Development of UR238, the First Small-Molecule Inhibitor of HE4 for Treatment of Ovarian Cancer
Abstract
Scientific Objectives: This study aims the bench-to-bedside translation of biomarker HE4 targeted novel therapeutic candidate UR238 developed in our laboratory. Rationale: Our ongoing studies suggest that HE4 overexpression leads to tumor immune evasion and causes resistance against cisplatin and Taxanes. A targeted therapy against HE4 is urgently needed to control HE4 orchestrated ovarian tumorigenesis. Who Will Be Helped: Serous, endometrioid and a portion of clear cell ovarian carcinoma who overexpress HE4 will benefit from UR238 as single agent or in combination with mechanism-based co-therapeutics identified under the aegis of this proposal. In addition, endometrial and a subset of breast cancer patients who overexpress HE4 will likely be the beneficiaries. Potential Clinical Benefits: 1. UR238 will likely block HE4 orchestrated tumor immune evasion. Our studies show that HE4 overexpression promotes increased expression of immune checkpoint inhibitor ligand PD-L1 on tumor cells and on the tumor associated macrophages, resulting into reduced CD8+T cell infiltration in ovarian tumors. In addition, HE4 overexpression caused immune suppressive myeloid switch to facilitate immune surveillance. 2. UR238 will likely abrogate HE4-mediated chemoresistance against cisplatin and paclitaxel. A majority of ovarian cancer patients recur shortly after nearly complete response to platinum+taxanes presenting an aggressive disease that is broadly chemoresistant to progressive lines of therapies, eventually leading to death due to lack of effective therapies in the new setting. 3. Our newly generated data indicate that HE4 is overexpressed in metastasis. It is anticipated that UR238 will block HE4 orchestrated metastasis in ovarian cancer patients and force the disease to remain localized. Risk: Since HE4 expression is mostly restricted to ovaries and other reproductive organs with relatively limited expression seen in lungs and arial pathways, targeting HE4 with UR2238 is unlikely to affect the rest of the vital organs. Similarly, hematopoiesis will not be affected due to HE4 inhibition because hematopoietic cells functions HE4 independently, diminishing the overall risks associated with HE4 targeting greatly. Projected Time to Clinically Relevant Outcome: Proof-of-concept data have already been generated in ovarian and endometrial cancer models. Successful completion of this proposal will enable us to initiate UR214-9 in clinical trials within the next 2-3 years. If the goals of the phase-0/1 are met, UR238 can be brought to clinics in 9-12 years. Likely Impact of This Study on the OCRP’s Mission to End Ovarian Cancer: Ovarian cancer is one of the most lethal malignancies that women of both civilian and military families face. Previously, our laboratory led the efforts to earn U.S. FDA approval of HE4 as the biomarker for detecting and monitoring ovarian cancer. Now, this field-leading study aims to translate HE4 biology into a therapeutic agent for treatment of ovarian cancer. UR238 is likely to be selective to ovarian carcinoma cells and will spare most of the vital organs and hematopoiesis, meeting or exceeding the stated missions of the OCRP. Mitigating the undesired side effects to vital organs of the body and indiscriminate destruction of fast diving hematopoietic cells arising from the currently used cytotoxics remains the major unmet challenge in the management of ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110331
Entities
People
- Richard Moore
Organizations
- United States Army
- University of Rochester