HSP-90 Inhibitor Zytiga Combo

Zytiga has a very good safety profile and so is ideal for combining with other drug therapies. Such combinations may be designed to overcome Zytiga resistance. Many combination therapies are currently under investigation that are rationally targetted against prostate cancer and the signalling pathways involved in drug resistance including the PI3 kinase inhibitor salvestrol zytiga combo. An HSP-90 inhibitor is a good combination with Zytiga since it will have its own anticancer activity and may overcome Zytiga drug resistance. The inhibition of HSP-90 is rational since this is a chaperone protein that is responsible for the stability of other proteins including the androgen receptor (AR).

Clinical trial tests new combination treatment for advanced prostate cancer

Scientists hope to reverse resistance that can develop to the next-generation prostate cancer treatment abiraterone by combining it with a promising experimental treatment, and believe the combination also has potential when given at an earlier stage to prevent resistance developing.

The Institute of Cancer Research, London UK, and its partner The Royal Marsden Hospital will lead an international, multi-centre Phase I/II study to assess the combination of an HSP90 inhibitor called AT13387 with abiraterone. A second stage of the trial will also test AT13387 as a single agent.

Abiraterone was discovered by Professor Gerry Potter whilst at The Institute of Cancer Research (ICR) and this year he was acknowleged with an award from the Royal Society of Chemistry for his key role in devloping this drug. Abiraterone is now marketed as Zytiga by Johnson & Johnson and is now available on the NHS to treat men with advanced prostate cancer who were no longer responding to standard treatments including docetaxel chemotherapy. Abiraterone can extend life for men with advanced cancer by several years but some patients’ tumours ultimately develop resistance.

Professor Potter said "Zytiga is now widely used to treat prostate cancer and is being currently used worldwide in over 10,000 patients. Zytiga resistant prostate cancer is now emerging as a problem in oncology and various strategies are being investigated to overcome Zytiga resistance. The use of an HSP-90 inhibitor in combination with Zytiga makes good sense since this prevents the androgen receptor mediated signalling from functioning. This will make the prostate tumours shrink and the cancer should regress significantly with this combination. It also has the potential of targeting the bone mets which are normally difficult to treat."

HSP90 is a protein found in all human cells that is vital for helping other proteins fold into their correct shape. Cancer cells are especially dependent on HSP90, and so blocking this protein with drugs is considered a promising strategy to treat cancer.

The ICR carried out the important early work that uncovered the potential of targeting HSP90 to treat cancer, including publishing the first detailed 3D image of the protein. Many HSP90-inhibiting drugs are in development globally and being tested in a range of cancer types, including AT13387 from Astex and AUY922, which was discovered at the ICR and is licensed to Novartis.

Trial brings together two important research strands

The new trial, sponsored by Astex, will test the drug AT13387 in combination with abiraterone, following laboratory studies that highlighted the promise of this strategy in men with advanced prostate cancer.

The first part of the new study, Phase I, will include up to 52 patients with castration-resistant prostate cancer who are no longer responding to treatment with abiraterone. They will continue to receive their normal dose of abiraterone and will also be randomly allocated one of two different treatment regimens of AT13387.

If the trial shows the combination is safe and establishes biological effectiveness, the best of the two treatment regimens will be taken into Phase II testing. In this stage, up to 112 patients will be randomly assigned to receive AT13387 either in combination with abiraterone or alone.

Professor Paul Workman, deputy chief executive of the ICR and head of the Cancer Research UK Cancer Therapeutics Unit at the ICR, said: “We are pleased to act as clinical lead on this trial, which for the first time brings together two important strands of research pioneered at the ICR – new-generation anti-hormone treatments and inhibitors of the molecular chaperone HSP90. Our pre-clinical work has shown that combining these two approaches gives a powerful anticancer effect and should reduce the potential for drug resistance to arise. Initially we will be testing the combination in patients who have stopped responding to abiraterone in a bid to renew the drug’s effectiveness, but ultimately we hope that the combination could one day also be used up front to prevent resistance developing.”

Trial lead investigator Professor Johann de Bono, head of the drug development unit at the ICR and The Royal Marsden said: “Our hypothesis is that advanced prostate cancers that progress on all available treatments remain dependent on androgen receptor signalling. HSP90 is necessary for the functional stabilisation and processing of the androgen receptor protein, and also supports several signalling pathways that control cell growth and resistance to apoptosis, while abiraterone targets an enzyme involved in androgen synthesis. Combining HSP90 and abiraterone should offer a multi-pronged attack against androgen receptor signalling and therefore cancer growth. We hope this strategy will lead to further treatment options for this clinically important disease.”