Effect of plasma SPARC on outcome in cancer models.

Abstract

10600 Background: SPARC is overexpressed in many cancers, including melanoma, breast, lung, and pancreas. SPARC overexpression in tumors enhances progression, angiogenesis, and metastasis and is generally associated with poor prognosis. However, plasma SPARC levels have not been previously investigated in relation to outcomes in cancer. Methods: Plasma SPARC level in melanoma patients (pts, n = 321 from 76 pts, baseline and post-treatment) was compared to normal controls (n = 50 from 50 pts) using a validated SPARC ELISA. Human SPARC protein was overexpressed in HEK293 cells and purified. Angiogenic activity of SPARC was tested in a 3D HUVEC tube formation assay. HT29 (colon), PC3 (prostate), MDA-MB-231 (breast) xenografts with a range of SPARC expression were grown in nude mice and treated with 5FU, docetaxel, nab-paclitaxel [nab-P], or nab-P + sunitinib with or without exogenously administered SPARC (IP, 200 mg/mouse, 2x wkly). The effect of exogenous (exo) SPARC and an anti-SPARC antibody (IP, 200 mg/mouse, 2x wkly) on lung metastases was examined in MDA-MB-435 (melanoma) or the syngeneic LL/2 (Lewis lung carcinoma) model. Results: Plasma SPARC levels were higher in melanoma pts than normal controls (259 ng/ml [95% CI = 273-327] vs 153 ng/ml [95% CI = 99-207], p < 0.0001). Exo SPARC counteracted antitumor activity of chemotherapy (chemo) in all xenografts. Exo SPARC also abolished synergy of nab-P with antiangiogenic agent sunitinib in vivo. In vitro, SPARC showed angiogenic activity which may partly explain the in vivo observations. Exo SPARC added to nab-P treatment resulted in a 3 fold increase in lung metastasic burden vs nab-P alone in MDA-MB- 435 xenografts. Conversely, SPARC antibody inhibited lung metastasis and increased survival of mice relative to a non-specific mouse IgG control (p = 0.02, log rank) in the LL/2 model. Conclusions: Plasma SPARC levels were higher in melanoma pts than normal controls. Exogenously administered SPARC in melanoma and other xenograft tumors counteracted the activity of chemo. In contrast, a SPARC antibody increased survival relative to controls. These data suggest that plasma SPARC may contribute to poor outcomes and a SPARC antibody may have potential applications in the treatment of cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abraxis BioScience Abraxis BioScience Abraxis BioScience Abraxis BioScience Abraxis BioScience