New drugs take aim at cancer cells: Side effects could be cut if tests work

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.

"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?"