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Ribonucleotide reductase inhibition restores platinum-sensitivity in platinum-resistant ovarian cancer: a Gynecologic Oncology Group Study.

ABSTRACT: BACKGROUND:The potent ribonucleotide reductase (RNR) inhibitor 3-aminopyridine-2-carboxyaldehyde-thiosemicarbazone (3-AP) was tested as a chemosensitizer for restored cisplatin-mediated cytotoxicity in platinum-resistant ovarian cancer. METHODS:Preclinical in vitro platinum-resistant ovarian cancer cell survival, RNR activity, and DNA damage assays were done after cisplatin or cisplatin plus 3-AP treatments. Six women with platinum-resistant ovarian cancer underwent four-day 3-AP (96 mg/m(2), day one to four) and cisplatin (25 mg/m(2), day two and three) infusions every 21 days until disease progression or adverse effects prohibited further therapy. Pre-therapy ovarian cancer tissues were analyzed by immunohistochemistry for RNR subunit expression as an indicator of cisplatin plus 3-AP treatment response. RESULTS:3-AP preceding cisplatin exposure in platinum-resistant ovarian cancer cells was not as effective as sequencing cisplatin plus 3-AP together in cell survival assays. Platinum-mediated DNA damage (i.e., ?H2AX foci) resolved quickly after cisplatin-alone or 3-AP preceding cisplatin exposure, but persisted after a cisplatin plus 3-AP sequence. On trial, 25 four-day overlapping 3-AP and cisplatin cycles were administered to six women (median 4.2 cycles per patient). 3-AP-related methemoglobinemia (range seven to 10%) occurred in two (33%) of six women, halting trial accrual. CONCLUSIONS:When sequenced cisplatin plus 3-AP, RNR inhibition restored platinum-sensitivity in platinum-resistant ovarian cancers. 3-AP (96 mg/m(2)) infusions produced modest methemoglobinemia, the expected consequence of ribonucleotide reductase inhibitors disrupting collateral proteins containing iron. TRIAL REGISTRY:ClinicalTrials.gov NCT00081276.

SUBMITTER: Kunos C

PROVIDER: S-EPMC3403898 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Ribonucleotide reductase inhibition restores platinum-sensitivity in platinum-resistant ovarian cancer: a Gynecologic Oncology Group Study.

Kunos Charles C Radivoyevitch Tomas T Abdul-Karim Fadi W FW Fanning James J Abulafia Ovadia O Bonebrake Albert J AJ Usha Lydia L

Journal of translational medicine 20120427

<h4>Background</h4>The potent ribonucleotide reductase (RNR) inhibitor 3-aminopyridine-2-carboxyaldehyde-thiosemicarbazone (3-AP) was tested as a chemosensitizer for restored cisplatin-mediated cytotoxicity in platinum-resistant ovarian cancer.<h4>Methods</h4>Preclinical in vitro platinum-resistant ovarian cancer cell survival, RNR activity, and DNA damage assays were done after cisplatin or cisplatin plus 3-AP treatments. Six women with platinum-resistant ovarian cancer underwent four-day 3-AP ...[more]

PMID: 22541066

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Project description:PURPOSE Sorafenib is a kinase inhibitor targeting Raf and other kinases (ie, vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Flt3, and c-KIT). This study assessed its activity and tolerability in patients with recurrent ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC). METHODS This open-label, multi-institutional, phase II study used a two-stage design. Eligible patients had persistent or recurrent OC/PPC after one to two prior cytotoxic regimens, and they experienced progression within 12 months of platinum-based therapy. Treatment consisted of sorafenib 400 mg orally twice per day. Primary end points were progression-free survival (PFS) at 6 months and toxicity by National Cancer Institute criteria. Secondary end points were tumor response and duration of PFS and overall survival. Biomarker analyses included measurement of ERK and b-Raf expression in tumors and phosphorylation of ERK (pERK) in peripheral-blood lymphocytes (PBLs) before and after 1 month of treatment. Results Seventy-three patients were enrolled, of which 71 were eligible. Fifty-nine eligible patients (83%) had measurable disease, and 12 (17%) had detectable disease. Significant grade 3 or 4 toxicities included the following: rash (n = 7), hand-foot syndrome (n = 9), metabolic (n = 10), GI (n = 3), cardiovascular (n = 2), and pulmonary (n = 2). Only patients with measurable disease were used to assess efficacy. Fourteen survived progression free for at least 6 months (24%; 90% CI, 15% to 35%). Two patients had partial responses (3.4%; 90% CI, 1% to 10%); 20 had stable disease; 30 had progressive disease; and seven could not have their tumor assessed. ERK and b-Raf were expressed in all tumors. Exploratory analyses indicated that pERK in post-treatment PBL specimens was associated with PFS. CONCLUSION Sorafenib has modest antitumor activity in patients with recurrent OC, but the activity was at the expense of substantial toxicity.

Project description:ObjectivesTo review the translational research (TR) performed in the Gynecologic Oncology Group (GOG) to evaluate ovarian cancer markers, profiles and novel therapies.MethodsProspective trials with stand alone or embedded TR objectives involving patient and specimen accrual as well as retrospective studies using banked specimens and resources were and continue to be performed in the GOG. Appropriate statistical methods are employed to evaluate associations with clinical characteristics and outcomes including tumor response, adverse events, progression free survival and overall survival.ResultsHighlights are presented for some of the collaborative and multidisciplinary TR conducted with the GOG to evaluate markers, pathway and novel therapeutics in epithelial ovarian, primary peritoneal and/or fallopian tube cancer. For example, in GOG 111, high immunohistochemical (IHC) expression of cyclin E was associated with a shorter median survival (29 versus 35 months) and an increased risk of death (hazard ratio [HR]=1.4, 95% confidence interval [CI]=1.0-2.1, p=0.05). In GOG 114/132, non-detectable immunoblot expression of maspin was associated with debulking status (p=0.034) and an increased risk of disease progression (HR=1.89, 95% CI=1.04-3.45, p=0.038) and death (HR=1.99, 95% CI=1.07-3.69, p=0.030) while high CD105-microvessel density (MVD), but not CD31-MVD in tumor was associated with increased risk of disease progression (HR=1.873, 95% CI=1.102-3.184, p=0.020) but not death. In GOG 172, low IHC expression of BRCA1 was associated with advanced stage (p<0.001), serous histology (p<0.001) and a reduced risk of disease progression (HR=0.64, 95% CI=0.42-0.96) and death (HR=0.51, 95% CI=0.32-0.83) while the CA/AA versus CC genotypes in C8092A in ERCC1 were associated with an increased risk of disease progression (HR=1.44, 95% CI=1.06-1.94, p=0.018) and death (HR=1.50, 95% CI=1.07-2.09, p=0.018).ConclusionsThe GOG has an extensive TR program that provides clues regarding the molecular and biochemical mechanisms of disease, treatments and outcomes in women with or at risk for a gynecologic malignancy.

Dataset Information

Ribonucleotide reductase inhibition restores platinum-sensitivity in platinum-resistant ovarian cancer: a Gynecologic Oncology Group Study.

Publications

Ribonucleotide reductase inhibition restores platinum-sensitivity in platinum-resistant ovarian cancer: a Gynecologic Oncology Group Study.

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