MICA: Characterisation of a novel bromodomain inhibitor AZD5153 in castrate resistant prostate cancer

Context of Research:

Prostate cancer kills approximately 10,000 men in the UK each year. A protein found in prostate cells called the androgen receptor (AR) is an important driver of prostate cancer development and is the main target for therapeutic intervention. Drugs that reduce circulating androgen levels or directly antagonise the AR (called anti-androgens) block AR activity and initially cause the primary cancer to regress/shrink. Unfortunately, after approximately 2 years, patients usually relapse and the tumour re-appears in a more aggressive form called castrate-resistant prostate cancer (CRPC) that is no longer responsive to the initial treatments. This type of disease is very difficult to treat and is usually fatal. Recent advances have seen the introduction of new AR-targeted therapies, such abiraterone and enzalutamide, that have shown some promise in the clinic. However, even these treatments are not completely effective in all patients and resistance occurs to these agents rendering them useless. At this advanced stage, all treatment options have been exhausted and thus the development of new strategies to target the AR and treat CRPC patients is vital.

Aims and Objectives:

The research teams within the Northern Institute for Cancer Research, Newcastle University, and AstraZeneca are aiming to validate a newly developed drug as an AR-targeting therapy for the treatment of CRPC. This drug is aimed at inactivating the AR by blocking an important group of proteins in the cell called BET proteins. These are important for enabling the AR to become hyperactive in prostate cancer and thus by inactivating them, we hypothesise that we can disrupt AR activity and cause tumours to disappear. Importantly, during CRPC development, the AR undergoes several distinct changes that make it function in the presence of the current therapeutic agents; enabling progression of CRPC. It is important, therefore, that any new therapy targeting the AR has to be additionally effective against these altered receptors that are present in CRPC patients. Consistent with this, the main objective of this study is to address whether the new AstraZeneca drug works on normal, as well as altered AR proteins present in therapy-resistant CRPC. Key to this project is the identification of 'biomarkers' that will indicate whether the drugs are effective at inactivating the normal and altered forms of the AR and causing tumour cells to die.

Application and Benefits:

The study will use two main model systems to assess the effect of these new drugs on normal and altered AR activity: (i) cell line models of CRPC that reflect tumour cells growing in patients with different forms of the AR within them; (ii) biopsied primary prostate cancer specimens that are grown in the laboratory containing normal and altered AR proteins. Together, these strategies have the potential to indicate the effectiveness of the new drug in CRPC patients. Using 'Biomarkers' identified in the study, we can assess whether normal and altered AR proteins found in CRPC are affected by the new drug. This is an important aspect of the study as we would be only aiming to treat patients in the clinic with this new drug if it proved effective at inactivating the forms of AR present in their tumour, a process termed 'patient stratification'. By doing this, we will be treating a specific cohort of patients who will receive benefit from the new therapy and, importantly, not treating patients who would receive no benefit from drug treatment. Ultimately, the overarching goal of the study is to provide new treatment options in CRPC patients that are effective against disease that have failed conventional therapies.

Prostate cancer (PC) is the most prevalent UK male cancer, accounting for 10,000 deaths per year. The androgen receptor (AR) is a transcription factor that transmits androgenic signals to drive prostate growth and cellular transformation. Inactivation of the AR by anti-androgens is initially effective causing tumour regression. Unfortunately, most patients relapse with a more aggressive form of the disease termed castrate-resistant PC (CRPC) that is unresponsive to treatment, but is AR-dependent. The development of next-generation AR-targeted therapies, including enzalutamide, have shown promise in the treatment of CRPC, but response rates of just 50% and the development of resistance have limited their success in the clinic. Importantly, several aberrations to the AR signalling cascade have been identified in CRPC, including AR mutation and the formation of receptor splice variants, that facilitate AR activity in castrate conditions and contribute to conventional and next-generation anti-androgen treatment failure. A key challenge is to develop novel treatments for CRPC that antagonise all ARs and repress tumour progression.

Consistent with a role for Bromodomain and extraterminal motif (BET) proteins enhancing activity of CRPC-relevant forms of the androgen receptor, pre-clinical testing of first-generation BET inhibitors have been shown to compromise PC growth in vitro and in vivo. This study will assess a new and more efficacious BET inhibitor developed by AstraZeneca to attenuate receptor signalling and prevent tumour growth using CRPC cell line models and human PC biopsy samples ex vivo. The ability of this agent to inactivate all AR isoforms has major clinical implications and is the main focus of the project. By determining the efficacy of the BET inhibitor against clinically-relevant AR mutants and splice variants, we will advance our understanding of the receptor in CRPC, and comprehensively validate the compound for patient-tailored treatment.

Who will benefit from the research?

The study has several different categories of beneficiaries outside of the immediate academic professional circle, including
the large cohort of prostate cancer (PC) patients in the UK who would benefit directly from the research, and distinct private
and public sector workforces who would benefit from the commercialisation and educational impact of the work (as
discussed below).

PC patients:

The ultimate research objective of the study is to improve strategic healthcare for advanced PC in the medium to long term by provision of patient-tailored treatments that are beneficial to health and wellbeing. PC is a disease of ageing and hence poses a major clinical challenge in the developed world where life-expectancy is increasing year on year. In the UK alone, 10,000 deaths result from PC per year and this figure is likely to rise over the next 10 years. The development of new therapies that are efficacious in patients who have failed current therapies is key for the health and wellbeing of a large population of men in the UK. Therefore, our research has the capacity to benefit this expanding group of individuals by indicating novel therapeutic regimens in patients who have exhausted all treatment options.

Industrial Beneficiaries:

The research will be generating a number of specialist reagents that can be commercialised through our links with Cancer Research Technology (CRT) who have a repository of reagents for use in research. The CAS9/CRISPR-modified LNCaP and CWR22Rv1 cell lines will be marketed by CRT to provide researchers avenues for exploiting enzalutamide- and abiraterone-resistance mechanisms for new CRPC treatments. Additionally, we have forged strong links with Gillette/Proctor and Gamble through our Movember alliance with Prostate Cancer UK and hence we can facilitate knowledge transfer and impact on this funding stream by engagement with P&G representatives.

Public Sector:

We have engagement with local schools where our research is explained as part of distinct modules in lower school and sixth form. Students and teachers will directly benefit from this research as they will be introduced to the concepts of disease modelling in laboratories and technical advancements in cancer research.

How will they benefit?

PC patients

Specific cohorts of PC patients will benefit from this research by the provision of more effective therapies that could increase life-expectancy and improve quality of life. Ultimately, many thousands of males in the UK have the potential to be impacted by this study and outputs from our research could see a change in clinical practise within the next 5 years.

Public sector:

Provision of information from this study as teaching aids for students interested in cancer biology, biotechnology and other relevant modules in years 12 and 13 would indicate real-world relevance of scientific endeavours and how research can benefit general healthcare of the UK population. This is a key time to introduce these concepts as students may be attracted to pursuing a scientific career from being exposed to real-world examples of research in practise. Importantly, this project has very focussed objectives and deliverables that are relevant in today's society.

MICA-funded research associate:

The research associate who will undertake the day to day experimental work primarily at Newcastle, but will also be trained in bioinformatics and in vivo experimentation at Newcastle and AstraZeneca, respectively. This dual-site work schedule is one that the collaborative team have previously used and provides added value to the learning and technical outcomes of the study that will facilitate the career development of the researcher. Additionally, the project will also improve transferable skills of the researcher, including communication, data analysis and interpretation, that are key attributes for many employment sector