Description:
<jats:title>Abstract</jats:title>
<jats:p>Objective: The development of drug resistance is a major cause of gynecologic cancer deaths. Selenium (Se) inhibits the development of carboplatin (C) drug resistance in a mouse ovarian cancer xenograft model. Based on this data, a Phase I trial of a combination of Se, (C) and paclitaxel (P) was designed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and effects of Se in (C) pharmacokinetics (PK) in the treatment of chemo-naive women with gynecologic cancers. Correlative studies identified Se gene targets responsible for reversal of drug resistance.</jats:p>
<jats:p>Methods: Se (50-5000 mcg) IV was given on day 1, and (C) (AUC 5 in cycle 1, AUC 6 in subsequent cycles) IV and (P) 175mg/m2 IV on day 3. A standard 3 + 3 design was used in the selenium dose escalation phase. (C) and Se concentrations in plasma and ultrafiltrate were analyzed.</jats:p>
<jats:p>Results: 45 patients were enrolled. Worst grade toxicities from 291 cycles included neutropenia (Gr 3, n=24; Gr 4, n=19), febrile neutropenia (Gr 3, n=2), anemia (Gr 3, n=1), constitutional (Gr 3, n=3), gastrointestinal (Gr 3, n=5), neurolgic (Gr 3, n=6), pain (Gr 3, n=12), and pulmonary (Gr 3, n= 5). DLT was not reached but IV site pain was recorded at selenium doses higher than 2000 mcg. GFR did not change with Se treatment. Se also had no effect on (C) pharmacokinetics. The average observed AUC was the same as target AUC in each cycle. Between cycle 1 and cycle 2, the estimated PK parameters, clearance (138 vs 133 ml/min) and half-life (312 vs 305 min), were not significantly different. Plasma Se AUC showed dose proportionate increase at higher doses. Of 38 patients with ovarian cancer, there were 9 complete response, 8 partial response, 6 stable disease and 12 disease progression. The median progression-free survival from these 38 patients was 35 months. 33/45 pts had elevated serum CA125 at initiation of therapy. 21/33 had normalization of CA125 after cycle 2 (n=14), and after cycle 6 (n= 7). RNA expression of the tumors as well as cell lines was measured and compared before and after selenium treatment. The samples were run on the Human Exon 1.0 ST exon microarray platform. The results of this analysis pointed to Rad51-AP1 as a gene that is downregulated by selenium. Validation experiments done in vitro confirmed that treatment with Se decreased Rad51-AP1 protein levels, and the cells become more sensitive to (C). Also, cells treated with increasing amounts of (C) showed increased levels of Rad51-AP1.</jats:p>
<jats:p>Conclusion: Se in combination with (C) and (P) is safe, well tolerated and does not affect (C) pharmacokinetics. Although selenium DLT was not reached, at the dose of 5000 mcg, the patients needed central lines for selenium infusion, secondarily to IV site pain. Responses and protracted stable disease are noted in patients with gynecologic cancers. Downregulation of Rad51-AP1, a protein involved in DNA repair, may counteract the development of platinum based drug resistance by selenium.</jats:p>
<jats:p>Citation Format: Lorna Rodriguez-Rodriguez, Mihae Song, Neelakandan Muthukumaran, Murugesan Gounder, Darlene Gibbon, Wilberto Nieves-Neira, Ami Vaidya, Mira Hellmann, Susan Goodin, Brian Buckley. Selenium counteracts carboplatin drug resistance through Rad51-AP1 induction: A phase I trial in women with gynecologic cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT219. doi:10.1158/1538-7445.AM2014-CT219</jats:p>