Cutting edge Seminar
Speaker: Shinya Kimura (Professor, Department of Hematology, Respiratory Medicine and Oncology, Saga University)
Title: Molecular Targeting Agents; Make, Use and Stop
Date&Time: 31 May. (Wed.) 2017, 12:00- 13:00
Venue: Conference Room(1F), IMEG
Abstract:
Chronic myeloid leukemia (CML) is caused by the bcr-abl chimeric gene which was incurable disease without transplantation until the end of 20th century. ABL tyrosine kinase inhibitor (TKI), a molecular targeting agent, imatinib mesylate emerged in 2001 and showed dramatic clinical effects in most CML patients. However, some cases showed resistance or intolerance to imatinib.
We found that bisphosphonate (Blood 2003), bcl-2 inhibitor (PNAS 2006) and chloroquine (Cell Death Diff 2008) augmented the effects of imatinib. We also used genomic drug discovery and developed a second generation ABL TKI, bafetinib, which was about 55 times more potent than imatinib (Blood 2005, Blood 2007). We conducted a Phase I clinical trial, which showed good results (Cancer 2010). Although bafetinib overcame most imatinib-resistant mechanisms, it was ineffective for CML cells harboring T315I mutation as well as other ABL TKIs. Thus, we tried to search for novel agents and found that an Aurora kinase inhibitor, AT9283 could inhibited T315I clone (Blood 2010). In addition, we developed a fully automated gene analysis method using quenching probe method to detect point mutations which caused resistance to ABL TKIs (Cancer Lett 2011). At last, we investigated whether CML patients had been treated with ABL TKIs for several years could stop it safely. We performed a TKI stop clinical trial (DADI trial). After confirmation of stable deep molecular response for more than 1 year, 48% of patients did not relapse even after cessation of ABL TKI (Lancet Haematol 2015).
However, still, not all CML patients can be cured. Therefore, we have also tried to find novel agents which have different mechanisms of action. We discovered that a natural product, named GUT-70, isolated from Calophyllum brasiliense, significantly inhibited the growth of leukemic cells (Int J Cancer 2005). Then we, synthesized a more potent BNS-22 via GUT-70 research (Chem Biol 2011). Intriguingly, we found that GUT-70 and BNS-22 worked as a ubiquinin-1 inhibitor which had never been discovered before. GUT-70 showed anti-HIV effects in addition to antitumor effects (Bioorgan Med Chem Lett 2013, BBRC 2015). Furthermore, we very recently found that 2-Hydroxypropyl-β-cyclodextrin which had been used for Niemann-Pick disease patients acted as a novel anti-cancer agent (PLoS One 2015).
In near future, we will integrate these studies and hope to establish an ultimate treatment which can cure all CML patients only with oral medicine.
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