Insulin-like growth factors (IGFs) and insulin acting via the type I IGF receptor (IGF1R) and insulin receptor (IR) respectively regulate biology of estrogen positive (ER+) and triple negative (TN) breast cancer cells. In animal models, inhibition of IGF1R alone with antibodies has demonstrated significant inhibition of tumor growth and/or metastasis of several types of cancer cells. Unfortunately, the results of initial clinical trials with anti-IGF1R antibodies have been disappointing. One reason for this is that inhibition of the related IR through which insulin and IGF-II signal, may be necessary for optimal efficacy of this targeted approach. Second, there is a need to develop markers that can be used to stratify patients who may benefit from these drugs and/or monitor response to these drugs.
To examine the effectiveness of dual inhibition of IGF1R and IR, we evaluated the effects of BMS-754807, a small molecule dual tyrosine kinase inhibitor of IGF1R/IR on ER+ and TN breast cancer cells. In ER+ cells (MCF-7, T47D and ZR-75-1), BMS-754807 inhibited IGF-I, IGF-II and insulin stimulated activation of downstream PI3K and MAPK pathways, proliferation and anchorage-independent growth in vitro. BMS-754807 also blocked signaling in MCF-7 tumors and inhibited xenograft growth of MCF-7 tumors (n=10 per treatment) compared to vehicle. Interestingly, while tumor growth was suppressed over a period of five weeks, eventually the tumors displayed resistance to BMS-754807. In TN cell lines (MDA-MB-231; MDA-MB-231-LM2 and MDA-231-BoM, lung seeking and bone specific metastatic variants respectively of MDA-MB-231; and MDA-MB435A/LCC6) BMS-754807 also inhibited activation of the PI3K pathway and motility in vitro. In contrast to ER+ cells, BMS-754807 did not inhibit primary tumor growth of TN breast cancers cells injected into the mammary fat pad of mice. But BMS-754807 (50 mg/kg daily by oral gavage) inhibited metastasis of TN cells, MDA-231-LM2 and MDA-MB435A/LCC6 cells, in the orthotopic and tail vein models of metastasis compared to vehicle (n=10/group). Our data indicate that regulation of metastases and tumor growth by IGF1R can be discrete events and functional imaging to identify biological properties of metastatic breast cancer regulated by IGF1R/IR are needed to better define treatments. Therefore, we used a novel MR sequence called sweep imaging with Fourier transformation (SWIFT), where the data is acquired quasi-simultaneously with the radiofrequency pulse, to monitor response to BMS-754807. We used MDA-231-LM2 cells with the tail vein injection model of metastasis. Mice injected with breast cancer cells were treated with either vehicle or BMS-754807 and metastasis was monitored by BLI and SWIFT MRI weekly. SWIFT was sensitive in detecting inhibition of metastasis by BMS-754807.
Our results suggest that dual inhibition of IGF1R and IR is effective in blocking growth of ER+ and metastasis of TN breast cancers. However, combination of this therapeutic strategy with other agents may be necessary to prevent or delay onset of resistance. Further, noninvasive biomarkers of response to IGF1R/IR targeted drugs can be developed with SWIFT imaging.
Citation Format: Deepali Sachdev, Joel D Winer, Naoharu Kobayashi, Michael Garwood, Joseph Weber. Dual inhibition of IGF1R and insulin receptor in estrogen receptor positive and triple negative breast cancer and monitoring blockade of metastasis using novel MRI [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-03.