Understanding Drug Resistance in Lung Cancers Leads To Novel Treatment Combinations
Jeffrey Engelman, MD, PhD, scientific director of the Massachusetts General Hospital Cancer Center’s Center for Thoracic Cancer, and Pasi Jänne, MD, PhD, of the Lowe Center for Thoracic Oncology at Dana-Farber, an international research team of investigators from the DF/HCC, a Harvard Medical School consortium, have gained insight about how some lung cancers develop resistance over time to targeted therapies such as Iressa® (gefitinib) and Tarceva® (erlotinib). This new understanding of tumor resistance has led to the development of novel treatment combinations that may be useful in many different cancers.

Drugs like Iressa® and Tarceva® are used to treat non-small cell lung cancer (NSCLC), the leading cause of cancer deaths in the US. In 2004, researchers found that a portion of NSCLC patients responded rapidly and dramatically to these drugs. What they had in common was a common tumor mutation. In these patient tumors, the epidermal growth factor receptor (EGFR), a molecule on the cell membrane, was magnifying a potent signal that fueled tumor growth. Iressa® and Tarceva® specifically target EGFR, effectively starving the mutated tumors that rely on the molecule for growth.

Targeted therapies promised long-term hope for some patients with NSCLC. However, although tumors that respond to EGFR inhibitors do so quickly, eventually the tumors become resistant to the drugs and resume growth. In about half of the resistance cases a secondary mutation loosens Iressa’s bond and allows the cancer to circumvent the therapy.

Researchers are testing whether new drugs, called irreversible EGFR inhibitors, can prevent resistance in these tumors.
“We thought that if we could understand the resistance mechanism, we might be able to override it and extend the lives of these patients,” explains Engelman. He and his colleagues set out to discover what other unknown mechanisms would allow the resistant tumors to re-activate their growth pathways. They bathed tumor cells with mutant EGFR in Iressa® until the cells developed resistance and resumed growth, mimicking what happens in the body. Previously, the investigators had found that EGFR transmits its growth signal through a related protein called HER3 (or ERBB3) that initiates a potent growth pathway. Iressa blocks that pathway. Now, they discovered that MET amplification can also robustly activate HER3, creating an alternate route to the growth pathway. “About 20 percent of NSCLC patients become resistant because of the activity of a cancer-causing oncogene called MET that takes over for EGFR and fuels tumor growth,” explains Engelman, first author of the study, which was published in the journal Science in April 2007 and reviewed in the June Nature Medicine. “Importantly, we also identified a potential new way to treat these resistant tumors with combination therapy directed against both MET and the normal target of Iressa® ,” adds Jänne.

Analysis of tumor samples from 18 patients whose tumors became resistant after initially responding to Iressa revealed that MET was amplified in 4 of 18 patients. Blocking just MET or EGFR alone did not suppress the resistant cells’ proliferation. But combining MET and EGFR inhibitors both stopped growth signals and killed the tumor cells. “This method of reactivating the HER3 signaling pathway with MET may be a common resistance mechanism against other therapies that target receptors of the ERBB family, which are used against breast cancer, colon cancer, head and neck cancer and the brain tumor glioblastoma multiforme,” says Jänne. “Results from this study suggest why resistance occurs in some lung cancer patients and points to an obvious strategy for developing more effective therapies,” adds Engelman. To that end, researchers are now investigating the frequency of this resistance mechanism and are developing protocols that combine EGFR and MET inhibitors to treat NSCLC and other types of cancer. “There may be other resistance mechanisms we have yet to discover, but we have taken a significant step forward,” says Engelman.

4-D CT scanning

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Organ motion is problematic when using radiation therapy to treat certain cancers. This is particularly true with lung cancer, since patients breathe during treatments.

Radiation oncologist Noah C. Choi, MD, treats patients with lung and other thoracic (chest) cancers. Until about a year ago, he and his colleagues had to rely primarily on conventional 3-D CT scans to visualize the tumor and plan patients' radiation therapy.

For a tumor that is stationary or does not move that much, these images are adequate. But some lung tumors move significantly with each breath. The result, says Choi, is a distorted CT image and potentially a “geographic miss,” in which the tumor is not adequately treated and healthy tissue is irradiated, which can lead to serious complications.

Confronted with this clinical challenge, George Chen, PhD, Director, Radiation Physics Division, in collaboration with Choi and partners in industry, developed sophisticated software technology that takes into account the movement of organs over time. Called 4-D CT imaging (the four dimensions being width, height, depth, and time), this new technology provides clinicians with far more precise information on tumor motion with which to plan and administer radiation therapy.

Studies conducted by Choi and Chen using this technology have shown that in at least one-third of patients, tumors move significantly. Since there is no way to predict whose tumors will move and whose will not, all lung cancer patients who undergo radiation therapy at the Cancer Center have a 4-D CT scan for pre-treatment planning.

Respiratory gating
Patients whose tumors demonstrate a significant degree of movement with 4-D CT are treated using respiratory gating, another technology developed by the Cancer Center's radiation physics team in collaboration with industry partners.

In simple terms, respiratory gating means that the therapeutic beam from the linear accelerator is automatically synchronized with the tumor's motion and is turned off (or “gated”) when the tumor is not in the desired position.

“With 4-D CT imaging and gating technology, we are now able to target the lung tumors more precisely,” says Choi, adding that the Cancer Center is one of only a few sites in the U.S. to offer this new technology to patients. “As a result, we are able to achieve better tumor control; have fewer complications; and use higher, potentially more effective, doses of radiation.”

New Research in Lung Cancer Using Proton Beam Radiation

Compared to standard radiation, proton beam therapy offers the potential to destroy lung tumors just as competently while producing less damage to surrounding healthy tissue.

"In traditional radiation therapy, one must use multiple beams of x rays to deliver a uniform dose to a lung tumor; often at least one of the x-ray beams will exit from the healthy (non-tumor-containing) lung and potentially damage it. On the other hand, positively charged, subatomic protons only travel a limited distance through the body; they never make it to the other lung, and they also are more likely to spare nearby organs such as the esophagus and heart.

However, the protons' finite range makes their trajectories particularly sensitive to density changes in the lung, caused, for example, by the expansion of the lung during inhalation. For that reason, if the proton treatment is not carefully planned, there is the chance of missing the tumor, thus decreasing the chance of curing the patient. So in planning the treatment of lung cancer patients, the researchers adopted the 4D approach, which is already used in traditional x-ray cancer therapy.

In the 4D approach, one takes into account how the patient's breathing moves the lung back and forth over time (the fourth dimension) so that the radiation hits the tumor precisely over all phases of a patient's breathing cycle. In a study of four patients at Massachusetts General Hospital, the researchers have found that planning and carrying out 4D proton therapy delivers excellent dose levels to lung tumors in all cases. The only thing preventing this technique from wider use is the need to develop an algorithm that cuts down the currently lengthy time it takes to calculate and plan the proton beam's direction and intensity for each breathing phase."

To learn more about the Proton Beam Radiation >>>

Source: Physics News Update, Number 738 , July 21, 2005 by Phil Schewe and Ben Stein

The New Strategy: ‘Smart Drugs’ for Specific Lung Cancers

Researchers in the laboratories and clinical settings at the Massachusetts General Hospital Cancer Center have been pursuing an entirely new strategy—one that holds great promise for patients with thoracic and many other forms of cancer. They are zeroing in on specific molecular targets on or within cancer cells that make these cancer cells to rapidly grow.

This new strategy calls for identifying molecular targets that play a key role in cancer and then finding drugs that focus only on these targets—so called “smart drugs”—thus sparing normal cells. This strategy not only reduces or eliminates serious side effects; it is also potentially more effective.

Inhibiting EGFR
One main target is epidermal growth factor receptor, or EGFR. It plays an important role in the regulation of cell growth. Located on the surface of cancer cells, EGFR receives signals from outside the cell that trigger a number of events within the cell that allow it to grow out of control..

Because cancer cells are dependent on EGFR for their growth and survival, a few of the new anticancer agents seek to inhibit EGFR. One of the best known is Iressa [Ir-es-sa].

Iressa was approved by the Food and Drug Administration in 2003 as “third-line” therapy (after two types of conventional chemotherapy had failed) for patients with advanced non-small cell lung cancer (NSCLC). This is the most common form of lung cancer, a challenging disease that is diagnosed in approximately 174,000 Americans every year and is the leading cause of US cancer deaths among both women and men.
 
For most NSCLC patients, Iressa has little or no benefit. But for a fortunate minority in North America, (about 10 percent of patients, most of whom are women who have never smoked) Iressa’s effect is rapid and dramatic, leading to significant tumor shrinkage.

In the spring of 2004, a collaboration among laboratory and clinical researchers at the Cancer Center led to this discovery: NSCLC patients whose tumor had a particular mutation in the EGFR receptor were more likely to respond to Iressa than patients whose tumors lacked this mutation.

New Clinical Trial
Since then, researchers in Cancer Center laboratories and clinical settings have been working together to pursue the promise of Iressa and a similar drug, Tarceva [Tar-ce-va]. Among the many questions they are trying to answer is whether these drugs may be even more beneficial to patients as a first-line treatment instead of a "third-line" therapy.

Lecia V. Sequist, MD, MPH, a Cancer Center medical oncologist who cares for patients in the Center for Thoracic Cancers, is the principal investigator of a phase 2, multicenter, US clinical trial called TARGET (Trial to Assess Response to Gefitinib in EGFR-mutated Tumors). As its name suggest, this study is evaluating Iressa as a first-line treatment for NSCLC patients whose tumors have this mutation.

According to Sequist, several patients have had a good response to the drug (their tumors have shrunk), and are “going on with their lives as though they have a chronic condition.” While cure remains the goal of cancer treatment, many specialists predict that cancer will more likely become a chronic, but manageable, condition.

“The Iressa story illustrates the importance of close collaborations among researchers in the laboratory and the clinical setting,” says Sequist. “Observations made by doctors caring for patients in the clinic drove research in the lab, which then led to discoveries that returned to the clinic and resulted in better options for patients.

“Only in a unique environment like the Cancer Center, where basic scientists and clinicians routinely work together and maintain a focus on patients, can this pace of translational research take place,” she adds.

A moving target
In addition to dividing rapidly, another defining feature of cancer cells is their ability to mutate quickly in order to survive. These mutations lead to the problem of drug resistance. This occurs when cancer cells that were once controled by a particular drug undergoes genetic changes that make them resisitent to the drug’s effects, causing the cancer to return. While patients’ responses to Iressa or Tarceva can last as long as two to three years, typically patients develop resistance to these drugs and relapse, sometimes within as little as six to eight months.

At the Cancer Center’s basic research facility in Charlestown, Jeffrey Settleman, PhD, director of the Center for Molecular Therapeutics, and his co-workers are now focusing on the problem of drug resistance. “We need to understand the mechanisms of resistance to these new, agents before we can hope to find ways to prevent the problem,” says Settleman.

Circumventing resistance
Settleman and his colleagues in the Cancer Center, including Eunice L. Kwak, MD, and Cancer Center Director Daniel A. Haber, MD, PhD, have already made significant progress toward that goal. It was discovered by others in the cancer research community that some patients with the EGFR mutation who respond to Iressa or Tarceva acquire a second mutation that blocks the drugs’ ability to find the receptor—making the drugs ineffective.

Settleman and his colleagues discovered that a class of so-called “irreversible” EGFR inhibitors, which are similar to Iressa and Tarceva but bind permanently to the receptor, circumvent the resistance mechanisms to these drugs in human cancer cells. The results of this work were published in the May 2005 issue of the Proceedings of the National Academy of Sciences. “Our findings suggested that one of these irreversible EGFR inhibitors, a drug called HKI-272, may prove highly effectively in the treatment of NSCLC patients who have developed resistance to Iressa or Tarceva,” says Settleman. “It may also be that HKI-272 will work better than the first-generation drugs because it could potentially prevent resistance.”

New Clinical Trial
The next step in this research will take place in the clinical setting, where HKI-272 will be evaluated in patients in a clinical research study developed by Sequist and Thomas J. Lynch, MD, director of the Center for Thoracic Cancers. According to Sequist, most of the patients in this study will be NSCLC patients whose cancer has progressed following treatment with Iressa or Tarceva.

Kinases: ‘where the action is’
Because cancer cells are so adept at survival, acquired drug resistance may continue to pose a challenge, says Settleman, making it important to keep searching for other smart drugs. In Settleman’s lab, scientists are currently evaluating many other new agents in human cancer cells in the hopes of finding others that stop cell growth or cause their death, a process called apoptosis.

Like Iressa and Tarceva, most of the agents being evaluated selectively inhibit protein kinases—enzymes within cells that are known to play a key role in a complex cascade of events that regulate cell growth and survival, called signal transduction pathways. “Kinases are where the action is now,” says Settleman. He adds that he and his team are particularly interested in mutated kinases, as tumors that harbor these genetic alterations appear to be particularly vulnerable to kinase-targeting drugs.

Once a response to a drug is detected in a cell line, the next important step is to find out why. What is different about the cancer cells that respond to the drug compared to those that do not? Is it, as in the case of Iressa and NSCLC, a particular mutation? Or perhaps a difference in the genes?  Knowing why is essential, explains Settleman, because this information helps researchers identify a biomarker—a sort of molecular red flag—that indicates which tumors are likely to respond to a particular drug.

Since by their very nature, smart drugs will not work for everyone. Tt is very important to identify biomarkers so that clinical trials will evaluate the new drugs in the most appropriate patients. If the drugs turn out to be clinically useful, biomarkers will make it possible to identify patients who will most likely benefit. Another reason to find out precisely why tumor cells are sensitive or resistant to a particular drug is that this helps point the way to new drug targets.

Bench-to-Bedside
“Today you hear a lot about ‘bench-to-bedside’ research, but at the Cancer Center, collaborations go in two directions, from the clinic to the lab, or vice-versa, and back again,” says Settleman, who works regularly with his co-workers in the clinic. “This is a very exciting time in cancer research. We have good reason to believe that this new, targeted approach to fighting cancer will have a significant impact on patients with lung and many other cancers. By working together, we will be able to realize the full potential of this work as quickly as possible for the benefit of patients.”

Source: Synergy, Summer 2006

Researchers from the Massachusetts General Hospital Cancer Center have discovered a molecular marker that identifies lung cancer patients whose tumors will respond to treatment with the drug Iressa (gefitinib).

“This discovery will help us significantly improve the treatment of many lung cancer patients and is also an important next step in the molecular targeting of cancer drugs,” says Daniel Haber, MD, PhD, director of the MGH Cancer Center and senior author of the NEJM paper.

Frequently Asked Questions regarding the genetic marker, EGFR, and how to test for it:

What is EGFR testing?

Who should get EGFR testing?

What is needed to perform the test?

If my tumor has an EGFR mutation, should I get Iressa?

How can I get my tumor tested?

Answers:

What is EGFR testing? EGFR is a receptor found on the surface of some lung and other cancer cells. A recent study performed at the Cancer Center showed that some cancer patients have lung tumors with EGFR receptor mutations, or changes in the DNA, which make the tumor more susceptible to treatments like Iressa. EGFR testing involves taking your tumor and seeing if it has such a mutation in the EGFR receptors.

Who should get EGFR testing? At this time, the testing is most appropriate for patients with adenocarcinoma of the lung, especially female patients, patients without a history of tobacco smoking, or patients of East Asian descent.

What is needed to perform the test? A biopsy of your tumor and a blood sample are needed. If you have previously undergone a biopsy, your local hospital probably has a “paraffin block” of your tumor stored in the pathology department. This block can be sent to Massachusetts General Hospital for EGFR testing. In addition, you will need to have a tube of blood drawn and sent to the institution.

If my tumor has an EGFR mutation, should I get Iressa? This is a question that researchers at Massachusetts General Hospital Cancer Center are trying to answer through clinical research. Since the discovery of EGFR mutations is very new, we don’t have enough information yet to make recommendations for all patients. For specific patients, it may make sense and you should discuss this with your doctor.

How can I get my tumor tested? If you are interested in finding out if your tumor can be tested for EGFR mutations, call 1-877-726-5130 or 617-724-6862.