Identifying the molecular basis for resistance to apoptosis in breast and pancreatic cancer

由于细胞凋亡通路的改变而对化疗和放疗产生耐药性，常常导致患者无法从传统治疗中获益。目前，有几种IAP拮抗剂正在临床试验中，希望能使癌细胞对凋亡敏感，从而减少这一问题。然而，这些疗法在很大比例的患者群体和癌细胞系中缺乏疗效。本博士项目旨在揭示IAP拮抗剂敏感性的生物标志物，了解其敏感性机制，并确定替代和更普遍的靶标。为了实现这一目标，该项目将分为三个阶段：靶点和生物标志物鉴定、靶点验证和药物设计。最初，乳腺癌和胰腺癌细胞被分类为对LCL161和biinapant （IAPantagonists）敏感或耐药。然后在暴露于IAP拮抗剂的两个类别中进行全基因组CRISPR筛选。这将使我们能够识别潜在的致敏和耐药基因，这些基因可能是有效的靶点或生物标志物。与此同时，现有shRNA富集研究的生物信息学分析正在被用来证实和补充该项目的发现。总的来说，这项研究旨在为化疗或放疗耐药肿瘤患者提供更好的治疗选择。

Resistance to chemo- and radiotherapy through alterations in the apoptotic pathwayfrequently result in patients being unable to benefit from traditional treatments. Currently,there are several IAP antagonist in the clinical trial pipeline which hope to sensitise cancercells to apoptosis and reduce this problem. However, these therapies show a lack ofefficacy in a large proportion of the patient population and cancer cell lines. This PhDproject aims to uncover the biomarkers for IAP antagonist sensitivity, understand themechanisms of sensitivity as well as identify alternative and more ubiquitous targets. Inorder to achieve this, the project will be split into three phases: target and biomarkeridentification, target validation and drug design. Initially, breast and pancreatic cancer celllines are being categorised as sensitive or resistant to LCL161 and Birinapant (IAPantagonists). Then a genome-wide CRISPR screen will be performed in both categorieswith exposure to the IAP antagonists. This will allow us to identify potential sensitisationand resistance genes which could be effective targets or biomarkers. In parallel,bioinformatics analysis of existing shRNA enrichment studies is being used to confirm andcomplement the project's findings. Overall, this research aims to contribute towardsproviding better treatment alternatives to patients who have developed chemo- orradiotherapy resistant tumours.