Bryant, R. J. | Search bioRxiv

bioRxiv2020

Tumor irradiation combined with vascular-targeted photodynamic therapy enhances anti-tumor effects in preclinical prostate cancer.

RationaleThere is an important clinical need to improve the treatment of high risk localized and locally advanced prostate cancer (PCa), and to reduce the side effects of these treatments. We hypothesized that multi-modality therapy combining radiotherapy and vascular-targeted photodynamic therapy (VTP) could PCa tumour control compared against monotherapy with each of these treatments alone. This could provide proof-of-concept to take to the clinic. VTP is a focal therapy for localized PCa, which rapidly destroys targeted tumors through vascular disruption. Tumor vasculature is characterized by vessel immaturity, increased permeability, aberrant branching and inefficient flow. Fractionated radiotherapy (FRT) alters the tumor microenvironment and promotes transient vascular normalization. ObjectiveWe investigated whether sequential delivery of FRT followed by VTP 7 days later improves PCa tumor control compared to monotherapy with FRT or VTP alone. FindingsFRT induced vascular normalization changes in PCa flank tumor allografts, improving vascular function as demonstrated using dynamic contrast enhanced magnetic resonance imaging. FRT followed by VTP significantly delayed tumor growth in flank PCa allograft pre-clinical models, compared with monotherapy with FRT or VTP alone, and improved overall survival. ConclusionTaken together, these results suggest that combining FRT and VTP could become a promising multimodal clinical strategy in PCa therapy. This provides proof-of-concept for this multi-modality therapy approach to take forward to early phase clinical trials.

cancer biology↗

bioRxiv2020

Anti-androgens induce Rab11a-exosome secretion in prostate cancer by suppressing amino acid-sensitive PAT4-mTORC1 signalling

Advanced prostate cancer is typically treated with anti-androgens to reduce cancer growth, but patients almost inevitably develop treatment resistance and castration-resistant disease. Recently, extracellular vesicles known as exosomes, which are secreted from the endosomal compartments in which they are formed, have been implicated in drug resistance mechanisms. Here we investigate whether growth regulation by the amino acid-dependent kinase complex, mechanistic Target of Rapamycin Complex 1 (mTORC1), and associated extracellular vesicle secretion might be involved in the adaptive responses to anti-androgens. We show that expression and intracellular localisation of the glutamine-sensing PAT4 (SLC36A4) amino acid transporter is increased in malignant versus benign prostatic tissue, mirroring earlier in vivo fly studies suggesting that these transporters are more effective at promoting growth from internal versus cell surface membranes. Furthermore, androgens induce PAT4 expression in prostate cancer cell lines and PAT4 is required for a proportion of androgen-stimulated mTORC1 activation and growth. Consistent with previous studies in other cancer cell lines, we find that glutamine depletion, PAT4 knockdown and mTORC1 inhibition all independently increase the production of a specific exosome subtype, Rab11a-exosomes, which has recently been implicated in pro-tumorigenic signalling responses to mTORC1 inhibition. Furthermore, we show that these exosomes are also induced by anti-androgens. We hypothesise that the uptake of Rab11a-exosomes by cells with higher PAT4 levels could provide a growth-promoting boost, enabling them to out-compete others with lower PAT4 expression, resulting in tumours that are more resistant to nutrient-deprivation and anti-androgen treatment.

cancer biology↗