Inhibition of histone deacetylase for the treatment of biliary tract cancer: A new effective pharmacological approach

Javle

et al. 2016

Cancer

Background BTC are uncommon and associated with a dismal prognosis. Gemcitabine and platinum-combinations (GP) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for GP response in BTC, we evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. Methods Pretreatment FFPE samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression free survival (PFS) and overall survival (OS). Results Considering genes with an incidence >10%, no individual gene was independently predictive of GP response. In patients with unresectable BTC who received GP as first-line therapy, the joint status of CDKN2A, TP53 and ARID1A were associated with PFS (P=0.0004) and OS (P=<0.0001). Patients with mutations in CDKN2A and TP53 were identified as a poor prognostic cohort with a median PFS and OS of 2.63 and 5.22 months. Patients with mutant ARID1A regardless of single mutational status of TP53 or CDKN2A had similar outcomes. A patient who exhibited mutations in all three genes had a median PFS of 20.37 months and OS not reached. Conclusions In the largest exploratory analysis of this nature in BTC, the presence of three prevalent, mutually exclusive mutations represents distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker to GP response. Prospective studies validate these findings are needed, including the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC.

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Next‐generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance

Javle

et al. 2016

Cancer

“…Panobinostat induces tumor cell-specific cytotoxicity and has demonstrated anti-tumor activity in several in vivo tumor models. [5][6][7] In a Phase I trial, clinical evaluation of oral panobinostat in 10 CTCL patients demonstrated significant anti-tumor activity, 2 with complete remissions, 4 with partial response and 2 with stable disease, and durable clinical efficacy has also been seen in a Phase II study. 8,9 Another hydroxamic acid-based compound, vorinostat (ZOLINZA TM ), is the first DACi approved by the Food and Drug Administration for treatment of cancer patients with CTCL, having demonstrated clinical efficacy in two Phase II studies with overall response rates (RRs) of 30 and 24%, respectively.…”

mentioning

confidence: 99%

Activity of deacetylase inhibitor panobinostat (LBH589) in cutaneous T‐cell lymphoma models: Defining molecular mechanisms of resistance

Shao¹,

Growney²,

Feng³

et al. 2010

Intl Journal of Cancer

Panobinostat (LBH589) is a highly potent deacetylase inhibitor that has demonstrated clinical efficacy in patients with advanced cutaneous T-cell lymphoma (CTCL). To gain a better understanding of the compound activity in this tumor type, we investigated the cellular and molecular effects of panobinostat using both in vitro and in vivo models of CTCL. All 4 tested CTCL cell lines exhibited very high sensitivity to panobinostat-induced growth inhibition. However, only 2 of 4 lines exhibited significant response to the cytotoxic activity of panobinostat. In a CTCL xenograft mouse tumor model, panobinostat treatment resulted in complete tumor regression. The difference in cell sensitivity to panobinostat-induced death enabled us to further investigate potential mechanisms responsible for tumor sensitivity or resistance. In CTCL cell lines that were insensitive to panobinostat-induced apoptosis, constitutively activated NF-jB and high levels of Bcl-2 were observed. Inhibition of Bcl-2 sensitized cells to the cytotoxic activity of panobinostat. Conversely, knockdown of Bax diminished the CTCL cell sensitivity. Interestingly, panobinostat could induce cytotoxicity in vorinostat-resistant CTCL cells by downregulating phosphorylated STAT3 and STAT5 proteins. These studies suggest distinct mechanisms responsible for resistance to different deacetylase inhibitors. We show that the intrinsic apoptotic signaling plays an essential role in mediating panobinostat anticancer activity. Moreover, cancer cell sensitivity to panobinostat treatment may be further improved by combination with inhibition of anti-apoptotic factors. These data provide preclinical support that panobinostat, as a single agent or in combination with other anticancer agents, is a promising therapy for CTCL.Cutaneous T-cell lymphomas (CTCLs) are lymphoproliferative disorders characterized by clonal expansion and localization of neoplastic T lymphocytes to the skin, resulting in immune dysregulation and tumor growth. 1 The most common form of CTCL is mycosis fungoides (MF), which is typically indolent but may evolve into the leukemic variant, Sézary syndrome (SS) or large-cell lymphoma. Traditionally, a number of skin-directed and systemic therapies are applied to control CTCL progression. Patients with progressed or refractory CTCL generally have a poor prognosis. Subsequent relapses are common in treated MF patients, and few available treatments have impacted overall survival (OS) for CTCL patients, resulting in a serious unmet therapeutic need.Distinct subtypes of CTCL are currently delineated on the basis of clinical or morphological features, and neither underlying pathogenesis of cutaneous lymphomas nor the distinguishing molecular abnormalities have been identified. However, CTCL cells have been shown to have deregulation of apoptotic responses. 2,3 Thus, treatments that can overcome CTCL resistance to apoptosis may provide new therapeutic strategies. To this effect, several novel targeted agents have emerged, which show promise in treating CTCL.Deace...

“…Our results show that TSA could shorten the survival time of gallbladder carcinoma and cholangiocarcinoma cell lines in vivo and in vitro, indicating that TSA is a potential drug for the treatment of biliary tract cancer. It was reported that HDACIs MS-275, NVP-LBH589 and NVP-LAQ824 can effectively inhibit the growth of human biliary tract cancer cells [26,27] . However, early diagnosis and treatment of biliary tract cancer are still difficult [29][30][31][32][33][34] .…”

Section: Discussionmentioning

confidence: 99%

Effect of histone deacetylase inhibitor on proliferation of biliary tract cancer cell lines

Xu¹,

Wang²,

Zou³

2008

WJG

AIM:To explore the effect of histone deacetylase inhibitor, trichostatin A (TSA) on the growth of biliary tract cancer cell lines (gallbladder carcinoma cell line and cholangiocarcinoma cell line) in vivo and in vitro , and to investigate the perspective of histone deacetylase inhibitor in its clinical application. METHODS:The survival rates of gallbladder carcinoma cell line (Mz-ChA-l cell line) and cholangiocarcinoma cell lines (QBC939, KMBC and OZ cell lines) treated with various doses of TSA were detected by methylthiazol tetrazolium (MTT) assay. A nude mouse model of transplanted gallbladder carcinoma (Mz-ChA-l cell line) was successfully established, and changes in the growth of transplanted tumor after treated with TSA were measured. RESULTS:TSA could inhibit the proliferation of gallbladder carcinoma cell line (Mz-ChA-l cell line) and cholangiocarcinoma cell lines (QBC939, KMBC and OZ cell lines) in a dose-dependent manner. After the nude mouse model of transplanted gallbladder carcinoma (MzChA-l cell line) was successfully established, the growth of cancer was inhibited in the model after treated with TSA. C O N C L U S I O N :T S A c a n i n h i b i t t h e g r o w t h o f cholangiocarcinoma and gallbladder carcinoma cell lines in vitro and in vivo.