Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Radiation therapy for vaginal and perirectal lesions in recurrent ovarian cancer

The role for localized radiation to treat ovarian cancer (OC) patients with locally recurrent vaginal/perirectal lesions remains unclear, though we hypothesize these patients may be salvaged locally and gain long-term survival benefit. We describe our institutional outcomes using intensity modulated radiation therapy (IMRT) +/- high-dose rate (HDR) brachytherapy to treat this population. Our primary objectives were to evaluate complete response rates of targeted lesions after radiation and calculate our 5-year in-field control (IFC) rate. Secondary objectives were to assess radiation-related toxicities, chemotherapy free-interval (CFI), as well as post-radiation progression-free (PFS) and overall survival (OS). PFS and OS were defined from radiation start to either progression or death/last follow-up, respectively. This was a heavily pre-treated cohort of 17 recurrent OC patients with a median follow-up of 28.4 months (range 4.5-166.4) after radiation completion. 52.9% had high-grade serous histology and 4 (23.5%) had isolated vaginal/perirectal disease. Four (23.5%) patients had in-field failures at 3.7, 11.2, 24.5, and 27.5 months after start of radiation, all treated with definitive dosing of radiation therapy. Patients who were platinum-sensitive prior to radiation had similar median PFS (6.5 vs. 13.4 months, log-rank p = 0.75), but longer OS (71.1 vs 18.8 months, log-rank p = 0.05) than their platinum-resistant counterparts. Excluding patients with low-grade histology or who were treated with palliative radiation, median CFI was 14.2 months (range 4.7 - 33.0). Radiation was well tolerated with 2 (12.0%) experiencing grade 3/4 gastrointestinal/genitourinary toxicities. In conclusion, radiation to treat locally recurrent vaginal/perirectal lesions in heavily pre-treated OC patients is safe and may effectively provide IFC

BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

© 2017 The Author(s) PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Moreover, JQ1 and Olaparib showed synergistic suppression of growth of BRCA-proficient cancer in vivo in a xenograft ovarian cancer mouse model. Our findings indicate that a combination of BET inhibitor and PARP inhibitor represents a potential therapeutic strategy for BRCA-proficient cancers. Karakashev et al. show synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers. This combination of inhibitors can synergistically increase DNA damage and cell-cycle checkpoint defects, which allows cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe

Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer

BACKGROUND: Current cancer immunotherapies have made tremendous impacts but generally lack high response rates, especially in ovarian cancer. New therapies are needed to provide increased benefits. One understudied approach is to target the large population of immunosuppressive tumor-associated macrophages (TAMs). Using inducible transgenic mice, we recently reported that upregulating nuclear factor-kappaB (NF-κB) signaling in TAMs promotes the M1, anti-tumor phenotype and limits ovarian cancer progression. We also developed a mannose-decorated polymeric nanoparticle system (MnNPs) to preferentially deliver siRNA payloads to M2, pro-tumor macrophages in vitro. In this study, we tested a translational strategy to repolarize ovarian TAMs via MnNPs loaded with siRNA targeting the inhibitor of NF-κB alpha (IκBα) using mouse models of ovarian cancer. METHODS: We evaluated treatment with MnNPs loaded with IκBα siRNA (IκBα-MnNPs) or scrambled siRNA in syngeneic ovarian cancer models. ID8 tumors in C57Bl/6 mice were used to evaluate consecutive-day treatment of late-stage disease while TBR5 tumors in FVB mice were used to evaluate repetitive treatments in a faster-developing disease model. MnNPs were evaluated for biodistribution and therapeutic efficacy in both models. RESULTS: Stimulation of NF-κB activity and repolarization to an M1 phenotype via IκBα-MnNP treatment was confirmed using cultured luciferase-reporter macrophages. Delivery of MnNPs with fluorescent payloads (Cy5-MnNPs) to macrophages in the solid tumors and ascites was confirmed in both tumor models. A three consecutive-day treatment of IκBα-MnNPs in the ID8 model validated a shift towards M1 macrophage polarization in vivo. A clear therapeutic effect was observed with biweekly treatments over 2-3 weeks in the TBR5 model where significantly reduced tumor burden was accompanied by changes in immune cell composition, indicative of reduced immunosuppressive tumor microenvironment. No evidence of toxicity associated with MnNP treatment was observed in either model. CONCLUSIONS: In mouse models of ovarian cancer, MnNPs were preferentially associated with macrophages in ascites fluid and solid tumors. Evidence of macrophage repolarization, increased inflammatory cues, and reduced tumor burden in IκBα-MnNP-treated mice indicate beneficial outcomes in models of established disease. We have provided evidence of a targeted, TAM-directed approach to increase anti-tumor immunity in ovarian cancer with strong translational potential for future clinical studies

Genetic characterization of primary and metastatic high-grade serous ovarian cancer tumors reveals distinct features associated with survival

High-grade serous ovarian cancer (HGSC) is the most lethal histotype of ovarian cancer and the majority of cases present with metastasis and late-stage disease. Over the last few decades, the overall survival for patients has not significantly improved, and there are limited targeted treatment options. We aimed to better characterize the distinctions between primary and metastatic tumors based on short- or long-term survival. We characterized 39 matched primary and metastatic tumors by whole exome and RNA sequencing. Of these, 23 were short-term (ST) survivors (overall survival (OS) \u3c 3.5 years) and 16 were long-term (LT) survivors (OS \u3e 5 years). We compared somatic mutations, copy number alterations, mutational burden, differential gene expression, immune cell infiltration, and gene fusion predictions between the primary and metastatic tumors and between ST and LT survivor cohorts. There were few differences in RNA expression between paired primary and metastatic tumors, but significant differences between the transcriptomes of LT and ST survivors in both their primary and metastatic tumors. These findings will improve the understanding of the genetic variation in HGSC that exist between patients with different prognoses and better inform treatments by identifying new targets for drug development

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC

International demands for austerity: examining the impact of the IMF on the public sector

What effects do International Monetary Fund (IMF) loans have on borrow-ing countries? Even after decades of research, no consensus exists. We offer a straight-forward explanation for the seemingly mixed effects of IMF loans. We argue thatdifferent loans have different effects because of the varied conditions attached to IMFfinancing. To demonstrate this point, we investigate IMF loans with and withoutconditions that require public sector reforms in exchange for financing. We find thatthe addition of a public sector reform condition to a country’s IMF program signifi-cantly reduces government spending on the public sector wage bill. This evidencesuggest that conditions are a key mechanism linking IMF lending to policy outcomes.Although IMF loans with public sector conditions prompt cuts to the wage bill in theshort-term, these cuts do not persist in the longer-term. Borrowers backslide oninternationally mandated spending cuts in response to domestic political pressures