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).
Initial treatments for advancing prostate cancer focus on reducing the levels of circulating male hormones (androgens) in the body which
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
In an in vivo cancer xenograft model that is driven by AR-splice variants (22Rv1), CCS1477 can cause complete tumour stasis at a
Intriguingly, tumour stasis is maintained for a significant period after dosing cessation (and when
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
As the use of second-generation anti-hormonal drugs continues to increase, the numbers of patients that become resistant to them also
p300 and CBP have long been implicated in the progression of various cancers of the blood. The mechanism for this is not fully elucidated,
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
The evidence to date is not
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.