Translation

CCS1477 has potential for specific, significant unmet needs in oncology

CellCentric is primarily focused on treating patients with late stage prostate cancer. Additionally, breadth of efficacy testing highlights p300/CBP inhibition being relevant to a wide range of other specific cancer types, most notably haematological cancers. Unlike BET inhibitors, the therapeutic effect of CCS1477 is more targeted in certain tumour types.

The future woman image

As well as its own research efforts, CellCentric continues to work with multiple leading international academic researchers and clinicians on translational biology.  For prostate cancer, this includes Prof Johann de Bono (ICR, Royal Marsden Hospital) and Prof Karen Knudsen (Thomas Jefferson). Additionally, CCS1477 is the focus of a significant award from the Prostate Cancer Foundation. 

For haematological cancers, translational collaborators include Prof Tim Somervaille (CRUK Manchester Institute, The Christie Hospital) and Dr Laura Pasqualucci (Columbia University, New York).

Prostate Cancer

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.

CCS1477 lowers the levels of androgen receptors (AR) in prostate cancer cells, and importantly, of AR-splice variants that arise as disease progresses. It is these variants that are thought to drive resistance to current therapeutic agents, such as Xtandi, Zytiga and Erleada. CCS1477 also effects other key oncogenes including c-Myc.

In an in vivo cancer xenograft model that is driven by AR-splice variants (22Rv1), CCS1477 can cause complete tumour stasis at a well tolerated dose. Anti-tumour effects are dose dependent.

Intriguingly, tumour stasis is maintained for a significant period after dosing cessation (and when drug has completely cleared from the system). This suggests some kind of reprogramming of tumours with CCS1477. It also means that there is significant scope for different dosing schedules of CCS1477, as the first-in-class drug is used in patients.

As well as direct effects on AR and AR-SV protein levels, CCS1477 effects downstream biomarkers of AR-inhibition and prostate cancer. In pre-clinical efficacy models, plasma PSA is profoundly reduced by dosing with CellCentric’s drug, corresponding with tumour growth inhibition. Other downstream genes are also effected including TMPRSS2 and KLK3 in tumours.

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 is ideally positioned for these patients, either as a monotherapy or in combination with existing agents.

Haematological Cancers

Breadth of efficacy cell panel testing demonstrates that CCS1477 is highly potent against various haematological cancers, and in particular multiple myeloma and acute myeloid leukaemia AML.

p300 and CBP have long been implicated in the progression of various cancers of the blood. The mechanism for this is not fully elucidated, however there is evidence from cell models that p300/CBP inhibition interferes with the IRF4-Myc axis, resulting in cancer cell death.

Following the initiation of a prostate cancer-focused clinical trial (NCT03568656), CellCentric will be testing CCS1477 as a monotherapy in patients with multiple myeloma and non-Hodgkin’s lymphoma (NHL).

Tumours with p300 or CBP mutations

Particularly in bladder and certain lung cancers, but also in Non-Hodgkin Lymphoma (NHL) tumours, there is a relatively high prevalence (up to 20%) of tumours with a loss of function mutation in either p300 or CBP. There is some pre-clinical evidence that the tumours are then dependent on the non-mutated paralogue, and thus sensitive to an inhibitor of both p300 and CBP.

The evidence to date is not clear cutHowever these are significant areas of clinical unmet need that could potentially benefit from targeted treatment with CCS1477. Thus CellCentric will be testing the hypothesis in a small number of patients, in parallel to its prostate cancer clinical programme. 

Drug combinations

As CCS1477 advances and is adopted, the drug is likely to be used in combination with existing treatments. In prostate cancer, pre-clinical data clearly support the synergistic effect of CCS1477 in combination with Xtandi (enzalutamide), a current second generation anti-hormonal drug.

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.