A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth

Background:

Sorafenib is a potent inhibitor against Raf kinase and several receptor tyrosine kinases that has been approved for the clinical treatment of advanced renal and liver cancer. Combining sorafenib with other agents has been shown to improve its antitumour efficacy by not only reducing the toxic side effects but also preventing primary and acquired resistance to sorafenib. We have previously observed that tetrandrine exhibits potent antitumour effects in human hepatocellular carcinoma. In this study, we investigated the synergistic antitumour activity of sorafenib in combination with tetrandrine.

Methods:

This was a two-part investigation that included the in vitro effects of sorafenib in combination with tetrandrine on cancer cells and the in vivo antitumour efficacy of this drug combination on tumour xenografts in nude mice.

Results:

Combined treatment showed a good synergistic antitumour effect yet spared nontumourigenic cells. The potential molecular mechanism may be mainly that it activated mitochondrial death pathway and induced caspase-dependent apoptosis in the cancer cells. Accumulation of intracellular reactive oxygen species (ROS) and subsequent activation of Akt may also be involved in apoptosis induction.

Conclusion:

The antitumour activity of sorafenib plus tetrandrine may be attributed to the induction of the intrinsic apoptosis pathway through ROS/Akt signaling. This finding provides a novel approach that may broaden the clinical application of sorafenib.     

Phase 2 trial of linifanib (ABT‐869) in patients with unresectable or metastatic hepatocellular carcinoma

BACKGROUND:

The efficacy and safety of linifanib (ABT‐869), a selective inhibitor of vascular endothelial growth factor and platelet‐derived growth factor receptor tyrosine kinases, were assessed in this phase 2, single‐arm, open‐label, multicenter trial.

METHODS:

Eligible patients had unresectable or metastatic hepatocellular carcinoma and had received ≤ 1 prior systemic therapy. Patients received oral linifanib at a fasting dose of 0.25 mg/kg,. The primary endpoint was the progression‐free rate at 16 weeks. Tumor response was assessed every 8 weeks. Secondary endpoints included the time to disease progression, overall survival, and objective response rate. Safety was also assessed.

RESULTS:

Of the 44 patients enrolled, the majority were Asian (89%), had received no prior systemic therapy (82%), had Child‐Pugh class A hepatic function (86%), and had hepatitis B virus infection (61%). The estimated progression‐free rate at 16 weeks was 31.8% (34.2% for patients with Child‐Pugh class A hepatic function), the estimated objective response rate was 9.1% (10.5% for patients with Child‐Pugh class A hepatic function), the median time to disease progression was 3.7 months (3.7 months for patients with Child‐Pugh class A hepatic function), and the median overall survival was 9.7 months (10.4 months for patients with Child‐Pugh class A hepatic function). The most common linifanib‐related adverse events were diarrhea (55%) and fatigue (52%). The most common linifanib‐related grade 3/4 adverse events were hypertension (25%) and fatigue (14%). Serum levels of biomarkers cancer antigen (CA) 125, cytokeratin fragment (CYFRA)21.1, and protein induced by vitamin K absence or antagonist II (PIVKA) demonstrated potential as prognostic indicators of patient response or outcome.

CONCLUSIONS:

Single‐agent linifanib was found to be clinically active in patients with advanced hepatocellular carcinoma, with an acceptable safety profile. Cancer 2013. © 2012 American Cancer Society.     

Nutlin‐3 enhances sorafenib efficacy in renal cell carcinoma

The renal cell carcinoma (RCC) is one of the top 10 cancers in USA. The renal tumors are highly angiogenic and are resistant to conventional interventions, particularly radiotherapy. The advent of multi‐specific tyrosine kinase inhibitor sorafenib has improved the progression‐free survival in RCC, but overall survival in recurrent and metastatic RCC is still a concern that has lead to characterization of combinatorial regimens. Hence, we studied the effect of combination of nutlin‐3, an MDM2 inhibitor, which increases p53 levels, and sorafenib in RCC. Sorafenib along with nutlin‐3 synergistically inhibited the cell survival and enhanced caspase‐3 cleavage leading to apoptosis in RCC. Nutlin‐3 and sorafenib were more effective in reducing the migration of RCC, in combination than as single agents. Sorafenib and nutlin‐3 decreased the phosphorylation of vascular endothelial growth factor receptor‐2 (VEGFR‐2) and ERK along with inducing p53 activity. The sorafenib and nutlin‐3 co‐treatment lead to enhanced levels of p53, p‐p53, and increase in the levels of p53 pro‐apoptotic effector PUMA, Bax, and decrease in the anti‐apoptotic Bcl‐2 levels. Importantly, our studies revealed that sorafenib alone can activate p53 in a concentration dependent manner. Thus, co‐treatment of nutlin‐3 with sorafenib leads to increased half‐life of p53, which in turn can be activated by sorafenib, to induce downstream pro‐apoptotic and anti‐proliferative effects. This is the first report showing the synergistic effect of sorafenib and nutlin‐3 while providing a strong clinical‐translational rationale for further testing of sorafenib and nutlin‐3 combinatorial regimen in human RCC. © 2011 Wiley Periodicals, Inc.     

Is the efficacy of sorafenib treatment in patients with hepatocellular carcinoma affected by age?

Cancer is a prevalent disease in the elderly population and hepatocellular carcinoma (HCC) is a major health problem among all tumors. Curative treatments for early-stage include liver transplantation, resection and percutaneous ablation. Transarterial chemoembolization (TACE) and sorafenib, classified as non-curative treatments, can improve survival for patients with intermediate and advanced tumors, respectively. Even if the incidence of HCC progressively increases with advanced age in all populations, reaching a peak at 70 years, few reports concerning correct management of HCC in elderly patients exist. Moreover, data from large randomized controlled trials (RCT) poorly reflect the elderly population that is often quantitatively and qualitatively underrepresented, as a result of the presence of tight enrolment criteria. The aim of this brief review is to highlight the main concerns, pitfalls and warnings regarding the management of HCC in elderly patients, with particular focus on systemic therapy with sorafenib.     

Intraarterial therapies for primary liver cancer: state of the art

Image-guided intraarterial therapies play an important role in the treatment of patients with hepatic malignancies. These therapies provide the dual benefit of reduced systemic toxicity and effective local tumor control. As a result, procedures such as transarterial chemoembolization have been included in the official treatment guidelines for hepatocellular carcinoma (HCC) and are fully accepted for the treatment of patients with intermediate stage disease. In this review, we will describe the scientific rationale for intraarterial therapies and discuss the available clinical evidence for primary liver cancer. Finally, we will touch on the current trends consisting of combining intraarterial approaches with systemically administered targeted agents.     

Advanced kidney cancer: treating the elderly

Advancing age represents the primary risk factor for renal tumors. Despite findings on the inhibition of angiogenesis that have led to six new drugs to treat metastatic renal cell carcinoma, elderly patients have not been fully represented in clinical trials. In addition, current opinions regarding nephrectomy in elderly patients are conflicting. Available data refer to the efficacy and safety of sorafenib, sunitinib, everolimus, bevacizumab and temsirolimus in patients aged 65 years and older; safety and efficacy data are available only for sunitinib, sorafenib,and everolimus in patients aged 70 years and older and only sorafenib has safety data for patients aged 75 years and older. A different approach based on evaluating comorbidities at baseline, risk of drug interactions and the impact of antitumor treatment in patients with polytherapy regimen is discussed. A decision-making algorithm is proposed to facilitate the selection of the best therapy for kidney tumors for a specific elderly patient profile.     

Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial

Until now, no effective systemic treatment options have been available for patients with unresectable advanced hepatocellular carcinoma (HCC). In the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP), patients with unresectable advanced HCC with Child–Pugh liver function class A and who had not received prior systemic therapy, received either oral sorafenib (400 mg twice daily) or placebo until radiological and symptomatic progression. The two groups of patients were well balanced with respect to baseline characteristics. The study was stopped at the second planned interim analysis because of an advantage in the median overall survival (10.7 vs 7.9 months; hazard ratio: 0.69; 95% CI: 0.55–0.87; p < 0.001) and the median time to radiological progression (5.5 vs 2.8 months; p < 0.001) in the sorafenib arm. However, sorafenib was not able to increase the time to symptomatic progression. In terms of toxicity, there were more cases of diarrhea, weight loss, hand–foot skin reaction and hypophosphatemia among the patients receiving sorafenib, the majority of which were of grade 1 or 2 severity. The SHARP trial has demonstrated that sorafenib is effective in prolonging median survival and time-to-progression in patients with advanced HCC and that it is generally well tolerated with a manageable adverse events profile.     

Impact of anti-angiogenic treatments on metastatic renal cell carcinoma

Patients with metastatic renal cell cancer (mRCC) have traditionally had poor responses to systemic therapies. Recent developments in molecular biology have increased our understanding of the oncogenic processes and pathways in clear-cell mRCC. The development of drugs that target these pathways has expanded treatment options, improved prognosis and changed standard management of patients with clear-cell mRCC. Sunitinib, sorafenib and pazopanib (oral tyrosine kinase inhibitors) as well as everolimus and temsirolimus (mTOR inhibitors) and interferon with bevacizumab (an antibody to VEGF) have improved patient outcomes in large Phase III trials. These drugs have been incorporated into standard practice. Sunitinib has been adopted as first-line standard of care. Many agents are in development for treatment of mRCC, including axitinib in Phase III trials. We will review these treatments, their toxicities and how these targeted agents have impacted on mRCC.     

Korean Red Ginseng Extract Enhances the Anticancer Effects of Sorafenib through Abrogation of CREB and c‐Jun Activation in Renal Cell Carcinoma

Although application of sorafenib in the treatment of human renal cell carcinoma (RCC) remains one of the best examples of successful targeted therapy, majority of RCC patients suffer from its side effects as well as develop resistance to this targeted therapy. Thus, there is a need to promote novel alternative therapies for the treatment of RCC. In this study, we investigated whether Korean red ginseng extract (KRGE) could inhibit the proliferation and induce chemosensitization in human renal cancer cells. Also, we used a human phospho‐antibody array containing 46 antibodies against signaling molecules to examine a subset of phosphorylation events after KRGE and sorafenib combination treatment. Korean red ginseng extract suppressed the proliferation of two RCC cell lines; activated caspase‐3; caused poly(ADP‐ribose) polymerase cleavage; abrogated the expression of B‐cell lymphoma 2, B‐cell lymphoma extra large, survivin, inhibitors of apoptosis proteins‐1/2, cyclooxygenase‐2, cyclin D1, matrix metallopeptidase‐9, and vascular endothelial growth factor; and upregulated pro‐apoptotic gene products. Interestingly, KRGE enhanced the cytotoxic and apoptotic effects of sorafenib in RCC cells. The combination treatment of KRGE and sorafenib more clearly suppressed cyclic adenosine monophosphate response element‐binding protein and c‐Jun phosphorylation and induced phosphorylation of p53 than did the individual treatment regimen. Our results clearly demonstrate that KRGE can enhance the anticancer activity of sorafenib and may have a substantial potential in the treatment of RCC. Copyright © 2017 John Wiley & Sons, Ltd.     

TACE联合索拉非尼治疗BCLC-C期肝细胞癌20例疗效分析

目的 评价TACE联合索拉非尼治疗BCLC-C期HCC的疗效,为临床选择合理的治疗方案提供依据.方法 回顾性分析2008年8月-2014年1月有完整资料的BCLC-C期HCC病例76例,按照不同治疗方法分为3组,其中A组单纯TACE组29例,B组TACE联合索拉非尼组20例,C组支持治疗组27例.观察指标主要为:中位总生存时间(MOS),中位肿瘤进展时间(MTTP),疾病控制率(DCR),3、9和15个月生存率.结果 3组的MOS分别是9.2,12.6和3.1个月(P＜ 0.01); MTTP分别为3.2,5.6和1.5个月(P＜0.01);1～2个月内的DCR分别是82.8％,85.0％和14.8％(P＜ 0.01);3个月生存率分别为100％,100％和51.9％(P＜ 0.01);9个月生存率分别为51.7％,85％和0(P＜ 0.01);15个月生存率分别为10.3％,40％和0(P＜ 0.01).但是A组与B组的DCR、3个月生存率相比较,差异无统计学意义(P＞0.05).结论 对于BCLC-C期HCC,TACE联合索拉非尼疗效最优;对于无法联合治疗的患者,单纯TACE优于支持治疗.