抗肿瘤药物Rigosertib研究进展
|
摘要
Rigosertib是一种非ATP竞争性多激酶抑制剂,具有显著的抗有丝分裂和抗癌活性,可诱导多种肿瘤细胞增殖停滞和凋亡,对正常细胞增殖的影响很小。Rigosertib已作为高危骨髓增生异常综合征患者的治疗药物应用于Ⅲ期临床试验。本文就Rigosertib的分子作用机制、体内外抗肿瘤活性以及临床试验等方面的研究进展做简要综述。
As a non-ATP competitive multi-kinase inhibitor with marked anti-mitotic and anti-cancer activity,rigosertib has been found to induce the proliferative arrest and apoptosis of many kinds of tumor cells with little affect on normal cells. Rigosertib is currently under phase Ⅲ clinical trials as a therapy for high-risk myelodysplastic syndrome(MDS). In this paper, recent advances in the molecular mechanism, antitumor activity in vitro and in vivo and clinical trials of rigosertib were comprehensively reviewed.
As a non-ATP competitive multi-kinase inhibitor with marked anti-mitotic and anti-cancer activity,rigosertib has been found to induce the proliferative arrest and apoptosis of many kinds of tumor cells with little affect on normal cells. Rigosertib is currently under phase Ⅲ clinical trials as a therapy for high-risk myelodysplastic syndrome(MDS). In this paper, recent advances in the molecular mechanism, antitumor activity in vitro and in vivo and clinical trials of rigosertib were comprehensively reviewed.
引文
[1] Reddy M V R, Mallireddigari M R, Cosenza S C, et al. Design, synthesis, and biological evaluation of(E)-styrylbenzylsulfones as novel anticancer agents[J]. J Med Chem, 2008,51(1):86-100.
[2] Reddy M V R, Venkatapuram P, Mallireddigari M R, et al. Discovery of a clinical stage multi-kinase inhibitor sodium(E)-2-{2-methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl] phenylaminoacetate(ON 01910.Na):synthesis, structure-activity relationship, and biological activity[J]. J Med Chem, 2011,54(18):6254-6276.
[3] Liu X. Targeting polo-like kinases:a promising therapeutic approach for cancer treatment[J]. Transl Oncol,2015,9(3):185-195.
[4] Gutteridge R E A, Ndiaye M A, Liu X, et al. Plk1inhibitors in cancer therapy:from laboratory to clinics[J]. Mol Cancer Ther, 2016,15(7):1427.
[5] Dufies M, Ambrosetti D, Boulakirba S, et al. ATPcompetitive Plk1 inhibitors induce caspase 3-mediated Plk1 cleavage and activation in hematopoietic cell lines[J]. Oncotarget, 2017,9(13):10920-10933.
[6] Chapman C M, Sun X, Roschewski M, et al. ON01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress[J]. Clin Cancer Res, 2012,18(7):1979-1991.
[7] Okabe S, Tauchi T, Tanaka Y, et al. Efficacy of the polo-like kinase inhibitor rigosertib, alone or in combination with Abelson tyrosine kinase inhibitors, against break point cluster region-c-Abelson-positive leukemia cells[J]. Oncotarget, 2015,6(24):20231-20240.
[8] Athuluridivakar S K, Vasquezdel C R, Dutta K, et al.A small molecule ras-mimetic disrupts ras association with effector proteins to block signaling[J]. Cell, 2016,165(3):643-655.
[9] Ritt D A, Abreublanco M T, Bindu L, et al. Inhibition of Ras/Raf/MEK/ERK pathway signaling by a stress-induced phospho-regulatory circuit[J]. Mol Cell,2016,64(5):875-887.
[10] Jost M, Chen Y, Gilbert L A, et al. Combined CRISPRi/a-based chemical genetic screens reveal that rigosertib is a microtubule-destabilizing agent[J]. Mol Cell, 2017,68(1):210-223.
[11] Palmisiano N D, Kasner M T. polo-like kinase and its inhibitors:ready for the match to start[J]. Am J Hematol, 2015,90(11):1071-1076.
[12] Cosenza S, Oussenko I, Divakar S, et al. Rigosertib, a novel ras inhibitor, overcomes azacitidine resistance in acute myeloid leukemia cell lines[J]. Leuk Res, 2015,39:S87.
[13] Fan A C, O′Rourke J J, Praharaj D R, et al. Realtime nanoscale proteomic analysis of the novel multikinase pathway inhibitor rigosertib to measure the response to treatment of cancer[J]. Expert Opin Investig Drugs, 2013,22(11):1495-1509.
[14] Anderson R T, Keysar S B, Bowles D W, et al. The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas[J]. Mol Cancer Ther, 2013,12(10):1994-2005.
[15] Chang K C, Chang W C, Chang Y, et al. Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-Cell lymphoma[J]. PLoS ONE, 2013,8(11):e79863.
[16] Olnes M J, Shenoy A, Weinstein B, et al. Directed therapy for patients with myelodysplastic syndromes(MDS)by suppression of cyclin D1 with ON 01910.Na[J]. Leuk Res, 2012,36(8):982-989.
[17] Agoni L, Basu I, Gupta S, et al. Rigosertib is a more effective radiosensitizer than cisplatin in concurrent chemoradiation treatment of cervical carcinoma, in vitro and in vivo[J]. Int J Radiat Oncol, 2014,88(5):1180-1187.
[18] Ohnuma T, Ren C, Lehrer D, et al. Phase 1 study of intravenous rigosertib(ON 01910.Na), a novel benzyl styryl sulfone structure producing G2/M arrest and apoptosis, in adult patients with advanced cancer[J].Am J Cancer Res, 2013,3(3):323-338.
[19] Jimeno A, Bowles D, Aisner D, et al. Phase I and molecular correlates study of oral rigosertib in patients with refractory metastatic head and neck cancer and advanced solid tumors[J]. Cancer Res, 2013,73:LB-198.
[20] Bowles D W, Diamond J R, Lam E T, et al. Phase I study of oral rigosertib(ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies[J]. Clin Cancer Res.2014,20(6):1656-1665.
[21] Ma W W, Messersmith W A, Dy G K, et al. Phase I study of rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and polo-like kinase 1 pathways, combined with gemcitabine in patients with solid tumors and pancreatic cancer[J]. Clin Cancer Res, 2012,18(7):2048.
[22] O′Neil B H, Scott A J, Ma W W, et al. A phaseⅡ/Ⅲrandomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer[J]. Ann Oncol, 2015,14(6):131-157.
[23] Komrokji R S, Raza A, Lancet J E, et al. Phase I clinical trial of oral rigosertib in patients with myelodysplastic syndromes[J]. Brit J Haematol, 2013,162(4):517-524.
[24] Roschewski M, Farooqui M, Aue G, et al. Phase I study of ON 01910.Na(Rigosertib), a multikinase PI3K inhibitor in relapsed/refractory B-cell malignancies[J].Leukemia, 2013,27(9):1920-1923.
[25] Navada S C, Garcia-Manero G, Hearn K, et al. A phase I study of the combination of azacitidine and oral rigosertib in patients with myelodysplastic syndromes(MDS)or acute myeloid leukemia(AML)[J].Leuk Res, 2015,39:S45.
[26] Seetharam M, Fan A C, Tran M, et al. Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na[J]. Leuk Res, 2012,36(1):98-103.
[27] Navada S C, Odchimar-Reissig R, Reddy E P, et al.Rigosertib activity in patients with a myelodysplastic syndrome(MDS)or acute myeloid leukemia(AML)relapsed or refractory to hypomethylating agents[J]. Leuk Res, 2013,37(Suppl 1):S146.
[28] Katragadda L, Kantarjian H M, Garcia-Manero G, et al. Phase1/2 single arm study of rigosertib(ON 01910.Na)in patients(Pts)with relapsed or refractory acute leukemia or transformed myeloproliferative neoplasms[J]. Blood, 2012,120(21):3606.
[29] Navada S C, Fruchtman S M, Odchimarreissig R, et al. A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes(MDS)and MDS progressed to acute myeloid leukemia[J]. Leuk Res, 2017,64:10-16.
[30] Silverman L R, Greenberg P, Raza A, et al. Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy[J]. Hematol Oncol, 2014,33(2):57-66.
[31] Silverman L R, Fenaux P, Al-Kali A, et al. Bone marrow blast(bmbl)response correlates with overall survival in rigosertib-treated patients with higher-risk MDS after failure of hypomethylating agents(HMAS):a new response criterion[J]. Leuk Res, 2015,39:S44-S45.
[32] Garciamanero G, Fenaux P, Alkali A, et al. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs(ONTIME):a randomised, controlled, phase3 trial[J]. Lancet Oncol, 2016,17(4):496-508.
[33] Garcia-Manero G, Fenaux P, Al-Kali A, et al. Randomized phase III study of IV rigosertib versus best supportive care(BSC)in patients with higher-risk MDS(HR-MDS)after failure of hypomethylating agents(HMAS)[J]. Leuk Res, 2015,39:S57-S58.
[2] Reddy M V R, Venkatapuram P, Mallireddigari M R, et al. Discovery of a clinical stage multi-kinase inhibitor sodium(E)-2-{2-methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl] phenylaminoacetate(ON 01910.Na):synthesis, structure-activity relationship, and biological activity[J]. J Med Chem, 2011,54(18):6254-6276.
[3] Liu X. Targeting polo-like kinases:a promising therapeutic approach for cancer treatment[J]. Transl Oncol,2015,9(3):185-195.
[4] Gutteridge R E A, Ndiaye M A, Liu X, et al. Plk1inhibitors in cancer therapy:from laboratory to clinics[J]. Mol Cancer Ther, 2016,15(7):1427.
[5] Dufies M, Ambrosetti D, Boulakirba S, et al. ATPcompetitive Plk1 inhibitors induce caspase 3-mediated Plk1 cleavage and activation in hematopoietic cell lines[J]. Oncotarget, 2017,9(13):10920-10933.
[6] Chapman C M, Sun X, Roschewski M, et al. ON01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress[J]. Clin Cancer Res, 2012,18(7):1979-1991.
[7] Okabe S, Tauchi T, Tanaka Y, et al. Efficacy of the polo-like kinase inhibitor rigosertib, alone or in combination with Abelson tyrosine kinase inhibitors, against break point cluster region-c-Abelson-positive leukemia cells[J]. Oncotarget, 2015,6(24):20231-20240.
[8] Athuluridivakar S K, Vasquezdel C R, Dutta K, et al.A small molecule ras-mimetic disrupts ras association with effector proteins to block signaling[J]. Cell, 2016,165(3):643-655.
[9] Ritt D A, Abreublanco M T, Bindu L, et al. Inhibition of Ras/Raf/MEK/ERK pathway signaling by a stress-induced phospho-regulatory circuit[J]. Mol Cell,2016,64(5):875-887.
[10] Jost M, Chen Y, Gilbert L A, et al. Combined CRISPRi/a-based chemical genetic screens reveal that rigosertib is a microtubule-destabilizing agent[J]. Mol Cell, 2017,68(1):210-223.
[11] Palmisiano N D, Kasner M T. polo-like kinase and its inhibitors:ready for the match to start[J]. Am J Hematol, 2015,90(11):1071-1076.
[12] Cosenza S, Oussenko I, Divakar S, et al. Rigosertib, a novel ras inhibitor, overcomes azacitidine resistance in acute myeloid leukemia cell lines[J]. Leuk Res, 2015,39:S87.
[13] Fan A C, O′Rourke J J, Praharaj D R, et al. Realtime nanoscale proteomic analysis of the novel multikinase pathway inhibitor rigosertib to measure the response to treatment of cancer[J]. Expert Opin Investig Drugs, 2013,22(11):1495-1509.
[14] Anderson R T, Keysar S B, Bowles D W, et al. The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas[J]. Mol Cancer Ther, 2013,12(10):1994-2005.
[15] Chang K C, Chang W C, Chang Y, et al. Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-Cell lymphoma[J]. PLoS ONE, 2013,8(11):e79863.
[16] Olnes M J, Shenoy A, Weinstein B, et al. Directed therapy for patients with myelodysplastic syndromes(MDS)by suppression of cyclin D1 with ON 01910.Na[J]. Leuk Res, 2012,36(8):982-989.
[17] Agoni L, Basu I, Gupta S, et al. Rigosertib is a more effective radiosensitizer than cisplatin in concurrent chemoradiation treatment of cervical carcinoma, in vitro and in vivo[J]. Int J Radiat Oncol, 2014,88(5):1180-1187.
[18] Ohnuma T, Ren C, Lehrer D, et al. Phase 1 study of intravenous rigosertib(ON 01910.Na), a novel benzyl styryl sulfone structure producing G2/M arrest and apoptosis, in adult patients with advanced cancer[J].Am J Cancer Res, 2013,3(3):323-338.
[19] Jimeno A, Bowles D, Aisner D, et al. Phase I and molecular correlates study of oral rigosertib in patients with refractory metastatic head and neck cancer and advanced solid tumors[J]. Cancer Res, 2013,73:LB-198.
[20] Bowles D W, Diamond J R, Lam E T, et al. Phase I study of oral rigosertib(ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies[J]. Clin Cancer Res.2014,20(6):1656-1665.
[21] Ma W W, Messersmith W A, Dy G K, et al. Phase I study of rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and polo-like kinase 1 pathways, combined with gemcitabine in patients with solid tumors and pancreatic cancer[J]. Clin Cancer Res, 2012,18(7):2048.
[22] O′Neil B H, Scott A J, Ma W W, et al. A phaseⅡ/Ⅲrandomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer[J]. Ann Oncol, 2015,14(6):131-157.
[23] Komrokji R S, Raza A, Lancet J E, et al. Phase I clinical trial of oral rigosertib in patients with myelodysplastic syndromes[J]. Brit J Haematol, 2013,162(4):517-524.
[24] Roschewski M, Farooqui M, Aue G, et al. Phase I study of ON 01910.Na(Rigosertib), a multikinase PI3K inhibitor in relapsed/refractory B-cell malignancies[J].Leukemia, 2013,27(9):1920-1923.
[25] Navada S C, Garcia-Manero G, Hearn K, et al. A phase I study of the combination of azacitidine and oral rigosertib in patients with myelodysplastic syndromes(MDS)or acute myeloid leukemia(AML)[J].Leuk Res, 2015,39:S45.
[26] Seetharam M, Fan A C, Tran M, et al. Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na[J]. Leuk Res, 2012,36(1):98-103.
[27] Navada S C, Odchimar-Reissig R, Reddy E P, et al.Rigosertib activity in patients with a myelodysplastic syndrome(MDS)or acute myeloid leukemia(AML)relapsed or refractory to hypomethylating agents[J]. Leuk Res, 2013,37(Suppl 1):S146.
[28] Katragadda L, Kantarjian H M, Garcia-Manero G, et al. Phase1/2 single arm study of rigosertib(ON 01910.Na)in patients(Pts)with relapsed or refractory acute leukemia or transformed myeloproliferative neoplasms[J]. Blood, 2012,120(21):3606.
[29] Navada S C, Fruchtman S M, Odchimarreissig R, et al. A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes(MDS)and MDS progressed to acute myeloid leukemia[J]. Leuk Res, 2017,64:10-16.
[30] Silverman L R, Greenberg P, Raza A, et al. Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy[J]. Hematol Oncol, 2014,33(2):57-66.
[31] Silverman L R, Fenaux P, Al-Kali A, et al. Bone marrow blast(bmbl)response correlates with overall survival in rigosertib-treated patients with higher-risk MDS after failure of hypomethylating agents(HMAS):a new response criterion[J]. Leuk Res, 2015,39:S44-S45.
[32] Garciamanero G, Fenaux P, Alkali A, et al. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs(ONTIME):a randomised, controlled, phase3 trial[J]. Lancet Oncol, 2016,17(4):496-508.
[33] Garcia-Manero G, Fenaux P, Al-Kali A, et al. Randomized phase III study of IV rigosertib versus best supportive care(BSC)in patients with higher-risk MDS(HR-MDS)after failure of hypomethylating agents(HMAS)[J]. Leuk Res, 2015,39:S57-S58.