IT took some serious sleuthing for physician and molecular biologist Jeremy Henson to turn what began as a hunch about abnormal DNA nine years ago into a screening test for aggressive cancers and a search for better treatments.
Henson, a postdoctoral fellow at the Children's Medical Research Institute in Sydney, has discovered a distinctive signature for a mechanism used by some of the hardest to treat cancers. He identified a specific, oddly shaped molecule absent in normal cells and he has developed a lab test to screen for it.
That makes it much faster for researchers to identify which genes are involved in such cancers and to trial compounds that could turn them off, thus stopping cancer cells from multiplying.
What makes cancer cells so threatening is their ability to make themselves immortal.
Each time a normal cell divides, the ends of DNA-bearing chromosomes, called telomeres, shorten a little. After about 50 divisions a stress response is triggered and the cell is unable to divide further.
"If a cancer cell were to divide 50 times and then stop it would grow only to the size of a grape and generally wouldn't cause a problem," Henson explains.
But in about 85 per cent of cancers a normally present enzyme, telomerase, becomes over-active and helps replenish the shortened chromosome tips, allowing the cell to multiply indefinitely.
About 15 years ago Roger Reddel, director of the CMRI and his then doctoral student, now associate professor, Tracy Bryan observed another method cancer cells use to secure eternal life.
It's called the alternative lengthening of telomeres mechanism. This ALT mechanism occurs in about 15 per cent of cancers, including malignant brain tumours, bone cancers and cancers of the connective tissues, as well as about 5 per cent of breast cancers and 40 per cent of stomach cancers.
The ALT mechanism tops up DNA sequences lost along with telomere tips during cell division by finding another telomere to use as a template to replace the lost DNA sequence. This repeatedly resets the cell's internal clock so it bypasses its use-by date and divides indefinitely.
This month Reddel was made a fellow of the Australian Academy of Science in recognition of his work.
Together, Reddel and Henson have teased out details of Henson's signature: copies of telomere DNA sequences arranged in an unusual circular form called C-circles.
"Very conveniently for us, the tumour sheds these C-circles into the bloodstream, so the cancer can be identified by a simple blood test," Reddel says.
They're using the test in the lab to screen for genes driving the ALT mechanism.
"Before this, it would take a year's work to test two or three genes and even then we were often uncertain [about whether they were involved]," Henson says. "Now we can look at 20 genes in less than a month and get a definite answer. That's important because every gene that we find involved in ALT is another target for killing cancer cells without harming normal cells."
He predicts the lab test will be developed into a blood test able to screen people at high risk of certain cancers. "It hopefully will allow us to pick up presence of tumour very early on," he says. "It's extremely sensitive in the lab. We can detect as few as 100 cancer cells."
Such a test could have a substantial effect, says David Thomas, a medical oncologist and researcher at Melbourne's Peter MacCallum Cancer Centre.
"If it's successful the C-circle test would enable us to measure tumours without the need for invasive tests. It could be used to identify whether tumours are responding to treatment or to tell when tumours come back. In some situations, early identification of relapse can be critical to whether or not we can cure people," Thomas says.
According to Thomas, not only could C-circle tests be done cheaply, they'd likely apply to multiple cancer types, including sarcomas, soft tissue cancers.
He adds: "At the moment, we're using CT scans, PET scans and MRIs to monitor treatment and detect early relapses for patients with sarcomas, but those tests are costly and time-consuming. And with CT scans, which are used most regularly, there's also a certain finite risk of new cancer developing due to the added radiation exposure."
In bone cancer, response to initial chemotherapy is one of the strongest predictors of prognosis. Typically after diagnosis a person will go on a few months of chemo, then the tumour is removed and sent to a pathologist. It is only then that it can be determined if the chemotherapy worked. However, that's too late to change an unsuccessful chemotherapy regime. If the C-circle test can pick up unsuccessful chemotherapy regimes in time to change them, it would give patients a much better chance of surviving.
Knowing whether the ALT mechanism is at work also can affect a patient's prognosis in some cases, changing how doctors manage the cancer, Henson says.
For example, a quarter of malignant brain tumours use the ALT mechanism. For those patients the average survival time is three times higher than for other patients, 2.5 years compared with nine months. Henson says this could make a difference in how aggressively to treat those patients to maximise their quality of life.
The need for more accurate, accessible tests isn't disputed. As Thomas says, the most reliable way to cure cancer is to detect it before it has spread.
But cancer screening is notoriously problematic. On a population-wide level, reliable and cost-effective screening tools are few and far between, as illustrated by the recent bowel cancer screening debacle. The government was forced to suspend its national screening program after more than 400,000 test kits containing a faulty solution were mailed out.
There may also be an imbalance between demand for a test and the amount and desirability of data to warrant it. For instance, the prostate-specific antigen test, used to screen for prostate cancer, measures levels of protein that can be a sign of cancer or of other non-life-threatening conditions. Moreover, follow-up tests are invasive and carry inherent risks, and there's no clear proof they save lives. That's so as prostate cancer usually progresses slowly and may not become life-threatening or cause symptoms.
However, there are definite criteria a good cancer test should meet, Thomas says. "What we need is a test that can be done anywhere, including for patients from remote areas, on a simple blood sample, which doesn't require expensive equipment or special knowledge and which does not expose patients to added risk," he says. "I hope the C-circle assay will meet this need."
Meanwhile, challenges remain.
What has made the ALT mechanism so difficult for researchers to investigate is the fact the very process it uses to make cells immortal is the same process normal cells use to repair damaged DNA.
It took two years of full- time work just to figure out what the C-circles look like, then another two years working flat-out seven days a week to develop a test to detect them.
The experience shows how tricky it can be to track down the inner workings of cancer cells.
"We're working with things that are smaller than the wavelength of light, so it's impossible to ever see them with a microscope," Henson says. "To narrow down exactly what these abnormal DNA structures look like we work indirectly."
That is, researchers use molecules they know bind only to specific structures and label them with tags to work out which ones bind to the C-circles. They watch how C-circles behave in different environments and with what molecules they interact.
At the moment, the lab test uses radioactivity as the final step to detect C-circle molecules. That makes it very sensitive but also impractical, as any activity involving radioactivity is highly regulated, requiring specially trained staff and designated radioactive areas.
Regardless, CMRI researchers are working to develop what Henson calls "a more clinically appropriate technique" that maintains the same level of sensitivity. And Henson, for one, is optimistic: "We are almost there."
First published in The Australian, 22 May 2010