Feature: Outflanking prostate cancer

Improving outcomes for sufferers of prostate cancer has driven the career of Dr Lisa Butler, taking her from a PhD at the University of Adelaide to postdoctoral work at the Sloan Kettering Memorial Centre in New York and back to head the Molecular Cancer Therapeutics Group at the Dame Roma Mitchell Cancer Research Laboratories in Adelaide, which is headed by Professor Wayne Tilley.

Butler’s research focus is on targeting androgen signalling in prostate cancer with the ultimate aim of devising new therapies for prostate and breast cancer.

Excepting basal and squamous cell carcinomas of the skin, prostate cancer is the most commonly diagnosed cancer and the second greatest cause of cancer deaths in men, according to the Australian Institute of Health and Welfare.

The latest data indicates that around 19,400 men are diagnosed with prostate cancer each year and that nearly 3000 of these die from the disease – more than the number of deaths caused by breast cancer in women.

The growth and survival of normal prostate tissue is dependent on male (androgenic) hormones such as testosterone, which act on prostate cells via binding to an intracellular protein, the androgen receptor.

Similarly, prostate cancer cells initially depend on androgens for their growth and survival and this is exploited in therapy for prostate cancer that has spread beyond the gland, by surgically or medically inducing hormone deprivation.

However, despite an initial response, prostate cancer cells nearly always become resistant to the hormone deprivation at some stage, and the tumour starts to grow again. Unfortunately, prostate cancer cells that are resistant to androgen deprivation typically are also intractable to cytotoxic drugs used in chemotherapy.

Traditional agents do virtually nothing to limit tumour growth and treatment options thus become quite limited for men in the later stages of disease. A major aim in the f ield of prostate cancer research is therefore to find new ways to treat this metastatic prostate cancer.

“We don’t really know what it is about prostate cancer that makes it resistant to traditional chemotherapy in the first place, but our research is identifying mechanisms to explain why it becomes resistant to hormone therapy,” says Butler.

“The cancer cells seem to evolve so that they no longer require the androgen hormone signalling pathway for growth and survival, become very sensitive to low levels of androgen, and/or start making their own androgen. With cytotoxic chemotherapeutics, it has been suggested that prostate cancer cells divide very slowly so that the drugs that target cell growth and division are not effective.”

---PB---

Under the hood

Butler and her group 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?

One of the current projects to come out of the explant work is trying to work out just why these certain combinations of agents are particularly synergistic.

“For instance, we kept reducing the doses of some individual agents right down, to a point at which they were still effective in combination – they completely suppressed growth of the cells and induced cell death – but the same drug had no effect whatsoever on the cancer cell growth or viability if used singly. In some cases, a 10-fold decrease in dose was very effective in the combinations.”

Butler knows that the promising combination strategies are very effective at blocking androgen signalling in the cancer cells, but is now trying to determine if this is the main reason for their exquisite synergy or there is an alternative mechanism.

“We have been transcript profiling prostate cancer cells treated with the various drugs both alone and in combination, and I will be presenting some of those results at Lorne 2011.

“We want to know exactly what genes are turned on and off, and when, with the hope of identifying some of these other targets we suspect are coming into play, and which, in turn, might be novel therapeutic targets in their own right.”

Butler hopes the profiling will tell her just which pathways the different combinations are affecting. “Even though there are different drugs, most likely with many different targets, we hope that the profiling will identify some consistent gene expression changes that we can then follow-up.”

What they don’t know yet, which is a priority for the next stage of Butler’s research, is to find out if any drug toxicity is also synergistic with the combination therapies. This will be checked in animal models using various doses.

“We are hoping that the lower doses might actually be less toxic, but we have to find that out in animals before going to clinical trials. Another focus at the moment is putting our promising combinations into our human tissue explants and seeing whether we can predict response to therapy.”

The group has established a strong collaborative relationship with surgeons and pathologists at the Royal Adelaide Hospital through the Australian Prostate Cancer BioResource, and Butler stresses the crucial nature of such collaboration to the entire research effort.

“We have a collection procedure set up whereby each time there is a surgery at the hospital we receive a small portion of the tumour for testing in our explant system.

Getting enough tissue as quickly as possible is absolutely essential and only happens by working very closely with the clinicians, who have been incredibly supportive, and we are really appreciative of the relationship.”

Butler stresses that the collaboration goes both ways and her group meets regularly with the clinical staff to update them on the experimental results.

“Initially we had to prove to everyone that we could keep the tissue alive and viable in the explant cultures so that the prostate cancer cells maintain their normal signalling pathways.

“While this involved a large amount of work, we are now seeing the benefit of testing the drugs with actual patient samples. It has been exciting for all concerned, because in the end we are all trying to achieve the best outcome for patients.”

Read Part II: Feature: Drug synergies can kill cancer