Overcoming resistance: Remodelling the Prostate Cancer Microenvironment using Synthetic Liposomes

前列腺癌（PC）是英国男性中最常见的癌症，也是第二致命的癌症，治疗无法手术（或复发），治疗抵抗性PC是主要的临床需求。虽然激素治疗最初是有效的，但不可避免地会发展为危及生命的去势抵抗性前列腺癌（CRPC）。PC肿瘤微环境以不同的方式驱动耐药性，作为一个纤维化的机械屏障，阻止药物渗透到肿瘤中。这种高瘤内压力也导致低氧肿瘤表型和t细胞浸润减少，进一步驱动耐药性。因此，靶向PC肿瘤微环境不仅可以提高已批准的小分子疗法（如多西他赛）的性能，还可以与有前途的免疫疗法（如检查点抑制剂）协同作用，这些免疫疗法迄今为止在CRPC中显示出有限的有效性。此外，肿瘤的微环境在原发和转移部位之间是不同的。伴有肝脏和其他内脏转移的PC患者预后比仅转移到骨骼的患者差。此外，内脏转移对当前PC治疗的反应也较差。我们已经证明，原发部位（前列腺）和转移部位（肝脏）的微环境对传统的激素治疗都有反应，并且微环境的反应可以促进有利于癌症生长、进展和对治疗的易感性的条件。这个多学科项目旨在利用并进一步开发一种新的方法来治疗CRPC，使用一种新的合成脂质体药物来重塑肿瘤微环境。这种方法能够选择性地将重塑化合物释放到微环境中，从而减少肿瘤纤维化。这反过来又降低了肿瘤内压力，增加了治疗药物在整个肿瘤中的渗透，并为进一步的临床干预做好了准备。在这个项目中，我们将使用3D微环境模型和外植体模型（来源于活检材料）来了解微环境重塑药物在原发性和转移性肿瘤（如肝转移）中的作用。我们将研究这些治疗对相关癌细胞对激素治疗和化疗联合治疗的反应的影响。我们将使用相同的模型和体内模型（异种移植，GEMMs）来测试新的合成细胞的递送，使用体外（免疫组化，PCR，发光）和体内（例如剪切波弹性成像，体内成像）分析来阐明效果。这个项目提供了一个独特的机会来发展对癌症生物学（重点是肿瘤微环境）和先进药物输送系统的微流体工程的详细了解。在项目期间，该研究员将帮助开发各种体外、离体和潜在的体内微环境模型，以测试各种重塑方法对微环境力学、信号传导和/或免疫抑制的影响。他们将发展我们对微环境对治疗反应的影响及其在原发性和转移性情况下对耐药性的贡献的理解。此外，该项目将推动翻译，促进合成脂质体药代动力学/药效学和触发释放行为在开发的微环境模型中的未来研究。

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.