Scripps Zeros in on Breast Cancer

Many aggressive breast cancer cells carry a Velcro-like molecule with the sinister talent of snagging onto other organs and starting new tumors.

Scientists at The Scripps Research Institute have discovered two antibodies uniquely designed to block that Velcro, rendering it useless and dooming the cancer cells to die.

The research is among a wave of new anti-cancer treatments under study that hold the promise of killing breast cancer cells with incredible precision, while eliminating the toxic side effects of chemotherapy.

By combing through the immune systems of 20 cancer patients, the Scripps scientists discovered two antibodies from some patients that served as a defense. These antibodies are now being cloned and studied for possible use as a drug to fight cancer’s spread in other patients.

Scripps Associate Professor Brunhilde Felding-Habermann, Scripps President Richard Lerner and Professor Kim D. Janda are among the authors of the study, which appears in a December issue of Proceedings of the National Academy of Sciences.

“There is nothing right now that is really effective to fight metastasis,” Felding-Habermann said. “We have good treatments against tumors, but it is very difficult to prevent cancer from becoming systemic.”

Felding-Habermann, a cell biologist, first described the Velcro- like target in a paper published in 2001. The next step, finding a way to disable it, required help from others at Scripps.

Lerner and Janda, both chemists, had created the library of antibodies in 2000 which the team recently searched – “like panning for gold” according to Janda – until they found antibodies specifically evolved to attack Felding-Habermann’s Velcro molecule.

The next step will be testing the antibodies against other cancer cells, she said.

“We have a whole array of studies planned to see how useful the antibodies will be,” Felding-Habermann said. “We are in a very pre- clinical state, but we definitely would like to try and translate it to the bedside and give it a chance.”

Old-line chemotherapy often works well, but it does so at great cost – by poisoning both cancerous and non-cancerous cells. The next generation of cancer drugs is being designed “rationally” by looking at the molecular and genetic signatures unique to cancer cells, said Richard Jove, a molecular oncologist who is associate director of the Moffitt Research Institute of the H. Lee Moffitt Cancer Center in Tampa.

As they find these targets, scientists are looking for ways to hit them with antibodies or small molecules that fit like a hand in a glove.

“We are entering a new era,” Jove said. “What we have to do – and it’s going to take time – is to identify all of the molecular targets that are present in cancer. We know how to do this now.”

Several drugs developed through this new approach recently were approved by the U.S. Food and Drug Administration, and in some cases are being used in conjunction with chemotherapy.

Herceptin, an antibody-based treatment, attacks some – not all – breast cancer cells. It fights those covered with a protein called HER2 that signals tumor cells to grow and divide. Gleevec treats chronic myeloid leukemia and gastrointestinal stromal tumors by blocking abnormal signaling proteins called abland c-kit.

Avastin, used to treat colon cancer, blocks a protein called Vascular Endothelial Growth Factor, which feeds tumors by growing new blood vessels. Tarceva is a new therapy for some types of lung cancer. It targets one kind of cell-signaling protein called an epidermal growth factor receptor. The new class of cancer treatments represents the tip of the iceberg, Jove said.

Many more are needed, and many more must be studied, he said.

That’s because there are literally hundreds of genetic variations between cancer cells, and no drug can be expected to work on all of them.

“How many genes are implicated in cancer? That’s a really good question, and that’s what a lot of people are trying to answer. We do know that hundreds of genes are implicated in cancer, but my guess is we’re going to find more,” Jove said.

Since not everyone’s cancer will respond to the new drugs, genetic tests are being developed that indicate one person’s likelihood of responding to a given product.

Complicating matters, cancer cells are continually mutating, meaning that the disease can be held in check by a drug for a while, until the few resistant stragglers multiply in sufficient numbers to require a different approach. “Just like antibiotics, they become resistant, and we need second-line and third-line treatments,” Jove said. “Our goal now is to turn cancer into a chronic disease so it can be managed.”

The Scripps antibodies, called Bc12 and Bc15, may one day join that arsenal. They also might offer a way to find out early on if a patient’s cancer is spreading. By engineering a substance onto the antibody that shows up in medical scans – such as iodine – it could help flag spreading breast cancer long before visible tumors form.

Felding-Habermann hopes it will offer real benefits for the hundreds of thousands of people suffering with breast cancer.

“I devote all the time I have to this research,” she said, “and I hope to really make a difference.”

stacey_singer@pbpost.com