Folate Receptor Alpha Protein Expression in Ovarian Serous Cystadenocarcinoma Tumors of The Cancer Genome Atlas: Exploration Beyond Single-agent Therapy

Overview

Journal medRxiv

Date 2024 Apr 22

PMID 38645083

Authors

Christianne Persenaire

Benjamin G Bitler

Bradley R Corr

Affiliations

Soon will be listed here.

Abstract

Epithelial ovarian cancer (EOC) can be highly lethal, with limited therapeutic options for patients with non-homologous recombination deficient (HRD) disease. Folate receptor alpha (FOLR1/FRα)-targeting agents have shown promise both alone and in combination with available therapies, but the relationship of FRα to other treatment-driving biomarkers is unknown. The Cancer Genome Atlas (TCGA) was queried to assess protein and mRNA expression and mutational burden in patients with differential FRα protein-expressing ovarian tumors, and the results referenced against the standard 324 mutations currently tested through FoundationOne Companion Diagnostics to identify targets of interest. Of 585 samples within TCGA, 121 patients with serous ovarian tumors for whom FRα protein expression was quantified were identified. FRα protein expression significantly correlated with FOLR1 mRNA expression (p=7.19×10). Progression free survival (PFS) for the FRα-high group (Q1) was 20.7 months, compared to 16.6 months for the FRα-low group (Q4, Logrank, p=0.886). Overall survival (OS) was 54.1 months versus 36.3 months, respectively; however, this result was not significant (Q1 vs. Q4, Logrank, p=0.200). Mutations more commonly encountered in patients with high FRα-expressing tumors included PIK3CA and FGF family proteins. Combinations of FRα-targeting agents with PI3K, mTOR, FGF(R) and VEGF inhibitors warrant investigation to evaluate their therapeutic potential.

References

Shimizu T, Fujiwara Y, Yonemori K, Koyama T, Sato J, Tamura K . First-in-Human Phase 1 Study of MORAb-202, an Antibody-Drug Conjugate Comprising Farletuzumab Linked to Eribulin Mesylate, in Patients with Folate Receptor-α-Positive Advanced Solid Tumors. Clin Cancer Res. 2021; 27(14):3905-3915. DOI: 10.1158/1078-0432.CCR-20-4740. View

Cheung A, Bax H, Josephs D, Ilieva K, Pellizzari G, Opzoomer J . Targeting folate receptor alpha for cancer treatment. Oncotarget. 2016; 7(32):52553-52574. PMC: 5239573. DOI: 10.18632/oncotarget.9651. View

Krook M, Reeser J, Ernst G, Barker H, Wilberding M, Li G . Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance. Br J Cancer. 2020; 124(5):880-892. PMC: 7921129. DOI: 10.1038/s41416-020-01157-0. View

OMalley D, Matulonis U, Birrer M, Castro C, Gilbert L, Vergote I . Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2020; 157(2):379-385. DOI: 10.1016/j.ygyno.2020.01.037. View

Ponte J, Ab O, Lanieri L, Lee J, Coccia J, Bartle L . Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha-Targeting Antibody-Drug Conjugate, Potentiates the Activity of Standard of Care Therapeutics in Ovarian Cancer Models. Neoplasia. 2016; 18(12):775-784. PMC: 5126132. DOI: 10.1016/j.neo.2016.11.002. View

Moore K, OMalley D, Vergote I, Martin L, Gonzalez-Martin A, Malek K . Safety and activity findings from a phase 1b escalation study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with carboplatin in patients with platinum-sensitive ovarian cancer. Gynecol Oncol. 2018; 151(1):46-52. DOI: 10.1016/j.ygyno.2018.07.017. View

Konstantinopoulos P, Barry W, Birrer M, Westin S, Cadoo K, Shapiro G . Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. Lancet Oncol. 2019; 20(4):570-580. PMC: 7025391. DOI: 10.1016/S1470-2045(18)30905-7. View

Walters C, Arend R, Armstrong D, Naumann R, Alvarez R . Folate and folate receptor alpha antagonists mechanism of action in ovarian cancer. Gynecol Oncol. 2013; 131(2):493-8. DOI: 10.1016/j.ygyno.2013.07.080. View

Pignata S, Cecere S, Bois A, Harter P, Heitz F . Treatment of recurrent ovarian cancer. Ann Oncol. 2017; 28(suppl_8):viii51-viii56. DOI: 10.1093/annonc/mdx441. View

10.

Lee E, Liu J . Antibody-drug conjugates in gynecologic malignancies. Gynecol Oncol. 2019; 153(3):694-702. DOI: 10.1016/j.ygyno.2019.03.245. View

11.

Gasparri M, Bardhi E, Ruscito I, Papadia A, Farooqi A, Marchetti C . PI3K/AKT/mTOR Pathway in Ovarian Cancer Treatment: Are We on the Right Track?. Geburtshilfe Frauenheilkd. 2017; 77(10):1095-1103. PMC: 5658232. DOI: 10.1055/s-0043-118907. View

12.

Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo H . Alpelisib for -Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019; 380(20):1929-1940. DOI: 10.1056/NEJMoa1813904. View

13.

Moore K, Oza A, Colombo N, Oaknin A, Scambia G, Lorusso D . Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I. Ann Oncol. 2021; 32(6):757-765. DOI: 10.1016/j.annonc.2021.02.017. View

14.

Konner J, Bell-McGuinn K, Sabbatini P, Hensley M, Tew W, Pandit-Taskar N . Farletuzumab, a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian cancer: a phase I study. Clin Cancer Res. 2010; 16(21):5288-95. DOI: 10.1158/1078-0432.CCR-10-0700. View

15.

Naumann R, Coleman R, Burger R, Sausville E, Kutarska E, Ghamande S . PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2013; 31(35):4400-6. DOI: 10.1200/JCO.2013.49.7685. View

16.

Manzano A, Ocana A . Antibody-Drug Conjugates: A Promising Novel Therapy for the Treatment of Ovarian Cancer. Cancers (Basel). 2020; 12(8). PMC: 7464539. DOI: 10.3390/cancers12082223. View

17.

Mishra R, Patel H, Alanazi S, Kilroy M, Garrett J . PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. Int J Mol Sci. 2021; 22(7). PMC: 8037248. DOI: 10.3390/ijms22073464. View

18.

Ruan G, Kazlauskas A . Axl is essential for VEGF-A-dependent activation of PI3K/Akt. EMBO J. 2012; 31(7):1692-703. PMC: 3321201. DOI: 10.1038/emboj.2012.21. View

19.

Karakas B, Bachman K, Park B . Mutation of the PIK3CA oncogene in human cancers. Br J Cancer. 2006; 94(4):455-9. PMC: 2361173. DOI: 10.1038/sj.bjc.6602970. View

20.

LoRusso P, Edelman M, Bever S, Forman K, Pilat M, Quinn M . Phase I study of folate conjugate EC145 (Vintafolide) in patients with refractory solid tumors. J Clin Oncol. 2012; 30(32):4011-6. PMC: 4104289. DOI: 10.1200/JCO.2011.41.4946. View