Phase 1B Trial With PTC-596 in High-Grade Serous Ovarian Cancer: A Targeted Approach Toward Chemoresistant Stem-Like Cancer Cells
[Technical Report, Annual Report]
UNIVERSITY OF OKLAHOMA
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This study, utilizes a second generation BMI1 inhibitor which has the potential to block development of platinum resistance among patients receiving neo-adjuvant chemotherapy NACT. Use of NACT is only increasing and with this certainly come safer surgeries, which is a great benefit. However - early development of platinum resistance is a likely consequence as well. The ability to thwart this is being tested, via inhibition of the proto-oncogene BMI1, which results in downregulation of the multidrug resistance gene 1, which prevents cisplatin induced chemotherapy cross resistance as well as inhibits glutathione production which decreases the export of cisplatin from tumor cells. Preclinical studies in mice models have shown that inhibition of BMI1 could significantly inhibit ovarian tumor growth and combination with cisplatin could abrogate ovarian tumor growth in mice model. Therefore we have undertaken a phase 1, 3x3 dose escalation study to determine the maximum tolerated dose of the BMI1 inhibitor that can be given in combination with standard-of-care carboplatin and paclitxel. When accrual is completed efficacy in terms of pharmaco-dynamic pathway alterations will also be addressed. This combination chemotherapy has the potential to maintain the high levels of initial response seen in epithelial ovarian cancer while preventing development of resistant clones which may help to prevent or prolong the time to recurrence and hopefully impact on survival.
- Medicine and Medical Research
- Anatomy and Physiology