演題詳細

シンポジウム / Symposium

【E】シンポジウム1 (Symposium 1 (JSH-ASH Joint Symposium)) : Understanding molecular pathogenesis and biological behavior of MM to further improve its clinical outcome

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日程
2013年10月11日(金)
時間
09:00 - 11:30
会場
第1会場 / Room No.1 (さっぽろ芸文館 1F ニトリ文化ホール)
座長・司会
照井 康仁 (Yasuhito Terui):1、Nikhil C. Munshi:2
1:The Cancer Institute Hospital Of JFCR, Japan、2:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston VA Healthcare System, Harvard Medical School Boston MA, USA
 
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Genome based therapeutics in myeloma

演題番号 : SY1-2

Alexander Keith Stewart:1

1:Division of Hematology - Oncology, Mayo Clinic Arizona, USA

 

Over 250 Myeloma genomes have now been sequenced and no universal target has emerged although druggable targets are evident in a minority of patients. However we have learned that myeloma is a heterogeneous disease characterized by numerous genetically distinct clones that respond differently to therapeutics and move in clonal tides from minor to dominant clones.

We have also explored the genomic basis for the Immunomodulator drugs (IMiDs) which are key components of myeloma (MM) therapy. Recently, we demonstrated that Cereblon (CRBN) is the major mediator of IMiD action in MM,. Both IRF4 and MYC are down regulated by lenalidomide (Len) treatment or CRBN knockdown. Conversely, over expression of IRF4 or MYC can rescue MM cells from Len exposure or CRBN deletion. Introduced mutations in the CRBN - thalidomide binding domains result in loss of Len-induced cytotoxicity. CRBN mutations are uncommon in newly diagnosed patients although CRBN expression levels drop in relapsed MM. However, sequencing reveals mutations in the CRBN pathway in ~5-10% of MM cell lines and in a highly drug resistant MM a truncating mutation in CRBN was identified . We analyzed CRBN gene expression in 53 relapsed/refractory patients treated homogeneously with pomalidomide 2-4mg daily and weekly dexamethasone 40mg. The percent of patients that demonstrated at least a partial response was 0% for CRBN low expressors, 19% for intermediate expression, and 33% for higher CRBN expression. Significant differences in PFS (3.0 months vs. 8.9 months, p = 0.0006) and in OS (9.1 months vs. 27.2 months, p = 0.01) were observed when the lowest quartile of CRBN expression was compared to the top three quartiles. In summary, CRBN is the major target of the IMiDs (now better named cereblon inhibitors) is mutated in some drug resistant patients, expression of CRBN predicts response to IMiD based therapy and survival outcomes. Inhibition of CRBN and its associated complex results in alterations in the IRF4 pathway and blocks E3ligase function.

We have also explored sensitizers to bortezomib. We employed a systematic unbiased approach to identifying potential targets in Myeloma using RNAi based screens. In this fashion we identified CDK5 inhibition as the most potent sensitizer of bortezomib (BTZ). Dinaciclib is a novel, potent, small molecule inhibitor which selectively inhibits CDK5 with 50% inhibitory concentrations in the low nanomolar concentration. We demonstrated a synergistic effect of Dinaciclib with BTZ (and Carfilzomib) in inducing cytoxicity in MM1. Consequently, in a phase II clinical trial we observed clear clinical efficacy in ~20% of patients including 90% tumor reductions in a BTZ intolerant and lenalidomide refractory patient sustained for 10 months. A second critical kinase target was identified in GRK6. GRK6 expression is limited to the brain and hematologic tissues and knockout mice exhibit hypogammaglobulinemia but are otherwise healthy illustrating a wide therapeutic index. GRK6 inhibitors are in development.

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