Feature: Drug synergies can kill cancer

Reat Part I: Feature: Outflanking prostate cancer

Butler’s research also involves working with cancer drugs that target either androgens or the androgen receptor and limit their action in prostate cancer cells, but on more of a grand scale. In particular, her group is testing a whole gamut of drug permutations and combinations to come up with better ways of killing prostate cancer cells.

The batch of compounds at Butler’s disposal all target generally the same pathway – androgen signalling – but in different ways. Some disrupt the androgen receptor either by affecting the way the receptor functions or by binding directly to the androgen receptors, while others stop the receptor being made.

What Butler and her team have found is that administering these different sorts of agents together synergises their effect on the cancer cells, in some case completely blocking key cancer survival pathways and stopping their growth.

“This means that we can get a much greater effect with a much lower dose of the drug, sometimes to the extent that if they were given on their own at that concentration, the same agents would have little or no effect.”

For instance, a very low level of anti-androgen drug, bicalutamide, inhibits cancer cell proliferation much more effectively when combined with other pathway inhibitors than when used as a single agent.

This work builds on several exciting findings made during Butler’s postdoc in New York, where she worked on new drug development with cell biologist Dr Paul Marks, and the world-leading genitourinary oncologist, Dr Howard Scher.

She was the first to demonstrate that a new class of histone deacetylase inhibitors had potent biological activity against prostate tumours and androgen signalling, leading to a number of clinical trials for these agents in the US.

This class of inhibitor basically disrupts the normal modulation of nuclear chromatin and regulation of gene transcription, which ultimately limits cell proliferation by inducing cell cycle arrest and/or cell suicide.

The use of histone deacetylase inhibitors as anti-cancer agents has now expanded considerably, with major pharmaceutical companies now having development programs and over 10 agents in clinical trials. Butler’s current armoury of agents to use in combination includes some histone deacetylase inhibitors as well as heat shock protein 90 inhibitors and other molecular agents such as dominant negative receptors.

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The next step for Butler and her team was to take these exciting in vitro results and start asking if they might be equally successful in the clinic. “We know that a lot of things can look very promising at the test tube or cell line stage, but end up being disappointing in the clinic,” Butler says.

“So we wanted to develop better pre-clinical models of prostate cancer – something that is closer to the human clinical disease so that we could better predict the combination of agents that is going to be most successful in an individual patient.”

To do that, Butler and a postdoctoral fellow in her group, Dr Maggie Centenera, have developed an explant model of prostate cancer whereby bits of resected tumours from patients are taken to the lab and grown in culture dishes.

The cultured tumour is then introduced to the group’s range of drug combinations to see what happens with respect to cell growth, viability and signalling effects: are they hitting the right targets and is that having an effect of clinical use?

So far this model has proven very successful in showing that various drug combinations can dramatically affect the growth of some prostate tumours in the dishes.

“We are hoping that this approach will be more clinically relevant than our classical cell line-based testing methods and provide a robust pre-clinical model for testing cancer drugs for clinical use in prostate cancer patients.”

A big plus for Butler’s research is that nearly all of the agents they are testing have already been studied extensively in clinical trials and thus could potentially be rapidly adapted for use in prostate cancer patients.

“Unfortunately, none of them individually have shown much promise in the treatment of prostate cancer in terms of improving patient outcomes or survival.”

This is despite the same agents being very effective and looking highly promising in pre-clinical studies, and probably reflects the cells’ ability to overcome the effect of a single agent on a single target and quickly become resistant.

It could also reflect that patients are being treated with these agents at too late a stage in their disease, or that there are no suitable means to identify patients who are likely to respond to a particular therapy, says Butler.

These results were collectively a great disappointment for the field of prostate cancer research and what Butler now hopes is that by using the combinatorial approach, multiple targets related to the same androgen signalling pathway will be hit at the same time, effectively blocking the cells’ escape routes long enough to have a real effect on tumour cell survival.