Simultaneous XIAP and cIAP1/2 inhibition by a dimeric SMAC mimetic AZD5582 induces apoptosis in multiple myeloma.

Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. Prior IAPi such as LCL161 has high affinity to cIAP1 and cIAP2 resulting in inferior inhibiting activity against XIAP. A novel dimeric IAPi, AZD5582 (C58H78N8O8), have high binding potency to XIAP with EC50 dose of 15 nM, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition and inhibited JAK-STAT signaling triggered by IL-6. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy.

Combination of psoas muscle mass index and neutrophil/lymphocyte ratio as a prognostic predictor for patients undergoing nonsurgical hepatocellular carcinoma therapy.

BACKGROUND AND AIM: Reliable predictors for hepatocellular carcinoma (HCC) are urgently needed. The psoas muscle index (PMI) is a simple and rapid method for evaluating muscle atrophy. Furthermore, the neutrophil/lymphocyte ratio (NLR) is a prognostic factor that is easy to calculate in everyday clinical practice. We aimed to investigate the value of the PMI and NLR as prognostic factors for patients receiving nonsurgical HCC therapy, hepatic arterial infusion chemotherapy (HAIC), transcatheter arterial chemoembolization (TACE), or molecular targeted drugs such as sorafenib (SOR) and lenvatinib (LEN). METHODS: We enrolled 87 patients with HCC who were treated with HAIC, TACE, SOR, or LEN. The primary endpoint was overall survival (OS) with variable PMI or NLR status. For Barcelona Clinic Liver Cancer (BCLC)-B patients, useful prognostic factors were examined by comparing the OS between stratified groups. Prognostic factors including PMI and NLR were evaluated by univariate and multivariate analysis. RESULTS: Analysis of HAIC or TACE (HAIC/TACE) and SOR or LEN (SOR/LEN) patients showed significant differences in OS between low and high PMI. In patients treated with TACE, there was a significant difference in OS between low and high NLR. For BCLC-B and low PMI, the prognosis was significantly worse for SOR/LEN than for TACE, although there was no difference for high PMI, suggesting that PMI may be useful for treatment selection. In addition, the prognostic formula composed of PMI, NLR, and up-to-seven criteria developed in the present study may be useful. CONCLUSION: PMI and NLR are considered to be independent prognostic factors for HCC.

FOXO3a Activation by HDAC Class IIa Inhibition Induces Cell Cycle Arrest in Pancreatic Cancer Cells.

OBJECTIVES: Pancreatic cancer (PC) is highly aggressive with multiple oncogenic mutations. The efficacy of current chemotherapy is poor, and new therapeutic targets are needed. The forkhead box (FOX) proteins are multidirectional transcriptional factors strongly implicated in malignancies. Their expression is consistently suppressed by several oncogenic pathways such as PI3K/AKT signaling activated in PC. A recent study showed that class IIa histone deacetylases (HDAC) can act as a transcriptional suppressor. In this study, we hypothesized that HDAC class IIa inhibition would upregulate FOXO3a expression, thereby inducing its transcription-dependent antitumor effects. METHODS: We confirmed the change of FOXO3a expression and the effect of the cell growth inhibition by HDAC class IIa inhibition in AsPC-1 cells. Because FOXO3a is subject to ubiquitylation-mediated proteasome degradation, we examined the synergistic activation of FOXO3a by HDAC class IIa selective inhibitor TMP269 combined with proteasome inhibitor carfilzomib. RESULTS: We observed that TMP269 induced FOXO3a expression in a dose-dependent manner and inhibited cell growth in AsPC-1 cells. G1/S arrest was observed. FOXO3a expression was further increased and cell growth inhibition was dramatically enhanced by TMP269 combined with carfilzomib. CONCLUSIONS: Dual inhibition of class IIa HDACs and proteasome could be a promising new strategy for modifying FOXO3a activity against PC.

[Treatment of POEMS syndrome with lenalidomide and dexamethasone].

We report three cases of POEMS syndrome treated with lenalidomide and dexamethasone who presented with peripheral neuropathy. All of them had markedly elevated serum vascular endothelial growth factor (VEGF) levels treated with lenalidomide and dexamethasone for severe peripheral neuropathy, which normalized serum VEGF levels and improved peripheral neuropathy. The standard treatment of POEMS syndrome has not been established, but has been effectively treated with high-dose chemotherapy with autologous stem cell transplantation. Newer agents currently used for plasma cell dyscrasias include bortezomib and immunomodulatory drugs, such as thalidomide and lenalidomide. A randomized controlled trial on thalidomide plus dexamethasone for POEMS syndrome showed reduced serum VEGF levels after therapy; however, the incidence of peripheral neuropathy, a well-known side effect of both thalidomide and bortezomib, increased. Lenalidomide is associated with lower incidence of peripheral neuropathy compared to thalidomide and bortezomib, making it a reasonable treatment option for POEMS syndrome.

[Zoledronic Acid Administration is Effective for Hematopoiesis Management in a Patient with Primary Myelofibrosis].

An 80-year-old man received a diagnosis of anemia and a decreased platelet count from his physician in 2008, and was referred to our department where primary myelofibrosis was diagnosed.The patient was classified into the lower risk group according to the International Prognostic Scoring System(IPSS), and was followed up without treatment.In June 2010, pancytopenia progressed, and the patient was reclassified into the higher risk group.Blood count did not increase with metenolone treatment, but increased with zoledronic acid(ZA)that he started receiving from January 2012. After ZA treatment, circulating levels of vascular endothelial growth factor(VEGF)and transforming growth factor-b(TGF-b)decreased, and bone marrow biopsy showed an absence of reticular fibers and collagen fibers.In the present case, we observed that the blood count increased because of ZA-induced improvements in myelofibrosis.

[Efficacy of levocarnitine for tyrosine kinase inhibitor-induced painful muscle cramps in patients with chronic myelogenous leukemia].

Muscle cramps are side effects commonly associated with tyrosine kinase inhibitor (TKI) treatment. Patients suffering from muscle cramps are treated with various medications such as calcium, magnesium and vitamin supplements, but these therapies are often ineffective. We report two patients with chronic myelogenous leukemia who developed muscle cramps caused by TKI. These patients were treated successfully with levocarnitine. Both of our cases revealed the beneficial effects of levocarnitine treatment on TKI-induced muscle cramps.