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

去势抵抗性前列腺癌（CRPC）和结直肠癌（CRC）的靶向治疗主要集中在与非常小的患者群体相关的特定驱动突变上。我们认为IKKalpha是传导和维持炎症信号的关键信号通路，它在功能上与基因改变的肿瘤细胞、邻近的免疫浸润和肿瘤血管系统相关。因此，在靶向IKKalpha的过程中，我们有机会靶向肿瘤微环境（TME）中的多个贡献区室，系统性地破坏炎症信号，并消除肿瘤对当前治疗干预（如化疗、雄激素剥夺疗法）的动态免疫抑制反应。我们已经开发了第一个系列的选择性ikkalpha抑制剂（PCT申请号：PCT/GB2023/051242）和一个后备系列（PCT申请号：2306601.2），创造了一个明显的竞争优势和独特的机会，以确定在炎症驱动的实体肿瘤中对这种激酶的药理干预是否提供了一个新的治疗范例。我们的ikkalpha抑制剂将适用于更大的炎症人群。例如，在结直肠癌中，目前的靶向治疗，如免疫检查点抑制剂（派姆单抗、纳沃单抗或伊匹单抗）仅限于IV期疾病，仅对3-5%的患者有效，而恩科非尼和西妥昔单抗仅对8-10%的患者有效。如果我们针对IKKalpha的靶向方法成功，它将与更大的炎症队列相关，从而将目标患者人群扩大到30 - 50%的CRC病例，由我们的指导性生物标志物，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，我们是唯一开发出针对IKKalpha的先导化合物系列的团队，对其相关异构体IKKbeta具有显著的靶向选择性。这种选择性是制药行业的关键期望，因为先前的ikkβ -抑制剂试验会产生不良反应，包括严重和慢性炎症、免疫抑制和对感染的易感性。我们拥有一支成熟且经验丰富的跨学科团队，拥有PC和CRC的临床前和临床专业知识，以确保临床视线。我们有一个明确的和集中的先导优化策略，以达到一种适合在我们尖端的、与患者相关的基因工程小鼠模型中进行广泛临床前体内验证研究的化合物，这些模型的特征是强烈的炎症驱动，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）。我们有多种基于人工智能的方法来定义生物标志物，为未来的临床翻译提供信息。

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.