Abstract 4238: Exploring the therapeutic potential of IR and IGF-1R/IR (co-)targeting in ovarian cancer

Abstract

Abstract Ovarian cancer is the most lethal gynecological malignancy. Despite high response rates to platinum based therapies most patients relapse with resistant disease. For these patients novel therapeutic strategies are needed. Hyper-activation of the insulin-like growth factor receptor (IGF-1R) has been implicated in the development, progression and platinum resistance of ovarian cancer. However, targeting the IGF-1R has shown limited clinical benefit. The insulin receptor (IR), highly homologous to the IGF-1R, confers resistance to IGF-1R targeted therapies. Furthermore, in ovarian cancer alternative splicing results in the expression of IR-A & IR-B isoforms, while in normal adult tissues IR-B is the predominant isoform. Therefore targeting the IR or IR-A may be of clinical importance. In this study we determined the therapeutic potential of IR targeting in ovarian cancer. First, the expression levels of the IR isoforms, IGF-1R and stimulatory ligands IGF-I & II were determined in a panel of ovarian cancers and ovarian cancer cell lines of different histological subtype (endometrioid, clear cell, serous) using RT-PCR. IR isoforms and IGF-1R were expressed in 96% (43/44) and 78% (35/44) of the ovarian cancers compared to 89% (8/9) and 100% (9/9) of the ovarian cancer cell lines. IGF-I and IGF-II were expressed in all the ovarian cancers compared to 11% (1/9) and 0% (0/9) of the ovarian cancer cell lines, indicating the presence of an autocrine loop. In addition, all cell lines showed membrane receptor expression and functional downstream signaling upon IGF-I, IGF-II & insulin, via PI3K as determined by western blot and flow cytometry. Subsequently, we investigated which splicing factors may be involved in the IR alternative splicing. Expression of splicing factors (hnRNPA1A, hnRNA2B1, CELF1, SRSF1, hnRNPH, hnRNPF) were determined by qRT-PCR. However, expression levels did not correlate with IR isoform levels, indicating a more complex regulation of IR splicing. Finally, we determined the effect of IR, IGF-1R and IR/IGF-1R (co-)targeting by S961 (1000nM), MAB391 (20µg) and OSI906 (10µM), respectively on ovarian cancer cell survival by MTT and clonogenic assays. IR inhibition by S961 resulted in a decrease in cell viability up to 40% in 7/9 ovarian cancer cell lines. Preliminary data showed similar results upon IGF-1R/IR inhibition with OSI906. IGF-1R inhibition by MAB391 did not affect cell viability. Furthermore a reduction in clonogenic capacity (75%) by OSI906 is observed in 2/3 ovarian cancer cell lines tested. In conclusion, in ovarian cancer functional IR and IGF-1R signaling as well as the presence of a possible autocrine loop may contribute to ovarian cancer pathogenesis and progression. Targeting IR signaling with the IR-antagonist S961 and co-targeting IR/IGF-1R signaling by OSI906 reduced ovarian cancer cell viability, indicating its therapeutic potential in ovarian cancer. Funded by the Dutch Cancer Foundation: Grant RUG 2011-5231 Citation Format: Jolanda A.L. Visser, Roelien A.M. Meijering, Anne K.L. Reyners, Ate G.J. van der Zee, Steven de Jong. Exploring the therapeutic potential of IR and IGF-1R/IR (co-)targeting in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4238. doi:10.1158/1538-7445.AM2014-4238