FoxO-1 contributes to the efficacy of the combination of the XPO1 inhibitor selinexor and cisplatin in ovarian carcinoma preclinical models.

The XPO1/CRM1 inhibitor selinexor (KPT-330), is currently being evaluated in multiple clinical trials as an anticancer agent. XPO1 participates in the nuclear export of FoxO-1, which we previously found to be decreased in platinum-resistant ovarian carcinoma. The aim of this study was to determine whether enriching FoxO-1 nuclear localization using selinexor would increase ovarian cancer cell sensitivity to cisplatin. Selinexor, as a single agent, displayed a striking antiproliferative effect in different ovarian carcinoma cell lines. A schedule-dependent synergistic effect of selinexor in combination with cisplatin was found in cisplatin-sensitive IGROV-1, the combination efficacy being more evident in sensitive than in the resistant cells. In IGROV-1 cells, the combination was more effective when selinexor followed cisplatin exposure. A modulation of proteins involved in apoptosis (p53, Bax) and in cell cycle progression (p21WAF1) was found by Western blotting. Selinexor-treated cells exhibited enriched FoxO-1 nuclear staining. Knock-down experiments with RNA interference indicated that FOXO1-silenced cells displayed a reduced sensitivity to selinexor. FOXO1 silencing also tended to reduce the efficacy of the drug combination at selected cisplatin concentrations. Selinexor significantly inhibited tumor growth, induced FoxO-1 nuclear localization and improved the efficacy of cisplatin in IGROV-1 xenografts. Taken together, our results support FoxO-1 as one of the key factors promoting sensitivity towards selinexor and the synergistic interaction between cisplatin and selinexor in ovarian carcinoma cells with selected molecular backgrounds, highlighting the need for treatment regimens tailored to the molecular tumor features.

Preclinical efficacy of ST1976, a novel camptothecin analog of the 7-oxyiminomethyl series.

In previous studies, we have documented the potential therapeutic advantages of camptothecin analogs modified at the 7-position, i.e., 7-oxyiminomethyl derivatives. The present study was performed to explore the therapeutic potential of novel hydrophilic derivatives of this series. With one exception (ST1976), the tested camptothecins exhibited a reduced antiproliferative activity and all compounds retained ability to stabilize the topoisomerase I-mediated cleavable complex. The two analogs (ST1976 and ST1968) characterized by the presence of a free amino group in the side chain also exhibited the formation of persistent cleavable complexes. The most potent compound, ST1976 (7-(4-aminobenzyl)oxyiminomethylcamptothecin), was selected for evaluation of its preclinical profile of antitumor activity in a large panel of human tumor xenografts. As expected on the basis of the introduction of a hydrophilic substituent, the novel camptothecin was a substrate for BCRP. However, in spite of an apparent recognition by BCRP, ST1976 was effective following oral administration. The antitumor activity was evaluated using various schedules and routes of administration (i.v. and p.o.). ST1976 exhibited a remarkable activity in all tested tumors and was effective in a number of tumors which are resistant to irinotecan. The biological and pharmacological profile of ST1976 supports the therapeutic potential of camptothecins containing hydrophilic substituents at the 7-position. On the basis of its excellent activity in preclinical models, ST1976 is a promising candidate for clinical development.

Intralesional topotecan in advanced ovarian cancer: a clinical report, based on a preclinical study.

The aim of this study was to evaluate the response of ovarian cancer to intralesionally administered topotecan. Preliminary experiments were carried out in nude mice subcutaneously grafted with three different human ovarian carcinoma cells (A2780, IGROV/DDP and SKOV-3). Topotecan was administered intravenously (i.v.: 10-15 mg/kg every 4th day for 4 times) or intralesionally (i.t.: single dose of 15-20 mg/kg) and tumor size changes/drug toxicity were evaluated. The results indicate that the sensitivity of the three tumor models was different (rank: A2780 > IGROV/DDP > SKOV-3) but, for each tumor line, the pattern of response was similar after i.v. and i.t. administration. No local toxicity was detected, but appreciable systemic toxicity (animal death rate) was observed in spite of the use of a single i.t. dose. The effects of intralesional topotecan administration were then assessed in a patient with an advanced, epithelial ovarian tumor (endometroid type, poorly differentiated histologic grade), already treated with cisplatin and paclitaxel. The treatment (7.5 mg/m(2)) was repeated three times and, although drug plasma levels were in the range generally reported following i.v. administration and typical systemic toxicity occurred, no tumor regression was observed and the patient died 14 months later. We conclude that the intralesional drug delivery is effective to achieve a rapid tumor shrinkage in large tumor lesions, but in the presence of drug resistance, either intrinsic or acquired, intratumor drug administration can not be recommended.