CellCentric’s p300/CBP programme
We are developing CCS1477 for the large and growing population of prostate cancer patients that are unresponsive to second generation anti-hormonal drugs. The drug candidate also has potential for other oncology unmet needs, including for specific haematological, lung and bladder cancers.
CCS1477 is a potent and highly selective small molecule drug that inhibits the conserved bromodomains of p300/CBP. These are twin histone acetyl transferase regulatory proteins in cells (including as transcription factors), with a high association with cancer progression.
WhiIst CCS1477 acts by binding to the bromodomains of p300/CBP (and not the HAT catalytic site), it is clearly differentiated in profile from other bromodomain inhibitors, such as those targeting BETs. Strong pre-clinical data supports the compounds advancement to clinical trials to treat late stage prostate cancer patients in the first instance. Additional cohorts will examine the effects on tumours with p300 or CBP gene mutations, as well as haematological cancers (AML and multiple myeloma).
CCS1477 can be used as a monotherapy and in combination with other drugs. Initial clinical testing for late stage prostate cancer will assess its effectiveness in combination with enzalutamide or abiraterone, two second generation anti-hormonal drugs.
CCS1477 has profound effects on tumour growth, at well tolerated doses. Its efficacy is prolonged after drug dosing has stopped. It significantly lowers the key drivers of late stage prostate cancer, the androgen receptor (AR), AR-splice variants (AR-SV) and c-Myc. It profoundly effects key downstream biomarkers, such as PSA. CCS1477 potentially addresses the unresponsiveness and acquired resistance seen with second generation anti-hormonal drugs.
Breadth of efficacy testing against a wide range of cancer types highlights p300/CBP inhibition being relevant to specific other cancer types beyond prostate. Further in vivo data supports the use of CCS1477 potentially for Acute Myeloid Leukaemia, as well as potentially Multiple Myeloma and DLBCL, the most common form of Non-Hodgkin Lymphoma in adults.
Particularly in bladder and lung cancers, there is a high prevalence of tumours that have a mutation in either p300 or CBP. In principle, this makes them highly sensitive to a drug such as CCS1477 that inhibits both proteins.
Inhibition of p300/CBP has also been shown to affect regulatory T-cells and their suppressive function, thus increasing the ability of the body’s immune system to target tumour cells. Early in vivo data supports the potential additive effect of CCS1477 when administered with an immune checkpoint (PD-1) inhibitor.
Late Stage, Castration Resistant Prostate Cancer (CRPC)
- Prostate cancer accounts for over 25% of all new male cancers (Cancer Research UK data).
- Initial treatments for advancing prostate cancer focus on reducing the levels of circulating male hormones (androgens) in the body which the tumour requires for growth. Over time however, the cancer cells are able to circumvent such treatments and can develop into the castration resistant form of the disease (CRPC). This is lethal with overall survival typically less than 14 months.
- The development of CRPC is dependent upon the presence of functional but altered androgen receptors (AR). CCS1477 lowers the levels of the AR in prostate cancer cells, as well as AR-splice variants (which drives resistance to current therapeutic agents), and c-Myc.
- CCS1477 is therefore ideally positioned for this large and growing population of patients unresponsive to second-generation anti-hormonal drugs. It can be used as a monotherapy or in combination with existing agents.
- As the use of second generation anti-hormonal drugs continues to increase, the numbers of patients that become resistant to them also continues to grow. This is now a recognised and significant population of high unmet need
- CCS1477 has relevance to a range of different blood cancers, with most data supporting its application for Acute Myeloid Leukaemia (AML). Over 20,000 new cases of AML are diagnosed each year in the US alone. Over half of these fail to progress into long term remission with existing treatments.
- Lung cancer remains the largest cause of cancer death in both men and women. In 15-20% of small cell and non-small cell (NSCLC) lung cancers, gene mutations cause a loss of function of either p300 or CBP. Inhibiting the remaining protein drives cancer cell death, known as synthetic lethality. This offers an additional opportunity for phenotype-driven treatment.
- There are over 75,000 new cases of bladder cancer in the US every year, with over 16,000 deaths in 2016 (NIH data). Prevalence is slightly higher in men compared to women. Loss of function somatic gene mutation rates in p300 and CBP bladder cancer biopsies have been reported at 13.8% and 11.2% respectively; 25.0% in total, a significant proportion of sufferers overal