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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Determinants of sensitivity to proteasome inhibitors and strategies to overcome acquired resistance against bortezomib in multiple myeloma

演題番号 : SY1-4

飯田 真介 (Shinsuke Iida):1、李 政樹 (Masaki Ri):1

1:Department of Medical Oncology & Immunology, Nagoya City University Graduate School of Medical Sciences, Japan

 

 Myeloma cells depend on ubiquitin-proteasome pathway to keep their cellular homeostasis. Thus, constitutive proteasome and immunoproteasome have emerged as the important molecular targets. Bortezomib (BTZ), a reversible dipeptide boronate proteasome inhibitor (PI) that inhibits chymotrypsin-like protease activity of β5 subunit in 20S core, has become a key drug in the treatment of multiple myeloma (MM). Adverse events can be generally managed, although the special attention to the peripheral neuropathy needs to be paid. In clinical practice, a primary refractoriness to BTZ is observed in a small fraction of the patients, but an acquired resistance is often encountered during BTZ treatment. Eventually, most of the patients treated with BTZ relapse with their tumor cells being resistant. Therefore, it is important to search for clinically useful biomarkers predicting treatment outcomes to avoid unnecessary BTZ administration, and to elucidate the underlying mechanisms responsible for its acquired resistance.
 Proteasome inhibition accumulates misfolded proteins, hence it initiates ER stress followed by unfolded protein response (UPR), which has crucial roles in cytotoxic effect of PI. Thus, the magnitude of dependence on the proteasome and UPR may render the sensitivity to PI to MM cells. We have focused on the expression levels of proteasome- and ER stress-related genes in primary tumor samples obtained prior to BTZ/DEX (BD) treatment in association with clinical outcomes. Among those, a couple of genes encoding ATF family members and proteasome subunits seem correlated with sensitivity to BTZ, although the further validation study is necessary. Regarding the mechanisms of resistance, we have previously established BTZ-resistant MM cell lines whose mutation in proteasome β5 subunit is associated with reduced accumulation of ubiquitinated proteins after exposure to BTZ, resulting in avoidance of fatal ER stress. However, such PSMB5 mutations have not been detected in tumor samples collected at clinical relapse from BTZ. Other findings in artificially prepared BTZ-resistant cell lines by other investigators include overexpression of various genes such as PSMBs, HSPs, IGF-1R, eIF3s, RPA3 and AKR1A1. Currently, we are also trying to collect tumor samples sensitive and those resistant to BTZ in the same patients. In order to overcome BTZ-resistance and to reduce its neurotoxicity, carfilzomib (CFZ), a novel PI of the epoxyketone class that irreversibly and more specifically inhibits chymotrypsin-like activity, is being developed. An alternative strategy to overcome BTZ-resistance is to use synergistic effect of BTZ with other agents such as anthracyclines and histone deacetylase (HDAC) inhibitors. We have identified Toyocamycin (TM) as an agent cytotoxic for MM cells via augmenting ER stress through inhibition of IRE1α-induced XBP1 mRNA cleavage. TM alone or its combination with BTZ can induce marked apoptosis of MM cells including BTZ-resistant cells. We also introduce a mechanism of resistance against CFZ given by P-glycoprotein expression in MM cells.

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