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Collaborative Team Advances Lung Cancer Research


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Collaborative Team Advances Lung Cancer Research

Investigator William Pao acts as "master of ceremonies" for the Lung Cancer Oncogenome Group.

For much of the 20th century, cancer treatment was dominated by surgery, radiation therapy, and chemotherapy. New molecular and genetic understanding of tumor biology has led to an era in which researchers are setting out to more directly kill cancer cells, which are molecularly different from normal cells. These 21st-century targeted therapies are based on the idea that drugs can be developed to take advantage of those molecular differences and thereby block the activity of molecules necessary for cancer cells to survive.

Harold Varmus

Members of the Lung Cancer Onco-genome Group (LCOG), an assortment of Memorial Sloan-Kettering investigators first assembled about a year and a half ago by Memorial Sloan-Kettering Cancer Center President Harold Varmus, are working together to further the development of targeted therapies and to help translate the work of basic scientists investigating lung cancer into ideas and innovations that will directly affect patient care. The group's work thus far has focused largely on the molecular underpinnings of two new targeted therapies -- Tarceva™ (erlotinib) and Iressa® (gefitinib) -- both of which are used to treat patients with lung cancer.

"Understanding the actions of Tarceva and Iressa is one of the most promising advances in lung cancer in decades," said Dr. Varmus. "It has accelerated enthusiasm within the scientific and clinical community for targeted therapies. The LCOG is a response to this new promise. We've called upon experts from many different departments within the Center -- thoracic oncologists, surgeons, molecular biologists, pathologists, radiologists, and others -- to make some fundamental progress in treating this disease."

An x-ray (top left) shows the lungs of a patient with tumors. After five days of treatment with Iressa (top right), the tumors were shown to have mostly disappeared. Cross-section magnetic resonance image of mouse lungs (bottom left) shows tumors that form when expression of the mutant Kras gene is turned on in lung cells. Nine days later, after the gene has been turned off, the tumors are gone (bottom right). The striking similarities in the way tumors shrank both in patients and in mouse models suggested that the drug Iressa was attacking an "Achilles' heel" in lung cancer.

The Story of Two Drugs

Tarceva and Iressa were developed in the 1990s. Both drugs were designed specifically to inhibit a normal signaling protein called the epidermal growth factor receptor (EGFR), which is found on the surface of cells and is often overexpressed in cancer cells. Early clinical trials of Iressa were led by Mark G. Kris, Chief of Memorial Sloan-Kettering Cancer Center's Thoracic Oncology Service in the Department of Medicine; trials of both drugs indicated that they successfully shrank tumors in about ten percent of patients with non-small cell lung cancer (NSCLC), which comprises about 80 percent of all lung cancers.

Because about 170,000 Americans are diagnosed with lung cancer every year, responses in even ten percent of patients means that thousands of patients in the United States alone could benefit from these drugs. However, at the time these drugs were introduced in the clinic, the true target in human tumors was unclear. Studies suggested that there was no correlation between response to drug and overexpression of the EGFR protein in tumor cells.

Further clinical research, including that performed by Memorial Sloan-Kettering Cancer Center thoracic oncologist Vincent A. Miller, indicated that Tarceva and Iressa worked best in patients who had a subtype of NSCLC called adenocarcinoma; who smoked fewer than 100 cigarettes in their lifetimes (never smokers); and who were of East Asian descent. There was no obvious molecular explanation as to why patients with these clinical characteristics often exhibited dramatic responses to these drugs, but these clinical observations greatly diminished the size of the "haystack" in which researchers hoped to find the "needles" that would supply the answers they were looking for.

On the basis of clinical response, Iressa received approval from the US Food and Drug Administration in May 2003 for use in locally advanced or metastatic NSCLC as second- or third-line treatment after chemotherapies had failed. Tarceva received FDA approval in November 2004 for a similar indication.

At the same time that clinical studies were being done, interesting new information about lung cancer was emerging from the laboratory. In the December 15, 2001, issue of Genes and Development, Dr. Varmus and colleagues described a mouse model for lung cancer they had created by manipulating the expression of Kras (pronounced KAY-rass), a gene that encodes a signaling protein inside cells and is mutated in about 20 percent of NSCLCs. The investigators developed a strain of mice in which the expression of mutant Kras could be "turned on" or "turned off" in certain lung cells by either adding or taking away, respectively, the drug doxycycline in the mouse diet. Activating this gene caused the mice to develop lung cancer within two months. Deactivation induced cancer cell death, and within a week the tumors became nearly undetectable. These results showed that lung tumor cells required continued expression of the cancer-inducing signaling protein in order to live. This, in turn, suggested lung cancers could be treated by finding and identifying drugs that blocked signals from mutant Kras.

Physician-scientist William Pao, then a medical oncology fellow at Memorial Sloan-Kettering Cancer Center and postdoctoral fellow in Dr. Varmus's laboratory, began working on this mouse model to understand further how tumor cells became dependent upon mutant Kras for survival. While examining magnetic resonance images of lungs in mice in which Kras was turned on and then turned off, he observed striking similarities to the tumor shrinkage in patients who were being treated with Tarceva and Iressa.

"This was a decisive moment," recalled Dr. Varmus. "The similarities in the two situations suggested that the drugs that were being administered to these patients were inhibiting some oncogenic signaling protein to which the tumor cells had become 'addicted' -- in the same way that the tumors in the mice were 'addicted' to the activated Kras gene."

"The amazing resemblance between the mouse lungs and the real-life patient lungs indicated that these drugs were probably attacking an Achilles' heel in lung cancer," said Dr. Pao. "The main question became, 'What is that Achilles' heel in human patients?' That's why we assembled LCOG in the first place."

Medical oncologist Vincent Miller (right) has organized much of the clinical research done by the group.

New Developments, Exciting Results

In 2004, several important studies further explained how these two drugs work. In the spring, groups at the Harvard Medical School reported that specific mutations in the gene encoding EGFR were found in a proportion of NSCLCs, more commonly in East Asian patients, and the genetic mutations were associated with response to Iressa. Subsequently, the Memorial Sloan-Kettering Cancer Center LCOG team extended these findings by showing that such mutations were also found in patients who responded to Tarceva. This indicated that Iressa and Tarceva, which were developed to inhibit normal EGFR, were actually working against a mutant form of EGFR that happened to be highly sensitive to these drugs. Moreover, the Memorial Sloan-Kettering Cancer Center group demonstrated for the first time that tumors from never smokers were much more likely to have EGFR mutations than those from former or current smokers, indicating that lung cancer in these patients may be a different form of the disease. This work was published in September 2004 in the Proceedings of the National Academy of Sciences.

Clearly, one of the big issues facing physicians who treat patients with lung cancer has been determining who will benefit from Tarceva and Iressa. Last summer, Memorial Sloan-Kettering Cancer Center's Laboratory of Diagnostic Molecular Pathology, led by Marc Ladanyi, began developing a diagnostic test that could be used in routine clinical practice to determine which patients have the EGFR mutation. (However, a small percentage of patients with the mutation do not respond and a small percentage without the mutation do respond. Researchers continute to investigate how to better identify those patients whose tumors will not respond to the drugs and who might benefit from other forms of treatment.) This clinical test, or assay, involves genetic analysis of biopsy samples from patients' tumors. Just a few months later, in August 2004, Memorial Sloan-Kettering Cancer Center received the necessary approval from the New York State Department of Health to begin using this clinical EGFR mutation test for patient management. The laboratory now tests about ten to 15 patients per week.

Pathologist Marc Ladanyi (left) and surgeon and scientist Bhuvanesh Singh (right) discuss the next steps for LCOG's various research projects at the team's weekly meetings.

The Problem of Resistance

Approximately 90 percent of patients do not respond to Tarceva or Iressa -- a phenomenon called primary resistance. The genetics of primary resistance were unknown until, in the January 2005 issue of PLoS Medicine (an international journal published by the Public Library of Science), the Memorial Sloan-Kettering Cancer Center team reported that the presence of a mutated KRAS gene in a biopsy sample (the human version of the gene that had been studied in mice) was associated with primary resistance to Tarceva and Iressa.

This meant that for patients whose cancers were caused by KRAS mutations (about 20 percent of all NSCLC patients), these drugs did not induce significant tumor shrinkage. Thus, it is possible that having tumors tested for both EGFR and KRAS mutations might help better guide treatment decisions regarding the use of Iressa and Tarceva. Dr. Ladanyi's team is currently working to establish a clinical test for KRAS mutations in lung cancers. At this time there is no targeted therapy for patients with KRAS mutations; patients with metastatic disease usually are treated with standard chemotherapy and/or radiation therapy.

Even in patients for whom the drugs work, they are not curative, because those who do respond relapse within one to two years. Members of the LCOG published another study in PLoS Medicine in February 2005 showing why this occurs. "When the drugs stop working, and the tumors begin to grow again, we call this acquired or secondary resistance," explained Dr. Miller, who was one of the study's lead authors. "This is different from primary resistance, which means that the drugs never work at all."

In the study, involving six patients whose disease progressed on Iressa or Tarceva, researchers studied samples taken from patients' tumors at different times before and during treatment. All of the tumors had the kinds of mutations in the EGFR gene that were previously associated with responsiveness to these drugs. But, in three of the six patients, investigators found that tumors that grew despite continued therapy had an additional mutation in the EGFR gene. This second mutation is predicted to lead to a change in the protein that blocks binding of the drugs, strongly implicating this second mutation as the likely cause of drug resistance. In addition, further biochemical studies showed that this second EGFR mutation, which was the same in all three tumors, could confer resistance to the EGFR mutants normally sensitive to these drugs.

More Than Half of NSCLCs Have Unknown Genetic Causes

Currently, five oncogenes in the EGFR signaling pathway are known to be mutated in non-small cell lung cancers. The two most common are KRAS, found in about 20 percent of tumors, and EGFR, found in about ten percent. Memorial Sloan-Kettering Cancer Center investigators are studying samples of hundreds of lung tumors taken from patients to determine other genetic changes that lead to lung cancers. The genetic mutations that cause the majority of lung tumors are still unknown.

"It is especially interesting that the mutation we found is strictly analogous to a mutation that makes other kinds of tumors resistant to another targeted therapy, Gleevec® [imatinib mesylate]," said Dr. Varmus, senior author of the study. "Acquired resistance to Gleevec is a well-known problem, and understanding its molecular causes has led to the design of other drugs that overcome that resistance." Gleevec is used to treat chronic myelogenous leukemia, a stomach tumor called gastrointestinal stromal tumor, and other tumors caused by mutations that result in inappropriate activation of tyrosine kinase signaling, just as tumors caused by EGFR mutations do.

"Tumor cells from patients in our study who developed secondary resistance to Iressa and Tarceva after an initial response on therapy did not have mutations in KRAS," said Dr. Pao, the other lead author of the study. "Rather, these tumor cells had new mutations in EGFR. This is a further indication that secondary resistance is very different from primary resistance." Because only half of the patients studied had the additional EGFR mutation, investigators are looking for other genetic changes that may be linked to secondary resistance.

Important Resources

Many of the accomplishments of the LCOG have been made possible because of a tumor bank created by Valerie W. Rusch, Chief of the Thoracic Service in Memorial Sloan-Kettering's Department of Surgery. Several years ago, Dr. Rusch and her thoracic surgery colleagues, in collaboration with Bhuvanesh Singh, a head and neck surgeon, began collecting samples (with informed consent) from all patients on whom they had operated and linking each sample to a clinical record outlining the patient's treatment and progress. Studying tumors from that bank has allowed researchers to correlate the behavior of individual cancers with their molecular underpinnings.

Much of the sequencing for the EGFR and KRAS genes was done by the Genome Sequencing Center at Washington University Medical School, in St. Louis, because the huge amounts of data generated by this type of project require a very specialized expertise and tremendous computing power.

Team members (from left) pathologist Maureen Zakowksi, medical oncologist Mark Kris, and thoracic surgeon Valerie Rusch are all active participants in the LCOG's collaborative research.

Future Directions

Investigators agree there are several key areas of study still to be undertaken for effective treatment of lung cancer, including continuing to study both primary and secondary resistance and characterizing a wider range of tumors in order to identify new targets for treatment that may work in larger numbers of patients.

"Although these drugs were designed to inhibit normal proteins, they have turned out to be a fortuitous lead to dissect mutations that cause cancer," said Memorial Sloan-Kettering Cancer Center pathologist Maureen F. Zakowski, another member of the LCOG research group. "This work shows that there are tumors with specific mutations for which we can find specific drugs and show real results in patients."

Memorial Sloan-Kettering Cancer Center's High-Through-put Screening Core Facility, capable of screening thousands of chemicals per day in search of new targeted cancer drugs, has also begun a research collaboration with the LCOG. They are looking for new drugs that kill cancer cells while leaving healthy cells unharmed. The group hopes to begin testing compounds in mice with lung cancer within the next several months.

"We now hope to identify mutations in other potential cancer-causing genes that are critical for lung cancers to survive," said Dr. Pao, who is now an assistant attending physician in Memorial Hospital and an assistant member in the new Human Oncology and Pathogenesis Program (HOPP), a hospital-based translational research endeavor. "Even though many mutated oncogenes have already been found, the crucial genes are still unaccounted for in more than half of NSCLCs. Our analysis for new mutations will be greatly facilitated by the recent completion of the Human Genome Project." Dr. Singh is also doing molecular analysis of the samples from the tumor bank, looking for other genes that may contribute to lung cancer.

The search for cancer genes is about to get much larger in scope. Earlier this year, Dr. Varmus worked with a group of leading US scientists who put forward plans for creation of a Human Cancer Genome Project. This proposed federal program, projected to take nine years, seeks to compile a catalog of the genetic abnormalities that characterize most of the many forms of human cancer and create a database that would be freely available to all researchers. The program likely would start with smaller projects, such as the type undertaken by the LCOG.

The story of how this research has progressed is a testament to the importance of collaboration among clinicians and basic research scientists. "We could not have accomplished what we have without the involvement of every single person on this team," said Dr. Zakowski. "It is so exciting to be involved in this kind of research. Everyone contributes and adds to one another's work. It's a great example of how clinical groups can collaborate with basic scientists working in the laboratory to make advances in the treatment of lung cancer."

Secondary Mutation Blocks Drugs' Activities

A graphic representation shows how a mutation leads to resistance to Iressa or Tarceva. In the upper image, Tarceva (shown by yellow net) fits into a "pocket" of the epidermal growth factor receptor (EGFR, shown in blue). The green atoms indicate the amino acid threonine, which is part of the receptor. In the lower image, a mutation has caused threonine to change to the amino acid methionine (shown in red). The methionine protrudes into the pocket and prevents Tarceva from binding. (This mutation is also predicted to block binding of Iressa to the pocket in the same way.) These images were created by Memorial Sloan-Kettering Cancer Center structural biologist Nikola Pavletich, using the previously published structure for EGFR.

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