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

通过改变细胞凋亡途径而对化疗和放疗产生的抵抗常常导致患者无法从传统治疗中获益。目前，有几种IAP拮抗剂在临床试验管道中，希望能使癌细胞对凋亡敏感并减少这一问题。然而，这些疗法在大部分患者群体和癌细胞系中缺乏有效性。本博士项目旨在揭示IAP拮抗剂敏感性的生物标志物，了解敏感性的机制，并确定替代和更普遍的目标。为了实现这一目标，该项目将分为三个阶段：目标和生物标志物识别，目标验证和药物设计。最初，乳腺癌和胰腺癌细胞系被分类为对LCL 161和Birinapant（IAP拮抗剂）敏感或耐药。然后，将在暴露于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敏感和耐药基因，这些基因可能是有效的靶点或生物标志物。与此同时，对现有shRNA富集研究的生物信息学分析正在被用于证实和补充该项目的发现。总的来说，这项研究旨在为那些已经发展出化疗或放疗抵抗性肿瘤的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.