Abstract 2691: Smo-targeted sonic hedgehog signaling inhibitor enhances therapeutic antibody deposition and efficacy in a patient-derived pancreatic ductal adenocarcinoma model
Authors: Wang Jun , Qu Yang , Pitoniak Rose , Trueman-Fatallah Sheryl A. , Hylander Bonnie L. , Repasky Elizabeth A. , Ma Wen Wee , Straubinger Robert M. 
Published: May 2015

Tumor stroma supports growth, invasion, and treatment resistance of pancreatic ductal adenocarcinoma (PDAC), and in conjunction with hypovascularity, constitutes a barrier that minimizes tumor cell drug exposure. Targeting tumor stroma is an attractive strategy in PDAC, and Smo-binding inhibitors are reported to mediate stromal thinning and increased microvessel density in PDAC models.

No information exists as to the effect of sHHI upon deposition of macromolecular therapeutic agents such as monoclonal antibodies (mAb). Therefore we investigated effects of sHHI LDE225 upon tumor vascularity, mAb deposition, and mAb therapeutic efficacy in a patient-derived xenograft (PDX) model of PDAC in SCID mice.

PDAC tumor #18269 was established in SCID mice and has retained abundant stroma and low microvessel density reminiscent of the original patient tumor. It expresses EGF receptor. Tumor-bearing mice were dosed orally with LDE225 (40 mg/kg) for 10 days, and pharmacodynamic biomarkers of sHHI effect were quantified. Mouse-specific TaqMan probes demonstrated high Gli1 expression in stromal cells, which was deeply suppressed within 3 days of sHHI dosing. Human-specific probes showed little Gli1 expression in tumor cells and no effect of sHHI treatment. Over 10 days of sHHI treatment, tumor microvessel density did not change significantly (based on CD31 staining), but the fraction of functional vessels increased significantly by day 7 (based on staining with fluorescent Lycopersicon esculentum lectin injected IV prior to tumor harvest).

Fluorescently labeled mAbs that were tumor-targeted (cetuximab; anti-EGFR) or non-targeted (anti-topotecan) were co-injected on d7 of sHHI treatment. Compared to untreated controls, tumor exposure (AUC) of cetuximab more than doubled, and was observed to distribute to regions of the tumor enriched in tumor cells. Deposition of non-targeted mAb also was increased relative to controls, but distributed more to stromal areas than tumor cell areas.

To investigate whether the enhanced deposition of cetuximab mediated by sHHI pretreatment would enhance efficacy, cetuximab was administered on d 5, 8, 11 of a 10-day sHHI or vehicle (control) regimen. This sequence was repeated 6 times, with an inter-cycle gap of 5 days. Rituximab (anti-human CD20) was the non-targeted control. Cetuximab alone showed no therapeutic benefit. However, cetuximab combined with sHHI suppressed tumor progression for more than 80 days, and median time to study endpoint was more than 250% longer than for all other treatment groups except sHHI-alone, which mediated a 30% increase.

Conclusions: increased perfusion and vascular permeability mediated by sHHI pretreatment permits access of therapeutic mAb to otherwise inaccessible regions of the tumor interior, and reveals anti-tumor activity of a mAb that previously failed clinically for PDAC treatment.

Citation Format: Jun Wang, Yang Qu, Rose Pitoniak, Sheryl A. Trueman-Fatallah, Bonnie L. Hylander, Elizabeth A. Repasky, Wen Wee Ma, Robert M. Straubinger. Smo-targeted sonic hedgehog signaling inhibitor enhances therapeutic antibody deposition and efficacy in a patient-derived pancreatic ductal adenocarcinoma model. [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 2691. doi:10.1158/1538-7445.AM2014-2691