Tuesday, April 26, 2011

Future of Personalized Cancer Care Is Promising and Near


Newswise — BIRMINGHAM, Ala. – Cancer survival rates could improve soon with whole-genome sequencing, according to two studies published in the April 20, 2011, issue of the Journal of the American Medical Association that describe the first clinical applications of the high-tech process in patients with cancer.
The papers are remarkable examples of the power that genomic data hold for patients with a cancer diagnosis, according to an accompanying editorial by Boris Pasche, M.D., deputy director of the University of Alabama at Birmingham Comprehensive Cancer Center and professor of medicine, and Devin Absher, Ph.D., of the HudsonAlpha Institute for Biotechnology.
Whole-genome sequencing is a high-tech process that essentially maps a person’s DNA and analyzes it for mutations. This has enabled cancer therapies to evolve from a standard therapy for all patients with a given type of cancer to a slightly more personalized treatment.
“Whole-genome sequencing gives us the ability to screen a much larger number of tumors and correlate them with the outcome of the patient, so it is very likely that our targeted therapy is going to be exploding in the next decade,” Pasche says.
Half of all men and one-third of all women in the United States will develop cancer during their lifetimes, according to the American Cancer Society; and few, if any, do not know someone who has had cancer or died because of it. This new advance could change that.
“In one study, a patient with leukemia had a poor prognosis, but through sequencing, this patient was found to have a gene that showed they would react favorably with a different therapy than originally recommended,” Pasche says. “If patients have certain genes, they may not respond to certain treatments. But whole-genome sequencing gives a full picture of the genetic make-up of the tumor and the patient, and it may allow the physician to target a new treatment.”
Pasche says the unbiased picture of the sequenced DNA enables physicians to look at tumors in a way not possible previously. Even when the technology finally was available, it was too expensive. Now, the cost to sequence a patient’s entire genome and the genome of their tumor is down by more than 100 fold, but still ranges from $30,000 to $40,000.
“Prices are still dropping very rapidly; in the next 10 years, it will cost less than $10,000, and it certainly will be more affordable in the next five years,” says Pasche, who believes having sequencing covered by insurance or otherwise is a work in progress.
At UAB, Pasche says whole-genome sequencing is being used in many projects, most notably in a clinical trial for women with triple-negative breast cancer.
“There is a high degree of expectation with whole-genome sequencing,” he says. “The hope is that it will help survival rates of those with cancer.”
About the UAB Comprehensive Cancer Center
The UAB Comprehensive Cancer Center is among the 40 cancer centers in the nation to meet the stringent criteria for the National Cancer Institute's comprehensive designation. The center is a leader in groundbreaking research, reducing cancer disparities and leading-edge patient care.
EDITOR’S NOTE: The University of Alabama at Birmingham (UAB) is a separate, independent institution from the University of Alabama, which is located in Tuscaloosa. Please use University of Alabama at Birmingham on first reference and UAB on all consecutive references.

Scientists Decoded DNA of 50 Breast Cancer Patients


St. Louis, MO (Scicasts) - Scientists at Washington University School of Medicine in St. Louis have sequenced the whole genomes of tumors from 50 breast cancer patients and compared them to the matched DNA of the same patients' healthy cells. This is the single largest cancer genomics investigation reported to date, the university claims, and has allowed researchers to find mutations that only occurred in the cancer cells through this comparison process.

The above Circos plot is a visual representation of the genomic disruptions in one of the breast cancers studied. Image by: Matthew J. Ellis, MD, PhD.

This research was presented at the American Association for Cancer Research 102nd Annual Meeting 2011. According to the press report, the researchers uncovered incredible complexity in the cancer genomes, but also uncovered a glimpse of new routes toward personalized medicine.
In all, the tumors had more than 1,700 mutations, most of which were unique to the individual, said Matthew J. Ellis, MD, PhD, professor of medicine at Washington University School of Medicine in St. Louis and a lead investigator on the project. "Cancer genomes are extraordinarily complicated," Ellis continued. "This explains our difficulty in predicting outcomes and finding new treatments."
To undertake the massive task, Washington University oncologists and pathologists at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine collaborated with the university's Genome Institute to sequence over 10 trillion chemical bases of DNA — repeating the sequencing of each patient's tumor and healthy DNA about 30 times to ensure accurate data.
"The computing facilities required to analyze this amount of data are similar in scale to those of the Large Hadron Collider, used to understand the workings of sub-atomic particles," said Ellis.
The DNA samples came from patients enrolled in a clinical trial that Ellis is leading for the American College of Surgeons Oncology Group. All patients in the trial had what is called estrogen-receptor-positive breast cancer. These cancer cells have receptors that bind to the hormone estrogen and help the tumors grow.
To slow tumor growth and make the tumors easier to remove, patients received estrogen-lowering drugs before surgery. But, for unknown reasons, this treatment does not always work. Twenty-four of the 50 tumor samples came from patients whose tumors were resistant to this treatment, and 26 came from patients whose tumors responded. Comparing the two groups might help explain why some estrogen-receptor-positive breast cancer patients do well with estrogen-lowering drugs, while others do poorly.
Confirming previous work, Ellis and colleagues found that two mutations were relatively common in many of the patients' cancers. One called PIK3CA is present in about 40 percent of breast cancers that express receptors for estrogen. Another called TP53 is present in about 20 percent.
Adding to this short list of common mutations, the researchers found a third, MAP3K1, that controls programmed cell death and is disabled in about 10 percent of estrogen-receptor-positive breast cancers. The mutated gene allows cells that should die to continue living. Only two other genes, ATR and MYST3, harbored mutations that recurred at a similar frequency as MAP3K1 and were statistically significant.
"To get through this experiment and find only three additional gene mutations at the 10 percent recurrence level was a bit of a shock," Ellis explained.
In addition, the team found 21 genes that were also significantly mutated, but at much lower rates — never appearing in more than two or three patients. Despite the relative rarity of these mutations, Ellis stresses their importance.
"Breast cancer is so common that mutations that recur at a 5 percent frequency level still involve many thousands of women," he said.
Ellis points out that some mutations that are rare in breast cancer may be common in other cancers and already have drugs designed to treat them.
"You may find the rare breast cancer patient whose tumor has a mutation that's more commonly found in leukemia, for example. So you might give that breast cancer patient a leukemia drug," Ellis explained.
But such treatment is only possible when the cancer's genetics are known in advance. Ideally, according to Ellis, the goal is to design treatments by sequencing the tumor genome when the cancer is first diagnosed.
"We get good therapeutic ideas from the genomic information," he said. "The near-term goal is to use information on whole genome sequencing to guide a personalized approach to the patient's treatment."
This work builds on previous collaborations between Washington University oncologists and the Genome Institute. In a study published last year in Nature, they reported the complete tumor and normal DNA sequences of a woman with "triple-negative" breast cancer, a particularly aggressive type that is difficult to treat and more common in younger women and African-Americans.
While many mutations are rare or even unique to one patient, Ellis highlighted that quite a few can be classified on the basis of common biological effects and therefore could be considered together for a particular therapeutic approach.
Ellis looks to future work to help make sense of breast cancer's complexity. But these highly detailed genome maps are an important first step. "At least we're reaching the limits of the complexity of the problem," he said. "It's not like looking into a telescope and wondering how far the universe goes. Ultimately, the universe of breast cancer is restricted by the size of the human genome."

Sunday, April 24, 2011

Scientists Find Promising Breast Cancer Therapy


A new combination of drug therapies may prove effective in treating triple-negative breast cancer in human patients, according to a recent study published by researchers at Harvard Medical School and Baylor College of Medicine.
Triple-negative breast cancer is one of three classes of breast cancers and the only one that currently has no readily accessible treatment, said HMS Professor Stephen J. Elledge, the principle investigator for the Harvard lab.
The only treatment option for patients with these tumors is chemotherapy, and the median survival rate for such patients is very low.
The research sought to identify classes of molecules that, when down regulated, cause a cell to gain cancerous properties.
The study, which was published last month in the journal Cell, reported that the absence of a tyrosine phosphatase enzyme called PTPN12 caused human mammary cells to gain cancer-like properties in vitro.
The researchers separately found that PTPN12 was inactive in more than 50 percent of the triple-negative breast cancers tested, showing that the enzyme plays a significant role in this class of breast cancer, Elledge said.
Thomas F. Westbrook, a former postdoctoral fellow in Elledge’s Harvard lab and currently leading the research group at Baylor, discovered the PTPN12 enzyme while still at Harvard.
That enzyme is known to deactivate another group of enzymes called receptor tyrosine kinases that are responsible for cell growth.
So when PTPN12 is inactivated, cells are free to grow and divide rapidly, like cancer cells.
The research group identified three tyrosine kinases that are specifically regulated by PTPN12. These results indicated that the misregulation of these three enzymes could be a leading cause of triple-negative breast cancer, according to the study.
“If we figure out how to inhibit different kinases together, we might be able to treat this disease,” said Elledge.
The researchers tested in mice a combination of two FDA-approved, on-the-market drugs that are already used to treat other cancers and that inhibit the desired kinases. One drug, Tykerb, is known to inhibit two of the enzymes, and another, Sutent, is known to inhibit the third.
The study found that tumors in mice that were treated with a combination of both drugs shrank by more than 90 percent, and life expectancy for these mice more than doubled.
The researchers are now in the process of negotiating with drug companies to design a Phase II clinical trial that will test the new therapy in humans.
Ellidge said, “It may take two to three years to set up a clinical trial and get results, and then we can determine whether there will be a therapy.”
Ellidge said that while the research group has identified some of the kinases that are activated in triple-negative breast cancer, there is still more research to be done in order to understand the disease mechanisms completely.