract:4027 Background: Masitinib (MAS) is a selective c-Kit inhibitor that efficiently inhibits mast cell function. In vitro studies have shown that MAS could enhance efficacy of 5-fluorouracil (5-FU) an...
-
Masitinib in advanced gastrointestinal stromal tumor gist after failure of imatinib a randomized controlled open label trial
Annals of Oncology, 2014Co-Authors: A Adenis, François Bertucci, J Y Blay, B Buinguyen, Olivier Bouche, N Isambert, Emmanuelle Bompas, Loic Chaigneau, Julien Domont, I RaycoquardAbstract:Background Masitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance.
-
Masitinib mesylate in imatinib resistant advanced gist a randomized phase ii trial
Journal of Clinical Oncology, 2012Co-Authors: Antoine Adenis, Olivier Bouche, Julien Domont, Francois Montestruc, Axel Le Cesne, Isabelle Raycoquard, Binh Bui Nguyen, Nicolas Penel, A Blesius, Alain MoussyAbstract:10007 Background: Masitinib is an oral tyrosine kinase inhibitor with greater in vitro activity and selectivity than imatinib against wild-type and juxtamembrane mutations of KIT (Dubreuil, 2009, P...
-
Masitinib in imatinib naive advanced gastrointestinal stromal tumor gist five year follow up of the french sarcoma group phase ii trial
Journal of Clinical Oncology, 2012Co-Authors: Axel Le Cesne, Alain Moussy, Olivier Hermine, Olivier Bouche, Julien Domont, Jeanyves Blay, Angela Cioffi, Binh Bui Nguyen, Julie Le Boulicaut, Antoine AdenisAbstract:10089 Background: Masitinib is a tyrosine kinase inhibitor that in vitro has greater activity and selectivity than imatinib against KIT. This multicenter, open label, phase 2 study evaluated effica...
-
Masitinib in comparison to imatinib as first line therapy of patients with advanced gastrointestinal stromal tumor gist a randomized phase iii trial
Journal of Clinical Oncology, 2012Co-Authors: Antoine Adenis, François Bertucci, Olivier Bouche, N Isambert, Loic Chaigneau, Binh Bui Nguyen, Pierre Michel, Laurent Mineur, Tanios Bekaiisaab, Nicolas PenelAbstract:TPS10102^ Background: Masitinib is an oral tyrosine kinase inhibitor (TKI) that has greater in vitro kinase activity and/or selectivity than imatinib against KIT and PDGFRA/B. A phase 2 study has p...
Zhesheng Chen - One of the best experts on this subject based on the ideXlab platform.
-
abstract 1964 Masitinib antagonizes atp binding cassette subfamily c member 10 mediated paclitaxel resistance a preclinical study
Cancer Research, 2014Co-Authors: Rishil J Kathawala, Atish Patel, Charles R Ashby, Kamlesh Sodani, Kang Chen, Alaa H Abuznait, Nagaraju Anreddy, Yueli Sun, Amal Kaddoumi, Zhesheng ChenAbstract:Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that Masitinib, a small molecule stem-cell growth factor receptor (c-Kit) tyrosine kinase inhibitor, at non-toxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10. Our in vitro studies indicated that Masitinib (2.5 μM) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, Masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo. Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors and lungs compared to paclitaxel alone. In conclusion, the combination of paclitaxel and Masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10. Citation Format: Rishil Kathawala, Kamlesh Sodani, Kang Chen, Atish Patel, Alaa Abuznait, Nagaraju Anreddy, Yue-Li Sun, Amal Kaddoumi, Charles R. Ashby, Zhe-Sheng Chen. Masitinib antagonizes ATP-binding cassette subfamily c member 10-mediated paclitaxel resistance: a preclinical study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1964. doi:10.1158/1538-7445.AM2014-1964
-
Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance.
Cancers, 2014Co-Authors: Yijun Wang, Rishil J Kathawala, Yunkai Zhang, Zhesheng ChenAbstract:The phenomenon of multidrug resistance (MDR) has attenuated the efficacy of anticancer drugs and the possibility of successful cancer chemotherapy. ATP-binding cassette (ABC) transporters play an essential role in mediating MDR in cancer cells by increasing efflux of drugs from cancer cells, hence reducing the intracellular accumulation of chemotherapeutic drugs. Interestingly, small-molecule tyrosine kinase inhibitors (TKIs), such as AST1306, lapatinib, linsitinib, Masitinib, motesanib, nilotinib, telatinib and WHI-P154, have been found to have the capability to overcome anticancer drug resistance by inhibiting ABC transporters in recent years. This review will focus on some of the latest and clinical developments with ABC transporters, TKIs and anticancer drug resistance.
-
Masitinib antagonizes atp binding cassette subfamily g member 2 mediated multidrug resistance
International Journal of Oncology, 2014Co-Authors: Rishil J Kathawala, Junjiang Chen, Yunkai Zhang, Yijun Wang, Atish Patel, De Shen Wang, Tanaji T Talele, Charles R Ashby, Zhesheng ChenAbstract:In this in vitro study, we determined whether Masitinib could reverse multidrug resistance (MDR) in cells overexpressing the ATP binding cassette subfamily G member 2 (ABCG2) transporter. Masitinib (1.25 and 2.5 µM) significantly decreases the resistance to mitoxantrone (MX), SN38 and doxorubicin in HEK293 and H460 cells overexpressing the ABCG2 transporter. In addition, Masitinib (2.5 µM) significantly increased the intracellular accumulation of [(3)H]-MX, a substrate for ABCG2, by inhibiting the function of ABCG2 and significantly decreased the efflux of [(3)H]-MX. However, Masitinib (2.5 µM) did not significantly alter the expression of the ABCG2 protein. In addition, a docking model suggested that Masitinib binds within the transmembrane region of a homology-modeled human ABCG2 transporter. Overall, our in vitro findings suggest that Masitinib reverses MDR to various anti-neoplastic drugs in HEK293 and H460 cells overexpressing ABCG2 by inhibiting their transport activity as opposed to altering their levels of expression.
-
Masitinib antagonizes atp binding cassette subfamily c member 10 mediated paclitaxel resistance a preclinical study
Molecular Cancer Therapeutics, 2014Co-Authors: Rishil J Kathawala, Atish Patel, Charles R Ashby, Kamlesh Sodani, Kang Chen, Alaa H Abuznait, Nagaraju Anreddy, Yueli Sun, Amal Kaddoumi, Zhesheng ChenAbstract:Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that Masitinib, a small molecule stem-cell growth factor receptor (c-Kit) tyrosine kinase inhibitor, at nontoxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10 . Our in vitro studies indicated that Masitinib (2.5 μmol/L) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, Masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo . Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors, and lungs compared with paclitaxel alone. In conclusion, the combination of paclitaxel and Masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10. Mol Cancer Ther; 13(3); 714–23. ©2014 AACR .