New drugs take aim at cancer cells

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After cancer that originally started in her right breast returned for the fourth time, Lynn Luckey signed up for a clinical trial of an experimental chemotherapy drug at Augusta Oncology Associates. She had read that she might be hassled by her insurance company for trying a drug before it is approved by the Food and Drug Administration.

Lynn Luckey prepares to have blood drawn by Krystal Eagle at Augusta Oncology Associates in University Hospital. She is taking part in a trial of an experimental chemotherapy drug.  Rainier Ehrhardt/Staff
Rainier Ehrhardt/Staff
Lynn Luckey prepares to have blood drawn by Krystal Eagle at Augusta Oncology Associates in University Hospital. She is taking part in a trial of an experimental chemotherapy drug.

"But yet, well, why not?" said Mrs. Luckey, 50, who said she has been told she has three or four years left unless something changes for her.

Though the success in early-stage treatment is leading to a remarkable rate of 98 percent survival after five years for localized breast cancer, there are still not a lot of good therapies for women who have breast cancer that has spread to other organs or who see the cancer return, doctors say. Only 27 percent of women whose breast cancer has spread to distant organs are alive five years later, according to an American Cancer Society estimate.

But new drugs being tested in Augusta could offer approaches that more closely target the cancer cells and theoretically would be less toxic to healthy tissue and have fewer side effects. In the long run, the problem could be whether the cures will be affordable, Augusta oncologists said.

Many chemotherapy drugs damage the DNA of fast-dividing cells, which kills cancer cells but can also wipe out normal faster-producing cells in hair, bone marrow and the gastrointestinal system, said Medical College of Georgia Cancer Center Director Kapil Bhalla. This leads to the side effects of nausea, vomiting, diarrhea, hair loss and loss of blood cells, he said.

One of the first targeted therapies in breast cancer, Herceptin, approved in 1998, targets the HER2 protein that is overexpressed in breast cancer.

It used to signal a worse outcome, and that has now almost been turned on its head, said Thomas Samuel, the director of the clinical breast cancer program at MCG.

"When you have HER2-positive disease, that used to be a very bad thing," he said. Now, when breast cancer patients find out they don't overexpress HER2, "They're actually somewhat dismayed by that because they know that Herceptin is a fairly effective drug and it works really well for this type of cancer," Dr. Samuel said.

The approach for some of these potential second- and third-generation drugs is to take aim at molecules or pathways that are helping the breast cancer resist chemotherapy. Some of it pairs directly with research in the lab, including work being done at the MCG Cancer Center, Dr. Bhalla said.

"The name of the game is selectivity," he said. "Everything we do in cancer these days is to identify targets that are unique for cancer compared to normal. If we can find a protein in a cancer cell to which the cancer cell is uniquely addicted -- it may be an oncoprotein (cancer protein) or another protein that helps the oncoproteins do their nasty work -- if we can find a target and selectively target that, then we will not have the side effects."

Some of the drugs in clinical trials at MCG target "molecular chaperones," proteins that help shape the function of other proteins. In one case it is a chaperone called heat shock protein 90, or HSP90, he said.

"Tumors cells require (heat shock protein 90) to function more than normal cells because they have these oncoproteins in them that are hyperactive and have to stay active in an active confirmation, which is what HSP90 helps them do," Dr. Bhalla said. "So if you inhibit HSP90, as with this compound, you can then inhibit the function of these oncoproteins. And that sensitizes the cancer cell not only to this drug alone but also when combined with agents that target those oncoproteins or even regular chemotherapy."

A similar strategy is being taken with the drug Mrs. Luckey was hoping to get. It is a poly (ADP-ribose) polymerase or PARP inhibitor.

PARP is an enzyme involved in DNA repair in normal cells that is overactive in breast cancer, helping those cells resist DNA-damaging chemotherapy drugs, said Mark Keaton, the principal investigator for the clinical trial at Augusta Oncology.

"That combination of drugs does attack the DNA in the area where this repair mechanism would more normally repair it. The PARP-1 inhibitor blocks that particular repair mechanism," he said.

The number of patients then responding to the standard chemotherapy given along with it went from around 20 percent to 63 percent without much in the way of additional side effects, Dr. Keaton said.

The results were so promising that the FDA has taken notice and, when investigators take a preliminary look at the data for the current trial, might be willing to consider approval, he said.

"They may go to a very accelerated approval mechanism so the drug could be out, even early next year," Dr. Keaton said.

As luck would have it, Mrs. Luckey was randomly assigned to the arm of the study that is not receiving the experimental agent for comparison purposes, but she has been told that if she does not improve in about 40 days she could get it. She is fine with that.

"I thought I was going to have to go all the way to California to get it," Mrs. Luckey said.

With all of the genetic testing now happening in many breast cancer patients and the molecular targeting of therapy, Dr. Bhalla envisions a time when there won't just be breast cancer or lung cancer "but 20 different varieties of lung cancer and 20 different of breast cancer, each with a specific molecular signature, a drug-able target signature," he said. "And you use a cocktail of those targeted agents that will create very little side effects."

There may be one big impact on the patient or insurance company, however, once they receive a bill.

With the targeted therapies available now, the pharmaceutical companies have made a science of figuring out what the market will bear, Dr. Bhalla said.

"And they push it to the limit," he said.

A single dose of Herceptin can run anywhere from $3,000 to $5,000, depending on the setting in which it is administered, Dr. Samuel said.

It is easy to envision the trend continuing with the new therapies, he said.

"Now we have these great drugs," Dr. Samuel said. "Who is going to pay for them?"

Reach Tom Corwin at (706) 823-3213 or tom.corwin@augustachronicle.com.

FACTORS IN CHEMO

Chemotherapy is often added after surgery for breast cancer to reduce the risk of cancer returning, said Thomas Samuel, the director of the clinical breast cancer program at Medical College of Georgia Hospital. Among the tools now helping doctors decide whether to offer chemotherapy are genetic tests of the tumor itself, such as Oncotype DX, which looks at 21 genes associated with higher risk of recurrence and returns a score. Such information is considered along with the woman's medical history, clinical staging and other tests to calculate her risk of the cancer coming back.

Generally, if a woman's risk of recurrence is 10 percent in 10 years, she will be offered chemotherapy, Dr. Samuel said.

"But if it is less than 10 percent, that's where we have to kind of struggle," he said, weighing the risks and benefits to the patients. Augusta is holding a number of clinical trials to look at more targeted therapies that theoretically should carry fewer side effects and cause fewer long-term health impacts. But even standard chemotherapy regimens now are less burdensome than what patients endured years ago, said Mark Keaton of Augusta Oncology Associates.

"When I was in training, we almost admitted all of the patients to the hospital for chemotherapy, and they all had buckets by their beds," he said. That rarely happens now, Dr. Keaton said.

CLINICAL TRIALS OFFERED LOCALLYT

Augusta is holding a number of clinical trials for patients with breast cancer to try different, potentially more targeted approaches.

Medical College of Georgia is holding trials for both early stage and metastatic breast cancer patients. For more information, call the Cancer Clinical Research Unit at (706) 721-2730.

Augusta Oncology Associates has a clinical trial of an agent known as a PARP inhibitor that potentially interferes with the DNA repair of cancer cells. It is given alongside standard chemotherapy drugs. The patient must have recurrent breast cancer that has not responded to one or more therapies and be 18 or older. For more information, call nurse Sandra White at (706) 821-2944.

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soldout
1280
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soldout 10/11/09 - 03:32 am
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Some doctors say the

Some doctors say the elimination of HRT drugs for many women really helped the breast cancer rate go down over the past few years. I am sure there are other things being done to the body today, like abortions and alcohol: that when reduced, will drop the number more. Some believe the tumor is the body trying to stay alive by encapsulating the acidic material being generated at another point. If we spent research money looking at those who do not get breast cancer we would be further along. The question becomes; are we looking for a way to reduce cancer or a way to reduce cancer using a drug?

WMartin
119
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WMartin 10/11/09 - 12:15 pm
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Interesting question . . .

Interesting question . . . good question !

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