January 26, 2001

VICC pioneering efforts with new experimental cancer drug

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Dorothy and Beryl Arvin celebrate the positive effects of a new cancer drug being tested at Vanderbilt. (photo by Dana Johnson)

VICC pioneering efforts with new experimental cancer drug

While most folks have packed away their Christmas trees and trimmings, Dorothy Arvin’s tree is taking on a new look for the next big holiday.

The 69-year-old grandmother from southern Indiana has had her tree up since the Christmas before. It’s been a Valentine tree, an Easter tree, a 4th of July tree, a birthday tree, and so on. Having a year-round holiday tree is something Dorothy has done for herself, to celebrate each of life’s wonderful moments, since facing a recurrence of a particularly lethal form of lung cancer, bronchioalveolar carcinoma.

“I decided I liked my Christmas tree and there was no reason for me to take it down,” Dorothy said during a visit to the Vanderbilt-Ingram Cancer Center. “It makes me happy.”

Though no one knows what her future holds, Dorothy and Beryl, her husband of 43 years, have a lot to celebrate. Her recent scans showed no visible sign of the cancer that had taken hold in both her lungs.

An anti-cancer pill?

Dr. David Carbone, Ingram Professor of Cancer Research, is pleased and excited at his patient’s response to the experimental drug, Irressa, which Dorothy began taking a year ago. “I’m thrilled,” Carbone said. Carbone is pleased, of course, to see a patient doing well; but like other physicians and scientists familiar with this drug, he is also cautiously optimistic about a new approach to treating cancer.

Irressa is one of a new group of drugs called tyrosine kinase inhibitors, which target a specific step in signaling pathways that allow the runaway cell growth that is the hallmark of cancer. TKIs appear to be very targeted to tumor cells and have few side effects. Many can be given orally, offering the possibility of fighting cancer with a pill that patients could take at home.

While Irressa has had promising results in several patients, Carbone said Dorothy may hold the distinction of being the first patient with a documented complete response – her lung cancer no longer is detectable on CT scan.

Vanderbilt-Ingram has been involved in researching this drug from the earliest studies testing safety and dosage, led by Dr. Mace Rothenberg, Ingram Professor of Cancer Research and director of Phase I Drug Development, through Phase II studies in collaboration with colleagues at Memorial Sloan-Kettering in New York, to a large, multi-center Phase III trial that recently began.

Now, Dr. David Johnson, Vanderbilt-Ingram’s deputy director, is leading the national Phase III trial, which will compare Irressa combined with chemotherapy to chemotherapy alone in patients with metastatic non-small cell lung cancer. Dr. Alan Sandler is the principal investigator of the study at Vanderbilt-Ingram.

TKIs first hit the news about a year ago with headlines that a researcher in Oregon had developed a drug that had shown promising results in patients with chronic myelogenous leukemia. The so-called “leukemia pill,” STI-571, is still in clinical trials, including one that recently opened at Vanderbilt-Ingram and Vanderbilt Children’s Hospital in children with a rare but deadly form of leukemia.

Dr. Jim Whitlock, director of Pediatric Hematology-Oncology, is the principal investigator for the study in patients with “Philadelphia Chromosome-positive” leukemia. In this type of leukemia, a genetic abnormality fuses two proteins into one that then allows the proliferation of abnormal cells. STI-571 turns off that fused protein.

“This was the first chromosomal abnormality identified in human cancers, back in the early 1960s,” Whitlock said. “The fused protein is unique and found only in the leukemia cells. Anecdotal evidence suggests that STI-571 is effective, even in the early safety trials. Further research is needed, of course, but the thought that someone with a fatal disease might be able to treat it by taking a pill, with very few side effects, is pretty amazing.”

Scrambling the signal

“Tyrosine kinases are enzymes that mediate normal cell functions; by a series of chemical reactions, they propagate signals from the environment to the cell’s control center, the nucleus,” said Dr. Carlos Arteaga, Ingram Professor of Cancer Research. “Interestingly, some of these tyrosine kinases involved in normal development and physiology are present in very high levels or are hyperactive in some human tumors. In some cases, these tumors rely on these signals for their proliferation and survival. This scenario provides us with molecular ‘targets’ and with a therapeutic ‘window’ that can be exploited.”

The first tyrosine kinase, the epidermal growth factor, was discovered by Vanderbilt scientists, Nobel laureate Stanley Cohen, Ph.D., and Graham Carpenter, Ph.D., Ingram Professor of Cancer Research. Other tyrosine kinase inhibitors include HER2/neu, a cousin to the EGF receptor, both of which are found in breast and other carcinomas; platelet-derived growth factor receptor (PDGF), which is over-expressed in some brain tumors; the TRK and RET proto-oncogenes, found in high levels in neuroblastomas and thyroid cancers, respectively, among many others.

In some cases, scientists have figured out the three-dimensional structure for these tyrosine kinases, which has allowed drugs to be developed. In turn, these drugs fit into these molecular “pockets” and block kinase activation.

One of the biggest advantages to the TKIs is their relatively specific action against tumor cells, which for the most part spares normal patient tissues from undue side effects. In addition, these tyrosine kinases can be identified in diagnostic tumor material, thus allowing doctors to select specific tyrosine kinase inhibitors accordingly, Arteaga said. “Typically, they are about 300 to 400 times smaller than an antibody, so they can be given orally, be absorbed quickly, and exhibit good penetration into tumor tissues,” he said. They are nothing like traditional cytotoxic chemotherapy. These are drugs that can be taken daily by mouth before your morning jog or before going to work.”

Shutting down the whole system

Like all good scientists, Arteaga tempers his enthusiasm with skepticism. TKIs appear to be an important step forward in the fight against cancer, but he is concerned that, particularly as the new drugs are used in combination with other therapies, unexpected toxicities may become apparent. For example, blocking the VEGF receptor kinase can induce hypertension. Herceptin, an antibody that blocks the HER2/neu tyrosine kinase can enhance the side effects of chemotherapy on the heart. “We just don’t know,” he said. “The studies need to be done.”

A logical use of TKIs is in combination with chemotherapy, as in the Phase III Irressa study, or with radiation, as in a Phase I study begun at Vanderbilt-Ingram by Dr. Hak Choy, Rothenberg and other colleagues using a TKI called SU-5416. This drug blocks the action of a tyrosine kinase involved in the growth of new blood vessels to feed tumors.

“One of the reasons tumor cells over express some tyrosine kinases is to have a survival advantage, so if you administer something like chemotherapy or radiation that threatens the survival of the tumor cell, then by adding a TKI, one may enhance the effectiveness of the treatment,” Arteaga said.

He also doesn’t believe that such a cunning enemy as cancer will be defeated with a single magic bullet. Cancer cells protect themselves from destruction through complicated and redundant survival signaling programs, and stopping a single tyrosine kinase may not be enough to halt the whole program, Arteaga suggested. “Unless we think the tumor cell is so stupid as to rely on a single tyrosine kinase – and it’s not – then we have to think about targeting several of these enzyme systems simultaneously with a combination of anti-signaling approaches.”

For instance, a new study that Arteaga will lead this year will combine Iressa, which blocks the EGF receptor tyrosine kinase, and Herceptin, an antibody that blocks the related HER2/neu receptor tyrosine kinase at the cell surface. “We know that these two receptors ‘partner’ together in some breast cancers – HER2/neu needs a co-receptor to become active, and the EGF receptor is often that co-receptor,” Arteaga explained. In addition, HER2/neu and the EGF receptor are very similar in structure, so Iressa may have some “cross-over” effect on the HER2/neu kinase. Therefore, if we think of these receptor tyrosine kinases as part of a cooperative system that maintains the tumor cell, it makes sense to hit them simultaneously to enhance the effect of anticancer therapy.

“The excitement about these drugs is that we now have ways of targeting kinases or growth signals identified in tumors at the time of diagnosis and, hence, we can provide patients with better odds of response to treatment. In addition, we can give them something that is relatively non-toxic,” Arteaga said. “Once we figure out how to safely combine these with chemotherapy or radiation, or develop combinations of anti-signaling strategies, we are naturally going to prolong life and improve quality of life.”