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Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.

ABSTRACT: BACKGROUND:Sequential treatment with azacitidine can induce re-expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. A phase 1b-2a clinical trial of this sequential combination of azacitidine and carboplatin was initiated in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. METHODS:Patients with pathologically confirmed intermediate-grade or high-grade epithelial ovarian cancer who developed disease progression within 6 months (resistant disease, n = 18 patients) or during a platinum-based therapy (refractory disease, n = 12 patients) were eligible. All patients had measurable disease. RESULTS:Thirty patients received a total of 163 cycles of treatment. This regimen produced 1 complete response, 3 partial responses (overall response rate [ORR], 13.8%), and 10 cases of stable disease among 29 evaluable patients. For those patients who achieved clinical benefits, the median duration of the treatment was 7.5 months. The median progression-free survival (PFS) and overall survival (OS) for all patients were 3.7 months and 14 months, respectively. Patients with platinum-resistant disease achieved an ORR of 22%, with a median PFS of 5.6 months and a median OS of 23 months. The predominant toxicities were fatigue and myelosuppression. Correlative studies indicated that DR4 methylation in peripheral blood leukocytes was decreased during treatment in 3 of 4 objective responders (75%), but in only 5 of 13 nonresponders (38%). CONCLUSIONS:To the authors' knowledge, the results of the current study provide the first clinical evidence that a hypomethylating agent may partially reverse platinum resistance in patients with ovarian cancer. Further clinical evaluation of hypomethylating agents in combination with carboplatin is warranted.

SUBMITTER: Fu S

PROVIDER: S-EPMC3062960 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.

Fu Siqing S Hu Wei W Iyer Revathy R Kavanagh John J JJ Coleman Robert L RL Levenback Charles F CF Sood Anil K AK Wolf Judith K JK Gershenson David M DM Markman Maurie M Hennessy Bryan T BT Kurzrock Razelle R Bast Robert C RC

Cancer 20101108 8

<h4>Background</h4>Sequential treatment with azacitidine can induce re-expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. A phase 1b-2a clinical trial of this sequential combination of azacitidine and carboplatin was initiated in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.<h4>Methods</h4>Patients with pathologically confirmed intermediate-grade or high-grade ...[more]

PMID: 21472713

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Project description:ObjectivePrimary platinum-resistant epithelial ovarian cancer (EOC) is an area of unmet medical need. There is limited evidence from small studies that platinum-based combinations can overcome "resistance" in a proportion of patients. We investigated the efficacy and toxicity of platinum-based combination chemotherapy in the platinum-resistant and platinum-refractory setting.MethodsEpirubicin, cisplatin, and capecitabine (ECX) combination chemotherapy was used at our institution for the treatment of relapsed EOC. From the institutional database, we identified all patients with primary platinum-refractory or platinum-resistant relapse treated with ECX as second-line therapy between 2001 and 2012. We extracted demographic, clinical, treatment, and toxicity data and outcomes. We used logistic and Cox regression models to identify predictors of response and survival respectively.ResultsThirty-four 34 patients (8 refractory, 26 resistant) were treated with ECX. Response Evaluation Criteria In Solid Tumors (RECIST) response rate was 45%, median progression-free survival (PFS) was 6.4 months, and overall survival (OS) was 10.6 months. Platinum-resistant patients had better outcomes than did platinum-refractory patients (response rate, 54% vs 0%, P = 0.047; PFS 7.2 vs 1.8 months, P < 0.0001; OS 14.4 vs 3 months, P < 0.001). In regression models, time to progression after first-line treatment and platinum-refractory status were the strongest predictors of response and PFS or OS, respectively. Patients with time to progression after first-line treatment longer than 3 months showed PFS and OS of 7.9 and 14.7 months, respectively. Toxicity was manageable, with only 13% of cycles administered at reduced doses.ConclusionsEpirubicin, cisplatin, and capecitabine seems to be active in platinum-resistant relapsed EOC with manageable toxicity. Further prospective investigation of platinum-anthracycline combinations is warranted in patients who relapse 3 to 6 months after first-line platinum-taxane treatment.

Project description:DNA methylation causes silencing of tumor suppressor and differentiation-associated genes being linked to chemoresistance and stemness. Previous studies demonstrated that hypomethylating agents (HMA) re-sensitize ovarian cancer (OC) cells to chemotherapy, however, translation to the clinic has been slow. NTX 301 (PinotBio) is a novel, highly potent and orally bioavailable HMA, in early clinical development. We assessed the anti-tumor effects of NTX301 in OC models and studied the underlying molecular mechanisms by using cell proliferation, stemness and ferroptosis assays, RNA sequencing and validation. OC cells (SKOV3, IC50=5.089nM; OVCAR5 IC50=3.664nM) were highly sensitive to NTX301 (p<0.05) compared to immortalized fallopian tube epithelial cells (FT-190) (IC50=103.3nM). Treatment with NTX301 induced significant downregulation of the DNA methyltransferases (DNMTs) 1-3 expression in SKOV3 and OVCAR5 cells compared with decitabine (p<0.05). Treatment with low dose NTX301 (100nM) induced significant transcriptomic reprogramming with 15,000 differentially expressed genes (DEGs) compared to DMSO (p<0.05). Among the NTX301 down-regulated DEGs, Gene Ontology (GO) enrichment analysis identified pathways related to regulation of alcohol, cholesterol, and fatty acid biosynthetic process and molecular functions related to aldehyde dehydrogenase (ALDH) and oxidoreductase activity, known features of cancer stem cells (CSCs). Indeed, treatment with low dose NTX301 (100nM) reduced the ALDH(+) cell population and expression of stemness associated transcription factors (Oct4 and Sox2). Additionally, stearoyl-Coenzyme A desaturase 1 (SCD), a key enzyme that regulates unsaturated fatty acid homeostasis in the lipogenesis process was found among the top DEGs downregulated in response to NTX301 (fold change=9.36, FDR<0.05). As blockade of SCD had been shown to induce ferroptosis, oxidized lipids levels were measured by C11-BODIPY staining. NTX301 treatment increased the levels of oxidized lipids compared to DMSO and this was blunted by deferoxamine, indicating that NTX301 promoted cell death via ferroptosis. NTX301 induced ferroptosis was successfully rescued by addition of oleic acid (200mM) into the culture medium, supporting that it was mediated through SCD depletion. In vivo, monotherapy with NTX301 (1mg/kg), significantly inhibited subcutaneous OC and PDX xenograft tumor growth (p<0.05). Decreased SCD levels and increased oxidized lipids were recorded in NTX301-treated xenografts. In conclusions, NTX301 is a potent HMA active in OC models. Our findings point to a new mechanism by which epigenetic blockade disrupts lipid homeostasis and promotes cancer cell death.

Dataset Information

Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.

Publications

Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.

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