Targeting GALNT7 and truncated O-glycans for improved treatment of prostate cancer

前列腺癌是英国男性最常见的癌症。对于4期前列腺癌，癌细胞已经转移到附近的淋巴结或身体的其他部位，如骨骼和肝脏，五年生存率下降到50%左右，没有可用的治愈方法。晚期前列腺癌的标准治疗包括雄激素剥夺疗法（ADT）、雄激素信号传导抑制（ARSI）和化疗。然而，大量患者对治疗停止反应并发展为转移性去势抵抗性前列腺癌。这些挑战突出了开发新的治疗方法以改善目前晚期前列腺癌治疗的需要。聚糖是存在于所有真核细胞表面的碳水化合物。异常糖基化被鉴定为癌症的标志，并且可以与癌症进展的所有方面相关联。Munkley小组先前的工作确定了编码糖基转移酶GalNAc转移酶7的GALNT 7在前列腺癌中上调。GALNT 7显示出修饰前列腺癌细胞的O-糖基化并促进Tn抗原（一种癌症相关的截短O-聚糖）的合成。GALNT 7还被发现促进体内肿瘤生长并抑制免疫信号通路。在这项工作的基础上，本研究将探讨GALNT 7和截短型O-聚糖在前列腺癌转移中的作用，并研究GALNT 7和/或截短型O-聚糖是否可以作为治疗靶点。本项目旨在发现GALNT 7和截短型O-聚糖在前列腺癌进展中的作用，并获得原理性数据证明，靶向GALNT 7和/或截短型O-聚糖可以在前列腺癌转移中发挥作用。或其聚糖对前列腺癌具有治疗潜力。使用免疫组化技术破译前列腺肿瘤糖密码，并鉴定新的诊断和预后生物标志物和有望成为靶向治疗的聚糖.清楚地了解GALNT 7和截短的O-聚糖在前列腺癌进展中的作用（在转移、肿瘤微环境和免疫系统的背景下）。3.靶向GALNT 7和/或截短的O-聚糖以开发前列腺癌的新疗法。

Prostate cancer is the most common cancer in men in the UK. For stage 4 prostate cancer where cancer cells have metastasised to nearby lymph nodes or to other parts of the body like bones and liver, the five-year survival rate drops to around 50% with no available cure. Standard treatments for advanced prostate cancer include androgen deprivation therapy (ADT), androgen signalling inhibition (ARSI) and chemotherapy. However, a large number of patients stop responding to treatments and develop metastatic castration-resistant prostate cancer. These challenges highlight the need for developing novel therapeutic approaches to improve the current treatments for advanced prostate cancer.Glycans are carbohydrates that are present on all eukaryotic cell surfaces. Aberrant glycosylation is identified as a hallmark of cancer and can be linked to all aspects of cancer progression. Previous work in the Munkley group identified that GALNT7, which encodes the glycosyltransferase enzyme GalNAc transferase 7, is upregulated in prostate cancer. GALNT7 was shown to modify the O-glycosylation of prostate cancer cells and promote the synthesis of the Tn antigen, a cancer associated truncated O-glycan. GALNT7 was also found to promote tumour growth in vivo and suppress immune signalling pathways. To build on this work, this study will explore the role of GALNT7 and truncated O-glycans in the context of prostate cancer metastasis and investigate whether GALNT7 and/or truncated O-glycans can be targeted therapeutically.This project aims to discover the role of GALNT7 and truncated O-glycans in prostate cancer progression and obtain proof-of principle data to show that targeting GALNT7 and/or its glycans holds therapeutic potential for prostate cancer.Objectives1. Decipher the prostate tumour glyco-code using immunohistochemistry and identify new diagnostic and prognostic biomarkers and glycans which hold promise to be targeted therapeutically.2. Gain a clear understanding of the role of GALNT7 and truncated O-glycans in prostate cancer progression (in the context of metastasis, the tumour microenvironment and the immune system).3. Target GALNT7 and/or truncated O-glycans to develop new therapies for prostate cancer.