Treatment of Chronic Myeloid Leukemia with Bcr-Abl Kinase Inhibitors
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
For CML currently, we now have very highly active and durable primary therapy (imatinib) and two approved and convincingly proven salvage options, dasatinib and nilotinib. Other developments expanding the roster of novel therapies in Ph(+) leukemias include additional multikinase (Abl, Src, Lyn, etc) inhibitors such as SKI-606 and INNO-406, and the aurora kinase inhibitor MK0457, which is specifically active against the T315I mutant Abl kinase variant. In this revolutionary decade of development in CML, therapy has universally shifted away from the primary immunotherapy-based options of interferon (IFN) and allografting and adopted use of kinase inhibitor therapy as primary therapy and beyond.
Precision medicine for pediatric central nervous system tumors
Published in Expert Review of Precision Medicine and Drug Development, 2019
Daniel C. Moreira, Amar Gajjar
New biologic platforms facilitating high-throughput analyses of pediatric CNS tumors have identified dysregulated proteins that promote tumorigenesis and novel compounds to target these proteins. In cancers where oncogenesis is not heavily dependent on a single pathway, this strategy leverages nononcogenic mutations and cellular adaptations in cancer cells to identify new therapeutic approaches. In a high-throughput, cell-based assay in medulloblastoma, gemcitabine and pemetrexed synergistically inhibited Myc-driven medulloblastoma proliferation [8]. These drugs are now being used in first-line treatment for medulloblastoma (SJMB12). Additional candidate agents for medulloblastoma, such as inhibitors of cell cycle kinases, PARP, and tyrosine kinases, have been identified [9,10]. Atypical teratoid rhabdoid tumor (AT/RT) is a rare embryonal tumor defined by inactivation of the INI-1 locus, with poor prognosis despite multiagent cytotoxic chemotherapy. Insights into the molecular mechanisms driving AT/RT tumorigenesis have also identified candidate agents. Alisertib, an aurora kinase inhibitor, is currently undergoing investigation in a phase 2 trial for AT/RT (NCT02114229).
Management of chronic myeloid leukemia in myeloid blastic phase with novel therapies: a systematic literature review
Published in Expert Review of Hematology, 2022
Umut Yılmaz, Batuhan Bulan, Çağrı Belli, Ahmet Emre Eşkazan
Danusertib, an Aurora kinase inhibitor, was studied in a phase-1 trial for advanced-phase CML [15]. The trial recruited nine CML-MBP patients, all previously treated. The study investigated the aftermath of different doses. Only one CML-MBP patient (11%) responded to danusertib, and overall, only four of 20 evaluable patients had responses, all carrying the T315I ABL mutation. An interesting observation in this trial was that danusertib reduced the blast volume during treatment in most patients, only to have a rebound increase in the off days of each cycle. The trial concluded that danusertib dose at 180 mg/m2 for seven consecutive days at 14-day cycles should be used for the phase-2 part of its clinical development.
Discovery of a novel Aurora B inhibitor GSK650394 with potent anticancer and anti-aspergillus fumigatus dual efficacies in vitro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Yuhua He, Wei Fu, Liyang Du, Huiqiao Yao, Zhengkang Hua, Jinyu Li, Zhonghui Lin
Mitosis is a fundamental biological process essential for the growth and development of all eukaryotes, including fungus and humans. The serine/threonine kinase Aurora B is a pivotal mitotic regulator conserved from yeast to man and involves various aspects of cell division, such as chromosome condensation, kinetochore functions, spindle checkpoint activation, and cytokinesis completion4. Aurora B physically associates with the inner centromere protein (INCENP), borealin and survivin to form the chromosomal passenger complex (CPC)5,6. As a kinase, it can phosphorylate many proteins, including histone H37, mitotic centromere-associated kinesin (MCAK)8, and centromere protein-A (CENP-A)9. The overexpression of Aurora B is frequently observed in many cancers, including myeloma10, colorectal11, prostate12, pancreatic13, hepatocellular14, and ovarian15 carcinomas. It has been clinically linked to poor patient prognosis in cancers16. In contrast, reducing the expression of Aurora B kinase by short hairpin RNA (shRNA)17 or chemical inhibitors4,18–24 has been demonstrated to prevent tumour cells growth. For example, the highly selective Aurora B kinase inhibitor barasertib (AZD1152) exhibited an overall response rate of 45% in phase I/II trials in patients with acute myelogenous leukaemia (AML) when combined with low-dose cytosine arabinoside (LDAC)23. The selective pan-Aurora kinase inhibitor AMG 900 displayed potent inhibitory activity against a range of human solid tumour cell lines24. The Aurora kinases inhibitor VX680 has been shown to suppress the growth of HepG2 cells25. Thus, Aurora B has been a promising drug target for the treatment of many cancers, including AML23, osteosarcoma20, and myeloma10.