PROTECTIVE PUNCH
Polymorphisms, or variations of genes, may point oncologists toward the medicines that hold the most promise for individual patients.
USC medical scientists are leaping forward in time. And no time machine is involved, though their methods are advanced enough to lead them to file for patents on the technology.
The researchers are finding ways to predict, at an early age, if a person is likely to develop cancer in the future. That knowledge may be startling to a patient, but it would give needed, advanced warning and tip off doctors to screen for cancer during its earliest, most treatable stages, before it can wreak havoc.
All this from analyzing a patient's genetic blueprint obtained from a simple blood sample. Any cell in the human body can provide the necessary evidence.
The doctors look for something called a polymorphism: a variant of a gene that scientists have found is associated with cancer. Polymorphisms also account for characteristics that differ from person to person such as one individual having brown hair, while another has blond.
"USC is well known for identifying polymorphisms associated with cancer risks,” says Heinz-Josef Lenz, M.D., associate professor of medicine at the Keck School and scientific director of cancer genetics at USC/Norris Comprehensive Cancer Center.
USC scientists, such as Juergen Reichardt, Ph.D., associate professor of molecular biology and biochemistry, and Gerhard Coetzee, Ph.D., associate professor of urology and molecular biology and immunology, already have found polymorphisms associated with prostate, breast and lung cancers.
And not only can variations in genes be associated with risk of getting cancer, but they can help guide treatment decisions if a patient is diagnosed with the disease. A growing number of genetic tests may point oncologists toward the standard and investigational medicines that hold the most promise for individual patients.
With cancer, though, patients usually stand the best chance at survival and a long life when the disease is detected early.
For example, to detect early signs of colon cancer, doctors examine the large intestine through colonoscopy or sigmoidoscopy—a close-up look at the intestinal wall done with a flexible, fiberoptic tube.
Doctors recommend men and women start those screenings at age 50. (About 90 percent of people with colorectal cancer are 50 or older.) But when a patient is known to have a high risk for the cancer, doctors recommend beginning screenings earlier in life. Today, those considered at high risk are people with certain inherited traits and a significant family history of colon cancer—but doctors need even more tools to find those at risk.
In a promising development, Lenz and his cancer-battling colleagues identified a polymorphism that might tip them off to patients at greater risk of developing colon cancer before the age at which the disease typically strikes.
The USC/Norris scientists examined a gene connected to a special kind of natural protein called manganese superoxide dismutase, or MnSOD.
The gene signals the body to make MnSOD, one of the body's key chemical fighters against oxidative stress. If the gene works well, the MnSOD produced can effectively scavenge and neutralize oxidative radicals that damage human cells.
But if someone is found to have a certain polymorphism of this gene, the body produces a slightly different kind of MnSOD that is less effective, researchers believe. The substance packs less of a protective punch.
People with this polymorphism may not be as shielded from cellular damage as others—and may be more likely to get colon cancer at a young age, according to Lenz.
The USC research team conducted a test to understand the polymorphism's nuances. They looked at 172 patients diagnosed with colon cancer, and split them into two age groups with age 40 as the dividing line. Then they took a closer look at the MnSOD gene in each cancer patient.
They found that the group of colorectal cancer patients over age 40 had an equal distribution of each variation (or allele) of the gene—just like the population at large. In contrast, researchers found that 70 percent of those under age 40 with colorectal cancer had one specific, suspicious variation.
And while only 14 percent of the older colorectal cancer patients had a matching pair of the genes with the variation, a greater proportion—47 percent— of the under-40 patients had a pair of the suspicious alleles.
All of this leads researchers to suspect the variations are linked to a risk of developing colon cancer at an early age.
Lenz says the findings encourage further research: Future studies will monitor healthy, young people to see if study participants with genetic polymorphisms are indeed at greater risk. Already, medical scientists suspect that certain population groups, including Latinos and Asians, are more likely to have such polymorphisms.
If the findings bear out, they could significantly affect screening guidelines, Lenz notes. In the future, young patients found to have the suspicious polymorphism will know they need to be tested for colorectal cancer routinely, and their physicians will need to be especially vigilant for signs of the disease.
Lenz says MnSOD is just one clue among many in the search for the best ways to attack cancer.
His group is also exploring the role of the XRCCI gene, which is important in helping repair damaged DNA. The researchers are looking at the frequency and significance of polymorphisms in this gene, and are gathering data to show its potential role in early onset colon cancer.
But its power does not stop at detection. The XRCCI gene looks like a promising tool for oncologists seeking the optimal treatments for their patients' cancer, too. “It appears that XRCCI can predict resistance to chemotherapy,” Lenz says.
By testing colon cancer patients to see if they have a certain variety of the XRCCI gene, doctors may soon know in advance that a particular tumor is likely to resist certain drugs, leading physicians to suggest other more promising drugs for patients instead.
USC/Norris researchers already have found that a variety of genes in tumor cells can be tested in this same way.
The National Institute of General Medical Sciences, or NIGMS, one of the National Institutes of Health, believes this line of investigation holds great hope. NIGMS recently funded a $6.6 million partnership between Lenz and colleagues at Washington University School of Medicine in St. Louis to uncover how genes influence the effectiveness of drugs from person to person.
Part of an initiative known as the Pharmacogenetics Research Network, the effort will help medical scientists continue to associate new markers with new anti-cancer drugs.
"This area of molecular profiling is growing here at USC, and we want to revolutionize the way cancer will be treated,” Lenz says. "We hope these investigations will help protect patients at risk of developing the disease early, and optimize clinical outcomes for patients diagnosed with cancer.” ?
Round Two of Tumor Fight
Keck School of Medicine cancer researchers have added a valuable tool to the oncologist’s tumor-fighting toolbox: a way to find more effective medicines for advanced colon cancer patients if their first round of chemotherapy fails.
By analyzing tissue from a patient’s tumor, research oncologists at the USC/Norris Comprehensive Cancer Center can predict whether a patient is likely to respond to treatment that combines one of the world’s most-prescribed anti-cancer drugs and a powerful platinum-based chemotherapy.
Oncologist Heinz-Josef Lenz, M.D., associate professor of medicine at the Keck School of Medicine of USC, says the results mean physicians can better customize treatment for metastatic colon cancer patients and steer them toward medicines that hold the greatest potential for extending patients’ lives.
“For the first time, we are finding markers that identify the success of second-line therapy,” says Lenz, scientific director of cancer genetics at USC/Norris. “We can predict who will respond to this therapy, while sparing others the discomfort of a therapy that probably would not help them.”
Lenz and his team studied tumor response and patient survival using chemotherapy combining oxaliplatin and 5-FU, or fluorouracil. Oxaliplatin is an investigational platinum compound (not yet approved by the U.S. Food and Drug Administration for widespread prescription) and 5-FU is a longstanding drug used to battle many cancers. The team is the first to look at such tumor testing and patient outcomes with oxaliplatin.
The study included 50 patients with advanced colorectal cancer. Patients had already failed at least one prior chemotherapy regimen before oncologists placed them on 5-FU and oxaliplatin.
Researchers looked at tissues from tumors that had been removed through surgery and analyzed the samples to see how much of two key enzymes the tumors expressed. Those amounts can vary from patient to patient, depending on genes.
Lenz and colleagues looked at two important players: the excision repair cross-complementing gene 1 and the thymidylate synthase gene. Scientists call them ERCC1 and TS for short.
In a healthy person, ERCC1 helps repair damaged genetic material in cells. Much like a metal chain might have missing links or worn out pieces, human genetic material—DNA—can be damaged by agents such as sunlight and pesticides. Fortunately, ERCC1 helps fix those problems.
At the same time, the body uses TS to reproduce DNA, ensuring that cells are renewed and vigorous.
Unfortunately, though, cancerous tumor cells use the enzymes, too. They can feed off TS to reproduce their own DNA, and use ERCC1 to fix the DNA in cancer cells that chemotherapy is meant to damage and cripple.
This is important for cancer patients, Lenz explains, because it appears the more their tumors’ genes can make the enzymes, the more their tumors can resist certain chemotherapy drugs.
By testing tumor tissue samples through a unique technology, the USC/Norris researchers determined exactly how much of the enzymes each patient’s tumor produced.
They found that patients with low TS and low ERCC1 expression survived a median of 336 days after starting the 5-FU and oxaliplatin chemotherapy—more than three times longer than the median 95 days survived by patient with tumors that expressed high levels of TS or ERCC1.
So oxaliplatin and 5-FU therapy is indeed more effective for patients with low TS and ERCC1 expression, Lenz concludes. If patients can be tested for these characteristics before starting treatment, doctors can make sure they give oxaliplatin and 5-FU to patients most likely to benefit—and spare others uncomfortable chemotherapy that would not be of much help.
It also could point physicians to try other drugs for these patients.
“We now need to test whether these patients who would not do well with oxaliplatin should be treated with alternative therapies,” Lenz says. USC/Norris is now a site for a clinical trial of an investigational drug called TLK 286, which appears to work well against tumors that are resistant to oxaliplatin. And another new drug, known as NB 1011, actually focuses on tumor cells that express high levels of TS.
In the future, the USC/Norris team will conduct similar tests with other genes responsible for repairing DNA and other markers that may predict whether tumors will respond to standard and investigational chemotherapies. They also will examine such markers in different types of cancer. Finding out more about these markers may also help researchers develop more targeted anti-cancer drugs.
Colorectal cancer is the third most common cancer in the United States, and experts expect 130,000 new cases to be diagnosed this year. The need for more customized, effective therapy is clear: the five-year survival rate for patients with advanced or metastatic disease is less than 10 percent. ?
For more information about cancer research and treatment, or to learn more about The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).v
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