Interview: Charting a course towards a cure

Joe Sambrook tells Susan Williamson about the opportunities and challenges in understanding, treating and, ultimately, preventing breast cancer.

Anyone looking for a good perspective on the current state of breast cancer research in Australia could do a lot worse than track down Joe Sambrook.

Sambrook, a professor at the Peter MacCallum Cancer Centre in Melbourne, is a doyen of molecular biology. He is lead author of the three-volume mol biol bible Molecular Cloning: A Laboratory Manual, which you'll find in most science labs, and he helped to found the national familial cancer program kConFab.

More recently, he chaired the expert advisory committee that drew up Australia's national plan for breast cancer research. Published late last year by the National Breast Cancer Foundation (NBCF), the document sets out strategies for maintaining investment in basic research as well as working towards taking things further in the implementation of prevention and treatment for breast cancer.

Sambrook's career in molecular biology began with a PhD on the genetics of animal viruses with legendary immunologist Frank Fenner at the ANU in 1963. Born in the UK, Sambrook returned to Cambridge do a postdoc -- with Sydney Brenner -- on the genetics of E. coli.

During a second postdoc with Dr Renato Dulbecco at the Salk Institute in La Jolla, California, Sambrook met James Watson, co-discoverer of the structure of DNA. Watson had just taken over as director of the Cold Spring Harbour Lab in New York and approached Sambrook about joining the lab.

"[Watson] was keen to move the work of the institute into mammalian viruses and cells, and into animal genetics," recalls Sambrook. "So I moved there in 1969 with a three-year contract and stayed for the next 16 years. There were six people in the lab when I arrived; when I left there were more than 400."

Sambrook led Cold Spring Harbour's tumour virus group, which worked out how small DNA viruses, such as SV40 and adenoviruses, transformed normal cells into cancerous cells. Sambrook was appointed assistant director in 1977, and when he left the institute in 1985 a building was named after him, The Joseph F Sambrook Laboratory, acknowledging his achievements.

Keen to get involved in the translation of research to medical application, Sambrook then moved to Texas to head the biochemistry department at Southwestern Medical School in Dallas. One of the projects his lab tackled aimed to improve thrombolytic agents for dissolving blood clots. At the time, the enzyme tissue plasminogen activator (TPA) was being used clinically to dissolve coronary blood clots, but it had serious negative side-effects including strokes and cranial bleeding. Sambrook's team deciphered how TPA worked and then devised mutations that could be introduced to minimise the enzyme's side-effects and improve its therapeutic performance. This led to the design and synthesis of a new generation of tissue plasminogen activators that are still in clinical use today.

Sambrook's interest in breast cancer began during his last two years at Southwestern, around the time that two breast cancer genes, BRCA1 and BRCA2, were cloned -- BRCA1 by Myriad Genetics, and BRCA2 by Prof Mike Stratton, who is now at the Cancer Research Institute in the UK.

In late 1994, Sambrook returned to Australia to join the Peter Mac, which had just moved to new premises in East Melbourne. This gave Sambrook the opportunity to start new research programs and to set up projects that had clinical significance as well as good science.

In September 1995, Sambrook suggested that a consortium be formed to overcome some of the problems that prevailed in breast cancer research in Australia at that time, such as small-scale projects that had limited statistical power. That led to the founding of kConFab, a national consortium for research into familial breast cancer. Funded by the Kathleen Cunningham Foundation, (now the National Breast Cancer Foundation), kConFab was the first nationwide collaborative consortium to work on any cancer.

Breast cancer remains the most common form of cancer in women. In 2002, more than 11,000 Australian women developed breast cancer and more than 2500 died of the disease. Family history has long been known to be a risk factor for breast cancer, which can occur due to the inheritance of deleterious mutations in specific genes, such as BRCA1 and BRCA2 as well as hormonal, dietary and environmental influences. Hormonal influences play a significant role -- women who start menstruating at an early age or experience a late menopause have a higher risk of developing breast cancer. Conversely, being older at the start of menstruation and having an early menopause tends to reduce the risk of developing breast cancer.

Families with extremely strong histories of breast cancer are recruited into kConFab after being referred to familial cancer clinics, of which there are currently about 17 around the country. Sambrook says kConFab has been a powerful advocate to get these clinics involved in research: their aim is to collect a large number of the families in Australia that carry mutations in the BRCA1 and BRCA2. "There are about 10,000 of these families in total," says Sambrook. "And you need at least one or two thousand of them to get enough power to answer most of the interesting and important scientific and medical questions."

If a woman inherits a mutated version of BRCA1, her likelihood of developing breast and/or ovarian cancer increases markedly and the cancers tend to appear at a relatively early age.

Together, BRCA1 and BRCA2 account for about 5 per cent of all breast cancer. However, a much larger proportion of cancers appears in families with equally strong histories but with no detectable mutations in BRCA1 or BRCA2. This suggests that there are other, as yet unknown genes that can cause the inherited form of the disease.

kConFab collects clinical, genetic and epidemiological information on all these families, as well as blood from family members -- both men and women, who are affected and unaffected by the disease. So far they have recruited about 1000 families that fit the criteria for entry into kConFab, and about 30 per cent of these people have mutations in BRCA1 or BRCA2. The detection of these mutations enables carriers to be identified and offered intensive clinical surveillance appropriate to their high degree of risk of developing breast cancer.

The large number of families and individuals involved and the depth of information collected provides sufficient statistical power for studies on the interaction of environmental risk factors with genetic predisposition in breast cancer, and for correlating patterns of gene expression and chromosomal rearrangements in tumours with germline mutations in genes such as BRCA1 and BRCA2. "The idea is to collect comprehensive sets of information so researchers can integrate the molecular properties of the tumour with epidemiological exposures and medical outcomes," says Sambrook. "So far kConFab is supporting about more than 40 research programs worldwide." For example, kConFab is contributing to a large international study to map and identify additional genes that cause breast cancer.

"It is a general problem that as we know more about breast cancer, it becomes more heterogeneous," says Sambrook. "The heterogeneity can be overwhelming, when you realise how many different diseases there are under this one name." This heterogeneity suggests that it may be necessary to devise specific treatments for individual classes of tumours. However, this makes setting up clinical trials for new treatments difficult and expensive, unless, as Sambrook says, a quick, robust and reasonably cheap test could be devised to identify biomarkers specific to individual tumours.

Researchers are still looking for what drives the growth of BRCA1 tumours. Oestrogen may be involved in the initiation of the tumour, but soon afterwards, the majority of cancers in BRCA1 carriers lose expression of oestrogen receptors so that subsequent growth occurs independently of oestrogen. Drugs such as tamoxifen, which block oestrogen action, do not work against these tumours and there is an urgent need for new types of chemotherapy. An increasing number of women carrying BRCA1 mutations decide to reduce their risk of cancer by having children early, and then having their ovaries removed because this significantly reduces the risk of developing breast cancer.

A different approach is to focus on prevention of breast cancer, but to do this you need to know how and where the disease starts. Sambrook says he would place bets on breast cancer starting early in life. Ovarian hormones begin to surge in girls at around 10 years of age, which is when stem cells in the breast begin to develop into the mammary gland. One potential consequence of an increase in oestrogen levels is the chemical damage to DNA caused by breakdown products of oestrogen, "defence mechanisms exist to deal with this damage," says Sambrook. "But if these mechanisms are not fully in place before oestrogen begins to flow into breast epithelial cells, the initial events on the long road to cancer may occur early in life."

Plan of action

Are we going about understanding and curing or treating breast cancer in the right way? And is the way science is currently set up going to lead to better treatments? Those issues were raised by the National Breast Cancer Foundation and led to the formulation of a national action plan, one of Sambrook's not-so-small projects in the recent past.

The national action plan, Challenging Breast Cancer: a National Action Plan for Breast Cancer Research and Funding, was launched in Sydney last October. It defines priorities, sets goals and proposes structural and funding changes that aim to progress Australian efforts to develop strategies to prevent, detect and treat the disease.

One proposal is to form an alliance of funding bodies so as to enable the funding of larger long-term projects. Sambrook hopes the alliance will include the NBCF, the National Health and Medical Research Council, the state cancer councils and a number of other breast cancer organisations.

"In this country, breast cancer research tends to be funded in small packets and most of the projects are concentrated at the basic end of the research spectrum," Sambrook says. "There is a need for larger, long-term translational research. The goal should be to construct a continuous pipeline that starts with basic research and feeds all of the downstream components of the breast cancer continuum."

The immediate challenge, he says, is to persuade an alliance of funding bodies to commit $25-50 million in additional funding for large-scale projects over 20 years. The establishment of a funding alliance would also create opportunities to attract new funds, monitor progress in breast cancer research, improve accountability and communication between researchers, and serve as a political advocate for breast cancer and potentially generate and implement research policy.

Another issue raised in the NBCF report is the extreme shortage of research pathologists in Australia. Because pathology remains a lynchpin of both breast cancer diagnosis and research, "we need to find ways to encourage pathologists to get involved in research," says Sambrook. With the rise of commercial pathology, academic pathologists are almost extinct in this country.

Other proposals in the action plan include the harmonisation of data held in cancer registries, which varies from state to state, as do rules for accessing these data. This creates unnecessary bureaucratic problems for organisations like kConFab, which need to validate cases of cancer. At present kConFab has to apply to each state individually, as well as to the Australian Institute of Health and Welfare, to find information about individuals.

"There needs to be a federal fix to this problem," Sambrook says. Ethics is another problem area. "kConFab needs to obtain approval from 17 or more ethics committees around the country. We need to find a way to reduce duplication of effort and expense while maintaining ethical standards."

In part because of kConFab, breast cancer research in Australia is better organised, more coherent and more collaborative than ever before. But as Sambrook points out, this means nothing unless it is translated into lower incidence and more secure cures for the disease. "The National Breast Cancer Foundation plan is our best way forward", says Sambrook. "If it works for breast cancer, why wouldn't similar schemes be successful with other cancers, such as prostate and colon?"