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Drug-resistant prostate cancer treatment 'promising'

Tuesday January 12th 2021

Men with advanced prostate cancer could receive a promising, new experimental drug, it is reported today.

Scientists at the Institute of Cancer Research, London, and the Royal Marsden NHS Foundation Trust, believe the chemical structure of CCS1477, a new targeted drug, could be used to stop the growth of late-stage prostate cancers.

The new research, published in Cancer Discovery, also reveals the drug’s mechanism of action and it is now being evaluated in clinical trials as a monotherapy for patients with prostate cancer, and also in combination with existing drugs such as enzalutamide and abiraterone.

The team studied cell lines and tumour biopsies from 43 patients in the lab and showed that CCS1477 works by binding itself to two cancer gene regulators, the proteins p300 and CBP, which help activate androgen receptor signalling.

By blocking the activity of these two proteins, the drug can stop prostate cancer’s growth and potentially delay or prevent drug resistance.

Compared to those who had lower levels of the p300 protein, participating patients who had higher levels of the p300 protein did not live as long before their cancer progressed and became drug resistant than those with lower levels of the protein – 10 months compared with 21 months.

When researchers blocked the activity of the CBP and p300 genes – either separately or in combination – in cells in the lab, there was less activity in the androgen receptor and c-Myc, and slower growth of prostate cancer cells taken from patients,

This, they say, confirms that targeting those two proteins had an effect on androgen receptor signalling.

Re-activating p300 and CBP in patient samples switched on signalling through the androgen receptor and c-Myc, which helped to fuel the growth of cancer cells.

Using CCS1477 to block p300 and CBP in mice with prostate cancer was found to have a biological effect on androgen receptor signalling and could stop tumour growth.

The report’s authors suggest that CCS1477 can both target androgen receptor signalling and but also the potential genomic changes and adaptations prostate cancer may undergo to evade treatment, which may enable it to be used in combination with modern hormone drugs to overcome or delay resistance to treatment.

CCS1477 is also being trialled in patients with blood cancers and those whose tumours have a range of mutations, including changes in genes such as p300, CBP or c-Myc.

Study leader Professor Johann de Bono, professor of experimental cancer medicine at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said: “Our study offers a potentially exciting new approach to treating prostate cancer. For the first time, we have shown that blocking two proteins known as p300 and CBP with a new targeted drug can disrupt signals that help fuel the growth of prostate cancers.

“These initial results are very promising and suggest that the drug could help delay or prevent resistance to the modern hormone treatments abiraterone and enzalutamide, which have already played a critical role in helping patients to live for much longer.”

Study author Dr Adam Sharp, team leader in translational therapeutics at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, said: “Being able to target both androgen receptor signalling and its adaptions is a huge achievement, as it helps us tackle the huge challenge posed by cancer’s ability to evolve resistance to modern hormone treatments.”

Other collaborators on the study include researchers from the Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, USA.

Cancer Discovery 12 January 2021

Tags: Cancer | Men's Health | Pharmaceuticals | UK News

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