Introduction: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women. Dysregulation of the WNT/β-catenin pathway is the most commonly mutated pathway in CRC. R-spondins (RSPO), a family of secreted proteins, are enhancers of WNT signaling. Previous preclinical studies have demonstrated that WNT inhibition results in superior antitumor efficacy in combination with taxanes. This superior combinatorial activity with taxanes has been identified in lung, ovarian, breast and pancreatic cancers. Taxanes have been found to be generally ineffective in the clinical treatment of colorectal cancer. Analysis of the local microenvironment, or stem cell niche, has identified stromal cells as an abundant source of RSPO. In patient-derived tumor xenografts (PDX), the murine stromal cells replace human stromal cells and provide the microenvironment that supports tumor cell growth. We have classified PDX tumors as human RSPO3 high or low/negative using RNA sequencing and by expression studies. Inhibition of RSPO3 with OMP-131R10, a clinical stage therapeutic antibody which binds to human and murine RSPO3, has demonstrated efficacy in human RSPO3 high, APCWT PDX.
Purpose: Common features in CRC are mutations in APC or β-catenin which are present in approximately 90% of cases. Tumors with RSPO3 genomic translocation and/or overexpression of RSPO3 are generally APC WT and β-cateninWT, and thus RSPO overexpression represents an alternative mechanism to upregulate the Wnt pathway. Alternatively, RSPO3 may be secreted by murine stromal cells, or by a rare population of tumor cells. In this study, we tested OMP-131R10 in combination with taxane treatment in human RSPO3 low CRC PDX models with APC or β-catenin mutations and in a PDX model with a RSPO3 translocation.
Results: Anti-RSPO3 was highly effective in combination with nab-paclitaxel in a CRC model with an RSPO3 translocation and RSPO3 overexpression. Furthermore, the combination of OMP-131R10 and taxane treatment resulted in synergistic inhibition of tumor growth in 8/10 PDX models with APC or β -catenin mutations and low human tumor cell RSPO3 expression. Tumor regression or durable stable disease was evident in 6/8 models. Responsive models contained either heterozygous inactivating mutations in APC (6/8) or homozygous activating mutations in β-catenin (2/8). Combination of OMP-131R10 with paclitaxel potentiated mitotic arrest, enhanced terminal differentiation and reduced the tumorigenic cell frequency by 40 fold based on serial transplantation studies.
Conclusion: Anti-RSPO3 (OMP-131R10) was active in the majority of CRC PDX models tested when combined with taxane treatment. These CRC models harbored mutations in APC and β-catenin. This data indicates that RSPO3 inhibition is an effective means to target the mutated Wnt pathway in CRC, and that antagonizing RSPO3 in combination with paclitaxel may improve survival for CRC patients.
Citation Format: Marcus M. Fischer, V. Pete Yeung, Fiore Cattaruzza, Christopher Murriel, James W. Evans, Gilbert O'Young, Alayne Brunner, Min Wang, Belinda Cancilla, Ann Kapoun, Timothy Hoey. R-SPONDIN3 antagonism sensitizes colorectal cancer to taxane treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1911. doi:10.1158/1538-7445.AM2017-1911