Stromal Content in Prostate Cancer Correlates with Responses to Docetaxel and Prognosis

Docetaxel can deliver survival benefit to patients with metastatic castrate resistant prostate cancer (mCRPC). However, 50% of patients do not respond, and responders will eventually progress. Improving response rates or duration to docetaxel will ensure greater benefit can be achieved for mCRPC patients. We have previously shown that tumours stratify into two phenotypes based on tumour-stromal architecture; stromal-vessel (SV; high stromal content, complex) and tumour-vessel (TV; low stromal content, simple)¹. The majority of prostate tumours exhibit a SV phenotype, so we explored whether this dense stromal compartment contributes to tumour insensitivity to chemotherapy by impeding drug penetration, delivery, and efficacy. To evaluate this, 24 PDX prostate cancer models (LuCaP) were phenotyped for stromal content using immunoflourescent (IF) staining for α-Smooth muscle actin (αSMA) and CD31. Those with a SV phenotype (4/5) were resistant to docetaxel, while those with a TV phenotype (14/16) were highly responsive. In order to test the effect of stromal modulating agents on the response to docetaxel, four of these LuCaP models have been optimised for ex vivo tissue slice culture, acting as a 3D model to study the tumour microenvironment. Furthermore, immunohistochemical (IHC) staining of αSMA/CD31 was used to phenotype a cohort of FFPE prostate cancer biopsies and with the use of image analysis software HALO, stromal content and architecture was shown to significantly impact on prognosis, and in this cohort, was a better prognostic biomarker than Gleason, (p<0.05). Collectively, this data suggests that tumour stroma plays an important role in prostate cancer progression and that stromal modulation may be a means of improving drug delivery and response in this disease setting.

(1) Smith et al., Clin Cancer Res 2013 19(24):6943-6956.