Phase I study of combination of vorinostat, carboplatin, and gemcitabine in women with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer

Matulonis, Ursula A.; Berlin, Suzanne; Lee, Hang; Whalen, Christin; Obermayer, Elizabeth; Penson, Richard T.; Liu, Joyce F.; Campos, Susana M.; Krasner, Carolyn; Horowitz, Neil S.

doi:10.1007/s00280-015-2813-9

Cited by 48 publications

(28 citation statements)

References 26 publications

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“…One strategy to potentiate the effectiveness of platinum therapy is to use a combination therapy including HDAC inhibitors along with the platinum; however, such combination therapy is associated with significant drug toxicities [35, 36]. Since most HDAC inhibitors do not inhibit, or have only low levels of inhibition of HDAC10 [29], results from this study suggest that an HDAC10 isoform-specific inhibitor could improve the platinum sensitivity in ovarian carcinoma tumors and possibly with lower toxicity.…”

Section: Discussionmentioning

confidence: 99%

HDAC10 as a potential therapeutic target in ovarian cancer

Islam

Banerjee

Packard

et al. 2017

Gynecologic Oncology

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Objective We analyzed histone deacetylase 10 (HDAC10) for function in the context of the DNA damage response in BRCA1-null ovarian cancer cells as well as evaluated the potential of general HDAC inhibitors in primary ovarian carcinoma cells. HDAC10 had previously been shown to be highly stimulatory to the process of homology directed repair in HeLa cells, and in this study we investigated whether HDAC10 could impact in vitro the response to anticancer therapies. We hypothesized that the loss of HDAC10 would sensitize cells to platinum therapy. Methods We combined informatics analysis of large DNA sequencing datasets from ovarian cancer tumors with tissue culture based assays of primary and established cell lines to test for sensitivity to platinum therapy if HDAC10 activity was inhibited or depleted. Results Using The Cancer Genome Atlas (TCGA) dataset, we found that deep deletions in HDAC10 occurred in 5–10% of ovarian cancer tumors. From the TCGA data we found that low HDAC10 mRNA levels correlated with platinum sensitivity of the tumors. Cell proliferation and DNA damage assays in a BRCA1-null ovarian carcinoma cell line demonstrated reduced DNA repair capacity and sensitization of platinum therapy. Similarly, primary ovarian carcinoma cells demonstrated a sensitization to platinum therapies when treated with HDAC inhibitors. Conclusions From the results of this study, we suggest that the inhibition of HDAC10 may potentiate the effects of platinum therapies in ovarian tumors.

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Section: Discussionmentioning

confidence: 99%

HDAC10 as a potential therapeutic target in ovarian cancer

Islam

Banerjee

Packard

et al. 2017

Gynecologic Oncology

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“…HDAC may be induced by pazopanib and vorinostat, which demonstrates better antitumor activity with a significantly longer progression-free survival (PFS) and overall survival (OS) in patients bearing mutant P53 solid tumors, including ovarian cancers, compared with in P53 wild-type tumors (6). Stratifying HGSOC patients on P53 alteration status has, therefore, been proposed as a molecular rationale for the addition of vorinostat to anti-VEGF maintenance therapy, and may maximize the clinical benefits that limit the significant toxicities associated with the use of cytotoxic chemotherapy (7). …”

Section: Introductionmentioning

confidence: 99%

Beside P53 and PTEN: Identification of molecular alterations of the RAS/MAPK and PI3K/AKT signaling pathways in high-grade serous ovarian carcinomas to determine potential novel therapeutic targets

et al. 2016

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Despite great histological and molecular heterogeneity, the clinical management of high-grade ovarian carcinomas remains unspecialized. As a major subgroup, high-grade serous ovarian carcinomas (HGSOCs) require novel therapies. In addition to utilizing conventional histological prognostic markers and performing oncogenetic investigations, the molecular diagnostic method of next generation sequencing (NGS) was performed to identify ‘druggable’ targets that could provide access to innovative therapy. The present study was performed in 45 HGSOC patients (mean age, 59.1 years; range, 25–87 years) with histologically proven HGSOC. Breast cancer 1/2 (BRCA1/2) germline mutations were screened in 17 patients with a familial or personal history of cancer, which was justified by oncogenetic investigations. Tumor protein 53 (P53) and phosphatase and tensin homolog (PTEN) expression were assessed in formalin-fixed paraffin-embedded tissues using immunohistochemistry. Somatic mutations of Kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and MET proto-oncogene, receptor tyrosine kinase (MET) were screened using NGS on DNA extracts from frozen tumor specimens obtained at diagnosis. With a median follow-up of 38 months (range, 6–93 months), 20 patients are alive, 10 patients are disease-free and 14 patients progressed within 6 months following platinum-based therapy. P53 overexpression was detected in 67% of patients and PTEN loss was detected in 38% of the patients. The overexpression of mutant P53 was found to be associated with a longer progression-free and overall survival. In total, 2 NRAS (exon 3), 3 PIK3CA (exon 5 and 10) and 5 MET mutations (exons 14 and 18) were detected. In HGSOCs, in addition to P53 and PTEN alterations, somatic genetic abnormalities can be detected using NGS and provide molecular rationale for targeted therapies, potentially offering novel therapeutic opportunities to patients.

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“…In this field, in a Phase-II trial, platinum-resistant HGSOC patients treated with belinostat experienced severe adverse events without clinical benefits, leading to the termination of the study [112]. Accordingly, in a Phase-I trial, when vorinostat was administered in combination with gemcitabine or carboplatin, it provoked severe hematological toxicities, with a relative partial benefit, not sufficient to proceed the study [113].…”

Section: Histone Modifications: Implication and Inhibitionmentioning

confidence: 99%

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

Citron

Fabris

2020

Cancers

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Extensive efforts recently witnessed the complexity of cancer biology; however, molecular medicine still lacks the ability to elucidate hidden mechanisms for the maintenance of specific subclasses of rare tumors characterized by the silent onset and a poor prognosis (e.g., ovarian cancer, pancreatic cancer, and glioblastoma). Recent mutational fingerprints of human cancers highlighted genomic alteration occurring on epigenetic modulators. In this scenario, the epigenome dependency of cancer orchestrates a broad range of cellular processes critical for tumorigenesis and tumor progression, possibly mediating escaping mechanisms leading to drug resistance. Indeed, in this review, we discuss the pivotal role of chromatin remodeling in shaping the tumor architecture and modulating tumor fitness in a microenvironment-dependent context. We will also present recent advances in the epigenome targeting, posing a particular emphasis on how this knowledge could be translated into a feasible therapeutic approach to individualize clinical settings and improve patient outcomes.

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Phase I study of combination of vorinostat, carboplatin, and gemcitabine in women with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer

Abstract: Combination of carboplatin, gemcitabine, and vorinostat has activity in relapsed platinum-sensitive ovarian cancer, but was difficult to combine because of hematologic toxicities in this phase I study. No maximally tolerated dose was found, and the study was terminated early.

Cited by 48 publications

References 26 publications

HDAC10 as a potential therapeutic target in ovarian cancer

HDAC10 as a potential therapeutic target in ovarian cancer

Beside P53 and PTEN: Identification of molecular alterations of the RAS/MAPK and PI3K/AKT signaling pathways in high-grade serous ovarian carcinomas to determine potential novel therapeutic targets

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

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