Dr Nasioudis on the Potential for XPO1 Inhibition in TP53 Wild-Type Ovarian Cancer

“We did see significant antitumor activity of XPO1 [inhibition with] selinexor, both in vitro as well as in vivo, and we did not see as good activity in TP53-mutant tumors. We do feel that these results indicate that this genomic characteristic—[TP53 wild-type]—can be capitalized on in the clinic with XPO1 inhibition.”

Dimitrios Nasioudis, MD, assistant professor, obstetrics and gynecology, Perelman Center for Advanced Medicine, the University of Pennsylvania, discusses findings from a preclinical study regarding the use of XPO1 inhibition in low-grade serous (LGSOC) and clear cell ovarian cancer (CCOC).

Approximately 95% of patients with LGSOC and 85% of patients with CCOC do not harbor TP53 mutations, Nasioudis explains. TP53 is a gene that encodes P53, a key protein that acts as a tumor suppressor, he continues. However, he notes that this genomic finding has not translated into a therapeutic strategy. Thus, Nasioudis and colleagues hypothesized that utilizing XPO1 inhibition with selinexor (Xpovio) could lead to effective antitumor activity. XPO1 exports TP53 genes from the nucleus to the cytoplasm, he says, which is why inhibiting it may be an effective target.

Nasioudis explains that the results of the study, which were presented at the 2024 SGO Annual Meeting on Women’s Cancer, showed significant antitumor activity in vitro and in vivo with the use of selinexor. However, antitumor activity was lower in TP53-mutant tumors, he says. The result of their findings demonstrated that XPO1 inhibition could serve as a potential therapeutic strategy for patients with TP53 wild-type LGSOC or CCOC, according to Nasioudis.

He states that the next steps of research will include exploring the mechanism of resistance to XPO1 inhibition in vitro and in vivo. Following this step, he and his colleagues will try to capitalize the results from the study through an early phase clinical trial with patients with LGSOC and CCOC, Nasioudis concludes.