Preclinical Data Suggest XPO1 Offers Potential Treatment Pathway in TP53 Wild-Type LGSOC and CCOC

Dimitrios Nasioudis, MD

XPO1 inhibition may represent a viable treatment approach for patients with TP53 wild-type low-grade serous ovarian cancer (LGSOC) and clear cell ovarian cancer (CCOC), according to promising preclinical findings presented by Dimitrios Nasioudis, MD, given during the 2024 SGO Annual Meeting on Women’s Cancer.¹

“Lack of TP53 mutations may be a therapeutic opportunity,” Nasioudis, a fellow in Gynecologic Oncology at the University of Pennsylvania in Philadelphia, and colleagues wrote in their presentation. “LGSOC, and CCOC are chemo-resistant histotypes of ovarian cancer. Approximately 80% of CCOC and [over] 95% of LGSOC tumors lack TP53 mutations. TP53, a tumor suppressor, regulates the G1-S checkpoint, and can induce tumor cell senescence or apoptosis. XPO1/CRM1 facilitates nucleo-cytoplasmic shuttling of p53 and other cell cycle regulatory and tumor suppressor proteins. [The] XPO1 inhibitorselinexor [Xpovio] is FDA approved in [the] management of relapsed multiple myeloma and diffuse large B-cell lymphoma [DLBCL].”

Selinexor initially gained accelerated approval from the FDA in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who previously received at least 4 lines of therapy and were refractory to a minimum of 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody. In December 2020, the agency granted selinexor plus bortezomib (Velcade) and dexamethasone regular approval for the treatment of adult patients with multiple myeloma who had received at least 1 previous line of treatment. In June 2020, the FDA granted accelerated approval to selinexor monotherapy for the treatment of patients with relapsed/refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, following at least 2 prior lines of systemic therapy.^2,3

Nasioudis et al hypothesized that the absence of TP53 mutations in patients with LGSOC and CCOC can be capitalized on via inhibition of XPO1. The investigators then highlighted preclinical data which showed that treatment with an XPO inhibitor has been shown to decrease viability and colony formation in TP53 wild-type ovarian cancer cell lines. However, inhibition of the protein in TP53-mutated ovarian cancer cell lines did not decrease cell viability. Following XPO inhibition, cell viability rates in the 3 TP53-mutated lines were all approximately 50% compared with approximately 25% across the 4 TP53 wild-type lines.¹

Nasioudis then noted that XPO inhibition has been shown to lead to the nuclear accumulation of the p53 protein in a dose-dependent manner. Additionally, treatment with an XPO1 inhibitor upregulates the p53 signaling pathway and downregulates the MAPK and PI3K-AKT signaling pathways. Subsequently, XPO1 inhibition activates the p53 downstream apoptosis pathway, Nasioudis said. He also presented findings from 2 organoid models of LGSOC which demonstrated that selinexor therapy decreased the cell viability of both of the models in a dose-dependent manner.

Finally, Nasioudis presented data from 3 patient-derived xenograft models. WO-81 had recurrent LGSOC that was TP53 wild-type, KRAS-mutated, ERa-positive, and had been exposed to prior chemotherapy. WO-166 had treatment-naive, TP53 wild-type primary LGSOC. WO-38 had TP53 wild-type primary CCOC harboring an ARID1A mutation.

Preclinical findings demonstrated that treatment with an XPO1 inhibitor displayed better control of tumor volume compared with control therapy across all 3 patient-derived xenograft models. Additionally, WO-38 (P = .0035), WO-81 (P = .019), and WO-166 (P = .005) all displayed a statistically significant increase in survival probability compared with the models that received the control treatment.

“Further investigation of the therapeutic potential of XPO1 inhibitormonotherapy in TP53 wild-type LGSOC and CCOCs is warranted,” Nasioudis et al wrote in conclusion.

References

1. Nasioudis D, Wang X, Xu H, et al. Capitalizing on the absence of TP53 mutations in low-grade serous and clear cell ovarian cancer with XPO1 inhibition.Presented at: 2024 SGO Annual Meeting on Women’s Cancer; March 16-18, 2024; San Diego, CA.
2. FDA approves selinexor for refractory or relapsed multiple myeloma. FDA. December 18, 2020. Accessed March 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selinexor-refractory-or-relapsed-multiple-myeloma
3. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. FDA. June 22, 2020. Accessed March 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selinexor-relapsedrefractory-diffuse-large-b-cell-lymphoma