Instead of targeting faults in the DNA code, the drug - discovered in a collaboration between The Institute of Cancer Research (ICR) and Chroma Therapeutics - targets cancer-causing errors in the way the body reads the DNA code.
This second and equally important set of instructions takes the form of a series of chemical switches that determine whether genes are turned on or off, and ultimately what the cell will look like and how it will function.
Epigenetics influence nature in many ways including the ability of a caterpillar to morph into a butterfly, even though its DNA does not change. Alterations in epigenetic control can also lead to cancer.
Lead author Dr Udai Banerji from the ICR and The Royal Marsden says: “This is a new angle of attack against cancer. Scientists are already working hard to design drugs that target many cancer genes, but there is also huge potential in targeting these epigenetic changes. Although epigenetics is a normal part of biology, faults in epigenetic switches can cause cancer by switching on oncogenes or switching off tumour suppressing genes.”
The new drug acts on an enzyme called histone deacetylase (HDAC), which normally regulates gene expression – by switching genes on and off – via modification of the proteins that package and order DNA, called histones.
Of all known epigenetic targets, scientists have made the most progress in developing inhibitors for HDAC, with two HDAC inhibiting drugs already licensed to treat a type of lymphoma*. However, these existing drugs have limitations, including significant side-effects and for one of them the need for injections.
The next-generation HDAC drug, CHR-3996, has been designed so it selectively inhibits one type of HDAC enzyme (class one), which the collaborative team hopes will reduce side-effects associated with existing treatments while retaining its anti-cancer properties. It killed a range of different cancer cell types in laboratory testing.
In a Phase I study carried out in the Drug Development Unit of the ICR and The Royal Marsden, and the Erasmus University Medical Center in Rotterdam, CHR-3996 was tested in 39 patients with a range of advanced cancers.
“First-generation HDAC inhibitors have already demonstrated that this class of drugs can be effective for some cancer patients. The objective here was to develop a more specific drug that would be better tolerated, and could be formulated so it can be administered as tablets rather than an injection to maximize patient comfort and safety,” Dr Banerji says. “We found that CHR-3996 was active when taken in pill form, and the side-effects were favourable.”
The trial was primarily designed to assess safety, but one patient’s pancreatic tumours shrunk, and nine other patients were shown to have stable disease for at least two months. Blood tests revealed that the drug was reaching its target, and was present in a concentration that was sufficient to cause tumours to shrink in pre-clinical models.
CHR-3996 is one of 16 innovative drug candidates discovered over the past five years in the ICR’s Cancer Research UK Cancer Therapeutics Unit, and one of six taken into Phase I clinical trials at the ICR and The Royal Marsden’s Drug Development Unit.
Professor Paul Workman, Director of the Cancer Research UK Cancer Therapeutics Unit at the ICR, says: “It very gratifying to see promising results from the first stage of clinical evaluation for this epigenetic drug, which was discovered through a collaboration between Chroma Therapeutics and The Institute of Cancer Research. We are looking forward to seeing the results of larger-scale patient trials.”
The study was sponsored by Chroma Therapeutics while the Drug Development Unit receives infrastructural funding from Cancer Research UK, ECMC and the NIHR.
Dr Joanna Reynolds, Cancer Research UK’s director of centres, said: “This ‘epigenetic’ approach to therapy - which targets chemical switches rather than DNA - is an exciting new avenue for drug discovery and it’s great to see rapid progress being made in this field. We look forward to seeing the results of further trials, which will aim to discover whether this pill can help improve cancer survival in patients with advanced disease.”