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

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.

We aim to develop an optimised lead compound that targets IKKalpha to treat two inflammatory-driven cancers of clinical unmet need: castrate-resistant prostate cancer (CRPC) and colorectal cancer (CRC). More effective treatment of cancer will require an expansion of the therapeutic armamentarium to cover all driving biological mechanisms, including the role of inflammation in disease progression and to apply these new agents in more effective combinations with standard-of-care (SOC) treatments. An IKKalpha-inhibitor will address a major deficiency in current therapeutic options by targeting IKKalpha-promoted cytokine-mediated inflammation and the constitution of immunosuppressive and treatment-refractory microenvironments. Successful inhibition of IKKalpha will thus uniquely and simultaneously target two tumour-promoting mechanisms: (1) elimination of the numerous pathogenic inflammatory signalling inputs that originate from the tumour microenvironments (TME); (2) attenuation of cancer cell intrinsic pathogenic pathways. We have developed the first IKKalpha-inhibitors to have high selectivity for the target. Lead optimisation is required to improve PK properties, whilst maintaining on-target potency and selectivity. Our study of the IKKalpha-inhibitor in syngeneic models will unequivocally demonstrate the importance of targeting IKKalpha in CRPC and CRC, define the use of an IKKalpha-inhibitor with combination therapies, and establish its potential to transform the TME and reveal effective responses to immunotherapy. Our deliverables are:

Demonstration of anti-tumour activity of optimised lead compounds in specific inflammatory-driven pre-clinical models of CRPC and CRC.
Evaluation of the lead compounds in combination with SOC therapeutics in prioritised preclinical models
Robust biomarkers to guide future clinical use of IKKalpha-inhibitors in patient populations.

All evidence will support downstream licencing arrangements with a pharmaceutical partner.