Targeting YB-1 to overcome chemoresistance in ovarian cancer

/ABSTRACT Ovarian cancer is the most lethal gynecological malignancy, with most patients succumbing to recurrent disease due to resistance to available treatments. The primary treatment regimen—surgery followed by platinum- or taxane-based chemotherapy—offers limited long-term success, as 85-90% of women diagnosed with late-stage disease will recur post adjuvant combination chemotherapy, a highly undesirable outcome largely driven by the development of treatment resistance. Once ovarian cancer recurs, available treatments are palliative. The lack of treatment options for these patients is a critical unmet need in the clinic; we propose this need can be addressed with a novel therapeutic approach that directly addresses treatment resistance in recurrent patients. One such approach is to therapeutically inhibit Y-Box Binding Protein 1 (YB-1), a stress-responsive, multifunctional protein implicated in ovarian cancer progression and treatment resistance. Beyond its routine cellular roles in RNA stability, splicing, translation, cell proliferation, and DNA damage repair, YB-1 overexpression in ovarian cancer is associated with faster progression, increased metastasis, and higher mortality. This association with poor prognosis may be driven, in part, by YB-1’s contributions to treatment resistance, as YB-1 is associated with ovarian cancer resistance to cisplatin and paclitaxel. This dual role in ovarian cancer progression and treatment resistance makes YB-1 a compelling therapeutic target. We propose to therapeutically inhibit YB-1 using SU056, our novel azapodophyllotoxin that is, to our knowledge, the only small molecule inhibitor of YB-1. SU056 binds to YB-1, inducing ovarian cancer cell cycle arrest, apoptosis, and inhibition of ovarian cancer cell proliferation and migration. Importantly, both in vitro and in vivo, ovarian cancer cells are sensitive to SU056 single agent therapy and sensitized to paclitaxel in the presence of SU056. Our preliminary data suggests that SU056 decreases expression of the multi-drug efflux pump, MDR1, thereby reducing paclitaxel efflux and enhancing chemotherapy sensitivity. Because MDR1 upregulation is associated with treatment resistance against chemotherapies, this data suggests one mechanism by which SU056 could sensitize cells to chemotherapies commonly used to treat ovarian cancer. Building on this preliminary data, our central hypotheses are that YB-1 inhibition by SU056 effectively restrains tumor growth in chemoresistant ovarian cancer models, both as a single agent therapy and in combination with standard chemotherapies. Our goals are to 1) Elucidate mechanisms of SU056 single-agent activity; 2) Identify pathways of chemoresistance targeted by SU056; and 3) Evaluate SU056’s synergy with existing ovarian cancer treatments. Given the dismal prognosis for recurrent ovarian cancer, this research is significant because inhibiting YB-1 represents a highly promising therapeutic strategy, and through YB-1 inhibition, SU056 has high potential to increase sensitivity to available therapies, overcome treatment resistance, and improve outcomes for ovarian cancer patients. Project Number: 1R01CA299328-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: SANJAY MALHOTRA | Institution: OREGON HEALTH & SCIENCE UNIVERSITY, PORTLAND, OR | Award Amount: $356,850 | Activity Code: R01 | Study Section: Mechanisms of Cancer Therapeutics C Study Section [MCTC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11293624