First-in-class Selective IKKalpha Inhibitors for the Treatment of Castrate Resistant Prostate Cancer (CRPC) and Pancreatic Cancer

Despite real progress being made in the treatment of many cancers, there are still significant issues to overcome, particularly for patients who have become resistant to treatment, or where the cancer has spread beyond the original tumour. This is particularly true of prostate cancer, which is the most common cancer in men in the UK.
There are 36,000 new cases of prostate cancer diagnosed every year in the UK and this figure is predicted to double over the next 20 years.
Whilst there are treatments available for early-stage prostate cancer (cancer that is still confined to the prostate cancer), some men become resistant to treatment and the cancer progresses and spreads (metastasizes). This type of prostate cancer is called castrate resistant prostate cancer (CRPC) and current treatments can only extend life expectancy by up to 9 months. New medicines to treat this disease are therefore urgently needed.
We have discovered a new way to treat CRPC. We have shown that there are high levels of a protein called IKKalpha in the tumours of men who had shorter time to death. We and our Project Partners have also shown that this same protein is involved in the progression from early-stage prostate cancer to CRPC. We believe that a drug which stops this protein from functioning will prevent CRPC from developing and increase life expectancy by up to 3 years.
Evidence is also emerging that this IKKalpha protein also plays a role in pancreatic cancer, which is currently incurable.
We are the only group to have developed compounds that stop this protein from functioning, without also stopping closely-related proteins from functioning (and resulting in unwanted side-effects).
We have also demonstrated that our compounds, when added to prostate cancer cell samples in a laboratory environment, slow their growth and cause them to die. However, these compounds require further development and are not yet suitable as medicines for CRPC. For example, they are broken down in the body too quickly to exert their effects in a patient and they are also not very water-soluble, which would make them difficult to administer. The aim of this project is to design compounds with better properties (a process called lead optimisation).
We will then be able to determine whether our optimised compounds stop IKKalpha from functioning and stop cancers growing and spreading in mice, without adverse or toxic effects. This is essential to demonstrate before testing in humans.
This project involves medicinal chemists, biologists, clinicians and technology transfer professionals working together as a team to achieve the goal of effective new medicines for patients with CRPC and pancreatic cancer.

This proposal aims to identify two advanced lead compounds suitable for full preclinical evaluation as candidate drugs to treat patients with castrate resistant prostate cancer (CRPC) and potentially pancreatic cancer (PanC). Over the past 15 years, compelling evidence from several research groups has demonstrated that intracellular signalling involving constitutive activation of IKKalpha and the non-canonical NFkappaB pathway plays a key role in the progression of hormone-dependent prostate cancer to CRPC. In a retrospective analysis employing clinical CRPC specimens, we observed that patients with tumours expressing high levels of nuclear IKKalpha and RelB (a key biomarker of the noncanonical pathway) had a significantly worse prognosis than those with low expression. Studies by ourselves and others also demonstrated that IKKalpha and the non-canonical NFkappaB pathway have a role in other malignancies including pancreatic and haematological cancers.
Through extensive prior work, we are the only group to have developed a series of low nanomolar-potent, highly isoform selective IKKalpha inhibitors that could have clinical applications in CRPC, and potentially PanC. We have shown that it is possible both to improve the physicochemical and PK profile of our compounds while simultaneously abrogating off-target kinase activity and maintaining IKKalpha potency and selectivity over IKKbeta. We have a comprehensive assay cascade in place that includes validated primary cellular PD readouts that demonstrate target engagement for IKKalpha (e.g. p100 phosphorylation and RelB translocation) and for IKKbeta (IkappaB degradation) to enable selectivity assessment in the physiological context. We have also identified secondary downstream markers to provide orthogonal confirmation of target engagement that can be translated into in vivo models to test the efficacy of compounds emerging from optimisation of our currently most promising lead series and from a back-up series.

There are several broad categories of beneficiaries from this research. Foremost, are the patients that we hope will ultimately benefit from our new approach to treatment - we are aiming to identify two advance lead compounds suitable for preclinical development to treat patients with castrate resistant prostate cancer (CRPC) and potentially pancreatic cancer (PanC). Current therapies for CRPC are severely limited and for pancreatic cancer, are non-existent. We hope to achieve societal benefit by providing more effective treatments - specifically increasing survival times from 3-9 months to 2-3 years and enhancing the quality of life for CRPC and PanC patients and their carers and dependants.
There are 36,000 new cases of prostate cancer reported every year and this figure is predicted to double over the next 20 years. As CRPC is currently a major complication arising in 80% of patients, even with existing therapies, this will place a considerable strain on the healthcare sector. For pancreatic, it is essentially untreatable because the 9,000 cases that arise annually present with locally advanced or metastatic disease. More effective treatments will therefore achieve economic benefit for healthcare providers and employers by reducing hospital admissions and the costs of palliative and end of life care. Furthermore, the candidate drugs themselves are expected to be more cost-effective than current immunological-based therapies.
We anticipate that a pharmaceutical company partner will benefit from in-licensing this opportunity as this will add first-in-class agents to their pipeline and identify a new patient group that can benefit from their medicines. Ultimately, this provides economic benefit to that company through increased revenues. Cancer Research UK, Prostate Cancer UK and the University also benefit from a share of those revenues and will channel these funds into further research for continued societal benefit.
Once IP protection and the appropriate agreements are in place, our library of compounds, with selectivity ratios for IKKalpha against IKKbeta in the range 1:1 to 1:200, will provide a unique resource of immense benefit to academic and clinical researchers working in the NFkappaB field. Our compounds can be used to explore other disease scenarios linked with IKKalpha such as haematological malignancies, glioblastoma, naso-pharyngeal carcinoma, breast subtypes and colorectal cancers; inflammatory diseases such as rheumatoid arthritis, asthma and COPD and in cardiovascular and neurological diseases.
The team will also contribute to the benefits that arise from public engagement with cancer research by providing material for Cancer Research UK's targeted-giving site - members of the public have already donated £196,800 to the project and by continuing to be involved in the public-science open days organised by CRUK throughout Scotland to make the charity's volunteers aware of the importance of their activities in raising funds for research.