Overcoming resistance: Remodelling the Prostate Cancer Microenvironment using Synthetic Liposomes

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Damien Leach, Charlotte Bevan, Anabel Varela-Carver (Cancer)James Hindley, Oscar Ces (Chemistry)Prostate cancer (PC) is the most commonly diagnosed and second-most lethal cancer diagnosed in UK men, with treatments for inoperable (or recurrent), therapy-resistant PC being the major clinical need. Although hormonal therapies are initially effective, progression to life-threatening castrate-resistant prostate cancer (CRPC) inevitably occurs. The PC tumour microenvironment acts in different ways to drive drug resistance, acting as a fibrotic mechanical barrier that prevents the penetration of drugs into the tumour. This high intratumoral pressure also results in a hypoxic tumour phenotype and reduced infiltration of T-cells, further driving drug resistance. Targeting the PC tumour microenvironment could therefore not only improve the performance of approved small molecule therapies (e.g. docetaxel) but synergise with promising immunotherapies such as checkpoint inhibitors that have to date shown limited effectiveness in CRPC. Further, the microenvironment of tumours differs between the primary and metastatic sites. PC patients with liver and other visceral metastases have worse prognosis than those in whom metastases are to the bone only. Furthermore, visceral metastasis are also less responsive to current PC therapeutics. We have shown that the microenvironment in both the primary site (prostate) and metastatic site (liver) is responsive to traditional hormonal therapies, and that the response of the microenvironment can promote conditions favourable for cancer growth, progression, and susceptibility to therapeutics.This multidisciplinary project aims to exploit and further develop a new approach to treat CRPC using a novel synthetic liposomal medicine that remodels the tumour microenvironment. This approach enables selective release of remodelling compounds into the microenvironment that reduce tumour fibrosis. This in turn reduces intratumoral pressure, increasing the penetration of therapeutics throughout the tumour and priming the tumour for further clinical intervention. In this project we will use 3D microenvironment models and also explant models (derived from biopsy material) to understand the effects of microenvironment-remodelling drugs in the context of both primary and metastatic tumours (e.g. liver metastases). We will investigate the effects of such treatments on the response of associated cancer cells to co-treatment with hormonal therapies and chemotherapies. We will use the same models and also in vivo models (xenografts, GEMMs) to test novel synthetic cells for delivery, using ex vivo (IHC, PCR, luminescence) and in vivo (e.g. shear wave elastography, in vivo imaging) assays to elucidate effects.This project offers a unique opportunity to develop a detailed understanding of both cancer biology (with a focus on the tumour microenvironment) and microfluidic engineering of advanced drug delivery systems. During the project, the fellow will help develop a variety of in vitro, ex vivo and potentially in vivo microenvironment models to test the effects of various remodelling approaches on microenvironment mechanics, signalling and/or immunosuppression. They will develop our understanding of the effects of the microenvironment on therapy response and its contribution to resistance, in primary and metastatic contexts. Further, this project will drive translation, facilitating future studies on synthetic liposomes pharmacokinetics/pharmacodynamics and triggered-release behaviour across the developed microenvironment models.