Abstract PD9-11: Platelet derived growth factor receptor-β signaling: A novel therapeutic target for breast cancer associated brain metastasis

Abstract

Abstract PDGFRβ is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand, PDGFB, is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stromal signaling mediates breast cancer initiation, progression, and metastasis remains unclear. To test this important research question, we developed a mouse model of mesenchymal-specific PDGFRβ hyper-activation. PDGFRβ mutant mammary glands exhibit increased tertiary side-branching and epithelial proliferation confirming a stromal-specific PDGFRβ effect on neighboring epithelium during normal development. To test the effect of hyper-active mesenchymal PDGFRβ on disease progression, experimental tail vein metastasis assays were performed where we observed prominent brain metastases in 50% of the PDGFRβ mutantmice (n=5/10) with no brain lesions seen in controls (n=0/19). There was no difference in the incidence of lung or liver metastases in the mutant mice suggesting a pro-metastatic function for PDGFRβ in the brain metastatic niche. To rule out dysfunction of the blood brain barrier contributing to the observed metastatic spread, we then intracranially injected mammary tumor cells, and as expected based on our metastasis assay, found that larger tumors formed in the brains of PDGFRβ mutant mice versus controls. To our knowledge, these combined findings are the first example where genetic manipulation of the stroma increases breast cancer associated brain metastases (BCBM). Given that these pre-clinical data suggest that primary breast tumors expressing high PDGFB could preferentially metastasize to the brain, we analyzed PDGFB protein expression in a tissue microarray comprised of HER2-positive and triple negative breast cancer (TNBC) primary tumors (total n=425). While high PDGFB did not correlate with site-independent metastatic recurrence, it was prognostic of brain metastasis, mirroring our mouse data. Evaluation of PDGFB in a small cohort of matched primary breast tumors with associated brain (n=5) and lung metastases (n=2) revealed intense PDGFB staining in 100% of the brain metastases, but only 50% of the lung metastases. These findings further suggest that high primary tumor PDGFBexpression defines a subset of breast cancer patients predisposed to brain metastases and that these patients may benefit from therapeutic inhibition of PDGFRβ signaling. To test this pre-clinically, we treated mice harboring intracranial tumors with the PDGFR specific inhibitor crenolanib. Excitingly, crenolanib treatment significantly inhibited the brain tumor burden in these mice. Combined, our findings to date (1) advocate that primary tumor expression of PDGFB is a novel prognostic biomarker for the development of BCBM and (2) support clinical trial evaluation of PDGFR inhibitors for the prevention and treatment of BCBM. Ongoing studies are evaluating how the PDGFRβ-expressing mesenchymal cells within the brain promote a pro-metastatic niche. Citation Format: Sizemore GM, Hammer AM, Thies KA, Hildreth BE, Russell LO, Sizemore ST, Trimboli AJ, Kladney RD, Steck SA, Das M, Bolyard CM, Pilarski R, Schoenfield L, Otero J, Chakravarti A, Ringel M, Kaur B, Leone G, Ostrowski MC. Platelet derived growth factor receptor-β signaling: A novel therapeutic target for breast cancer associated brain metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD9-11.