Targeting Inhibitory kappa B kinase alpha (IKKalpha): a new treatment paradigm for inflammatory-driven cancers

靶向抑制性 kappa B 激酶 alpha (IKKalpha)：炎症驱动的癌症的新治疗范例

• 批准号: MR/Y015479/1
• 负责人: Simon Mackay
• 金额: $ 329.11万
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY015479%2F1
• 关键词: Targeting; Inhibitory; kappa; kinase; alpha

Targeted therapies in castrate-resistant prostate cancer (CRPC) and colorectal cancer (CRC) have focussed upon specific driver mutations relevant to very small patient populations. We propose that IKKalpha is a critical signalling nexus that channels and sustains inflammatory signalling, and which is functionally relevant to genetically altered tumours cells, the adjacent immune infiltrate and the tumour vasculature. In targeting IKKalpha, we therefore have the opportunity to target multiple contributing compartments within the tumour microenvironment (TME) to systemically disrupt inflammatory signalling, and to abrogate the dynamic immunosuppressive response of tumours to current therapeutic interventions (e.g. chemotherapy, androgen deprivation therapy). We have developed the first series of selective IKKalpha-inhibitors (PCT Application No: PCT/GB2023/051242) and a back-up series (Application No: 2306601.2), creating a clear competitive advantage and unique opportunity to establish whether pharmacological intervention against this kinase in inflammation-driven solid tumours offers a new treatment paradigm. Our IKKalpha-inhibitor will be relevant to a larger, inflammatory cohort. For example, in CRC, current targeted therapies such as immune checkpoint inhibitors (pembrolizumab, nivolumab or ipilimumab) are restricted to stage IV disease, and are only efficacious in the 3-5% of patients, whilst encorafenib and cetuximab are effective only in the 8-10% of patients. If our targeted approach against IKKalpha is successful, it will be relevant to a significantly larger, inflammatory cohort, thus expanding the target patient population to between 30 - 50% of CRC cases, defined by our guiding biomarkers, the Glasgow Prognostic Score (GPS) and Glasgow Microenvironment Score (GMS). This clearly differentiates our approach from all competitors in the field.To our knowledge, we are the only team to have developed a lead compound series against IKKalpha with significant target selectivity over its related isoform IKKbeta. Such selectivity is a critical expectation of the pharmaceutical industry, given that prior trials of IKKbeta-inhibitors gave rise to adverse effects, including severe and chronic inflammation, immunosuppression and susceptibility to infection.We have an established and experienced interdisciplinary team with pre-clinical and clinical expertise in in PC and CRC to ensure clinical line-of-sight. We have a definable and focussed lead optimisation strategy to reach a compound suitable for extensive preclinical in-vivo validation studies in our cutting-edge, patient-relevant genetically engineered mouse models that are characterised by a strong inflammatory drive and aligned to our principal target population to evaluate IKKalpha-inhibitory responses (alone or in combination with standard-of-care treatments). We have multiplex and AI-based approaches to define biomarkers to inform future clinical translation.

去势耐药前列腺癌(CRPC)和结直肠癌(CRC)的靶向治疗专注于与非常小的患者群体相关的特定驱动基因突变。我们认为IKKalpha是一个关键的信号网络，它引导和维持炎症信号，并且在功能上与基因改变的肿瘤细胞、邻近的免疫浸润物和肿瘤血管系统有关。因此，通过靶向IKKalpha，我们有机会靶向肿瘤微环境(TME)中的多个贡献间隔，以系统性地干扰炎症信号，并消除肿瘤对当前治疗干预措施(如化疗、雄激素剥夺治疗)的动态免疫抑制反应。我们已经开发了第一个选择性IKKalpha抑制剂系列(PCT申请号：PCT/GB2023/051242)和一个备用系列(申请号：2306601.2)，创造了明显的竞争优势和独特的机会，以确定针对炎症驱动的实体肿瘤中这种激酶的药物干预是否提供了一种新的治疗范式。我们的IKKalpha抑制剂将与更大的炎症性队列相关。例如，在结直肠癌中，目前的靶向治疗，如免疫检查点抑制剂(pembrolizumab、nivolumab或ipilimumab)仅限于IV期疾病，仅对3%-5%的患者有效，而恩可拉非尼和西妥昔单抗仅对8%-10%的患者有效。如果我们针对IKKalpha的针对性方法成功，它将与显著扩大的炎症性队列相关，从而将目标患者群体扩大到30-50%的CRC病例，这由我们的指导生物标记物格拉斯哥预后评分(GPS)和格拉斯哥微环境评分(GMS)定义。这显然使我们的方法有别于该领域的所有竞争对手。据我们所知，我们是唯一一个开发出针对IKKalpha的先导化合物系列的团队，对其相关亚型IKKbeta具有显著的靶向选择性。这种选择性是制药业的一个重要期望，因为之前的IKKbeta-抑制剂试验会产生不良反应，包括严重和慢性炎症、免疫抑制和感染易感性。我们拥有一支成熟和经验丰富的跨学科团队，在PC和CRC方面具有临床前和临床专业知识，以确保临床视野。我们有一个明确和有重点的先导优化策略，以获得一种适合在我们的尖端、与患者相关的基因工程小鼠模型中进行广泛的临床前体内验证研究的化合物，这些模型的特点是强烈的炎症驱动，并与我们的主要目标人群保持一致，以评估IKKalpha抑制反应(单独或与标准护理治疗相结合)。我们有多重和基于人工智能的方法来定义生物标记物，以告知未来的临床翻译。