Login to Access Video or Poster Abstract: MP83-16
Sources of Funding: NCI

Introduction

Prostate cancer (PCa) is commonly overtreated, producing iatrogenic side effects in patients without longevity benefits. Active Surveillance (AS), long term monitoring of patients without intervention until there are clear signs of disease progression is an alternative to the use of surgery or radiation-based approaches. This approach can allow patients with clinically indolent diseases to avoid major interventions for prolonged periods. Two major groups who could benefit from new medical therapies used as an adjuvant to AS are: men resistant to AS because of fear of death, and men who do not meet the current stringent AS criteria. _x000D_ _x000D_ Prostate tumors are surrounded by cell populations that include fibroblasts, immune/inflammatory cells, nerves and endothelium that interact to produce a pro-proliferative local microenvironment that contributes to prostate cancer progression. We hypothesize that coordinated suppression of key signaling pathways within the microenvironment represents a potential approach to render selected prostate tumors functionally indolent. The aim is to develop approaches to combine low dose therapeutics as adjuvants to AS. This should allow more comfort for patients who dislike a &[Prime]passive&[Prime] approach and an expansion of the AS criteria to include more men. _x000D_

Methods

We tested the TGF-β receptor kinase inhibitor Galunisertib alone and in combination with the Btk kinase inhibitor Ibrutinib to coordinately suppress SDF1/CXCR4 and TGF-β signaling in benign, initiated and malignant human prostate epithelial cell lines in 2D and 3D culture in control and carcinoma associated fibroblast-conditioned medium (CAF-CM).

Results

In 2D culture in CAF-CM we showed effects of both drugs individually on inhibiting proliferation of target epithelial cells. We were also able to demonstrate that combining the two drugs at doses that, individually, had minimal effects on proliferation was sufficient to significantly reduce cell growth. Cells were more resistant to the effects of drugs in 3D culture. However this approach has a number of advantages, including the ability to examine phenotypic and organization of the epithelium and the response to drugs in terms of these markers. _x000D_

Conclusions

Initial studies demonstrate that benign epithelial cells are much less sensitive to drug effects than cells that have undergone tumor-initiating events. 3D culture provides a better model of the in vivo environment than 2D culture. The differences in response under the culture conditions illustrate important limitations to the 2D cell culture model.

Funding

NCI