MEK: A Single Drug Target Shows Promise in Multiple Cancers
Cancer researchers have developed a number of drugs whose targets are specific proteins that help cancer cells do things like grow, migrate, or resist chemotherapy. But some complex proteins have proven nearly impossible to block with targeted therapies, earning them the moniker “undruggable targets.”
Proteins produced by a family of three closely related genes, the Ras genes, are among the most notorious of this group. The Ras proteins are “molecular switches” inside a cell that, when turned on by appropriate signals, activate signaling pathways that lead to cell growth and survival. Mutations in these genes keep them in a constantly active state, driving tumor development and progression.
Although there have been some recent hints of success, researchers have had difficulty designing a drug that binds tightly to these proteins and stops—or at least slows down—their activity. “Blocking the protein has been difficult chemistry,” acknowledged Roy Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center. “No one’s been able to work it out.”
As a result, researchers have tried to attack Ras proteins indirectly, via other proteins in the signaling pathways that Ras proteins regulate. One such protein is MEK, which acts downstream from Ras in the MAP kinase, or MAPK, pathway.
Recent findings suggest that blocking the activity of the MEK protein might be an effective way to attack tumors with mutated Ras proteins—or, for that matter, other proteins that influence MAPK activity.
“MEK has always held great promise as a drug target,” explained Jeffrey Infante, MD, of the Sarah Cannon Research Institute in Nashville, who has been involved in several studies of MEK inhibitors. “Often Ras signaling must go through MEK.”
The Food and Drug Administration (FDA) recently approved one MEK inhibitor, trametinib (Mekinist™), for the treatment of certain patients with advanced melanoma. And researchers recently reported the results of two small clinical trials which suggested that another MEK inhibitor, selumetinib, may help improve the outcomes of some patients with advanced thyroid and ovarian cancer.
In early-phase clinical trials, MEK inhibitors have also shown clinical activity in some patients with multiple myeloma, biliary cancer, and ocular melanoma, explained Helen Chen, MD, of NCI’s Division of Cancer Treatment and Diagnosis.
But some of the MEK inhibitors being tested have limitations, Dr. Infante stressed. For example, some of these inhibitors leave the bloodstream too quickly, which makes it difficult to maintain enough of the drug in the circulation to effectively slow or halt tumor growth. Others stay in the bloodstream too long, which increases the risk of serious side effects. Some of the side effects of MEK inhibitors have been severe, including serious skin rashes, diarrhea, and dangerous drops in white blood cell counts.
Learning how to gain the most benefit from these drugs while minimizing their undesirable effects will be a challenge, explained Dr. Infante.
Thyroid Cancer: Restoring the Hunger for Iodine
Thyroid cancer is one cancer in which researchers think MEK inhibitors may be effective. That hope is due in large part to the relationship between thyroid cells and iodine.
Thyroid cells absorb most of the iodine that enters the human body, and radioactive forms of iodine have been used for decades to help treat the most common forms of thyroid cancer. But some thyroid tumors eventually stop absorbing, or concentrating, iodine. Once that happens, a patient’s long-term prognosis worsens dramatically.
About 70 percent of patients whose thyroid cancers absorb iodine are expected to survive at least 10 years. In contrast, only 10 percent of patients whose tumors stop concentrating iodine are expected to live that long.
Over the past decade, James Fagin, MD, of Memorial Sloan-Kettering Cancer Center and his colleagues have published a series of studies showing that MAPK pathway activity is ramped up in thyroid cancer cells that no longer concentrate iodine and that disrupting MEK or BRAF, another important protein in the MAPK pathway, can restore iodine absorption.
The trial enrolled 20 patients whose tumors had stopped concentrating I-131, a form of radioactive iodine. In eight patients, short-term treatment with selumetinib restored iodine absorption in their tumors to such an extent that they could resume I-131 treatment.
Iodine uptake was measured using a PET-CT imaging technique refined by Steven Larson, MD, and his colleagues at Sloan-Kettering that relies on a type of radioactive iodine called I-124.
“It doesn’t provide just qualitative information, whether iodine uptake before was low and now it’s higher,” Dr. Fagin explained. This approach provides “quantitative numbers, so we know how much iodine tumors are trapping,” he continued. “It’s an absolutely key element and one that is groundbreaking in the field.”
In all eight patients who resumed I-131 treatment, tumors shrank or remained stable. In seven of the eight patients, the responses endured for at least 6 months after treatment resumed.
When the researchers assessed the patients’ responses to selumetinib according to the genetic alterations in their tumors, it turned out that all five patients in the trial with NRAS mutations became suitable for I-131 treatment after selumetinib, whereas only one of nine patients with a BRAF mutation did.
“We’re not sure why patients with Ras mutations were more responsive,” Dr. Fagin said.
He and his colleagues are investigating how to block MAPK signaling in thyroid tumors more effectively, he said, as well as how to cut off signaling pathways that thyroid tumors use when they run into MAPK signaling roadblocks. “If we can get more profound and sustained MAPK signaling inhibition,” Dr. Fagin said, “we believe we can get a greater response to radioiodine therapy.”
Ovarian Cancer: Hopeful Signs
As more is learned about ovarian cancer, new subtypes are being defined based on genetic makeup and other clinical factors. The most common form, serous ovarian cancer, is now considered to consist of two main subtypes: low-grade and high-grade. The low-grade subtype, which accounts for about 10 percent of serous cases, has a much better prognosis than the high-grade subtype.
Despite its better prognosis, low-grade serous ovarian cancer does not respond well to chemotherapy, explained David Gershenson, MD, of the University of Texas MD Anderson Cancer Center. So if the disease recurs after initial surgery and chemotherapy or hormone therapy, patients have no effective treatment options.
Anywhere from 20 to 40 percent of women with the low-grade subtype carry mutations in the Kras gene, Dr. Gershenson noted, and recent data suggest that a somewhat smaller percentage of those with a normal Kras gene carry BRAF gene mutations.
“So we believe that MAPK signaling is pretty important in the development of these tumors and that targeting MEK could offer an effective treatment,” he said.
In an early-stage, NCI-supported clinical trial of women with low-grade serous ovarian cancers that had returned after prior treatment, Dr. Gershenson and his colleagues reported that 8 of 52 patients had substantial tumor shrinkage after treatment with selumetinib, including one patient whose tumors disappeared entirely.
The researchers did not find an association between whether a patient’s tumor had a BRAF or Kras mutation and response to selumetinib. That result may reflect shortcomings with the study itself, Dr. Gershenson explained. For example, tumor samples were available for only about two-thirds of patients in the trial, and most of those samples had been collected when the patients were initially diagnosed, not after their disease had returned, by which time the tumors’ genetic makeup could have changed.
Even with such ambiguity, Dr. Gershenson expressed confidence in the possibility that MEK inhibitors may be used to treat ovarian cancer in the future. “I’m very excited about the findings so far and the advances that will occur in the future,” he said. “A large randomized clinical trial will be the next big step forward.”
Advanced Melanoma: Alone and in Combination
Trametinib is the furthest along of any of the MEK inhibitors currently in clinical testing. In May 2013, based on the results of a large clinical trial called METRIC, the FDA approve the drug for patients with advanced melanoma whose tumors have BRAF mutations. Approximately 40 to 60 percent of patients with advanced melanoma have these mutations in their tumors.
Compared with patients who received standard chemotherapy drugs, patients who received trametinib lived longer and saw their tumors shrink more.
Because BRAF and MEK inhibitors are effective individually in advanced melanoma, the natural next step was to test them in combination. Results from a small clinical trial of trametinib and dabrafenib suggested that the combination could be more effective than a BRAF inhibitor alone.
In addition, the combination treatment significantly reduced the risk of squamous cell carcinoma and keratoacanthoma, the small, highly treatable skin lesions that often develop in patients who receive BRAF inhibitors. It also dramatically reduced the occurrence of acneiform dermatitis, a serious skin rash that is a frequent side effect of trametinib and other MEK inhibitors.
More Trials and More Combinations
Researchers are delving more deeply into how MEK inhibitors function, including trying to understand why the drugs don’t always work in patients whose tumors have genetic mutations that should make them good candidates for these drugs.
In the meantime, numerous clinical trials are moving forward. Selumetinib, for example, will be tested in a large clinical trial of patients with thyroid cancer who are considered to be at high risk of relapse after standard treatment.
And, Dr. Gershenson noted, the NCI-funded Gynecologic Oncology Group hopes to launch a larger, international trial in the United States and United Kingdom that will compare a MEK inhibitor with either chemotherapy or hormonal therapy in women with low-grade serous ovarian cancer that has returned after initial treatment.
Although these trials will test a MEK inhibitor as a single drug, a consensus seems to be emerging that MEK inhibitors may be most effective when used in combination with traditional treatments, with treatments that target other proteins in the MAPK pathway, or with treatments that target other pathways in which Ras plays an important role, such as the PI3 kinase pathway.
Another opportunity, and challenge, for the field is to learn how best to use drugs that target the MAPK pathway, including RAF and MEK inhibitors, with treatments that help the body’s immune system fight cancer, Dr. Chen said. One of the most promising options may be in melanoma, she noted, where there is already an FDA-approved immunotherapy, ipilimumab (Yervoy®).
But side effects can be of particular concern when two drugs are combined, Dr. Infante cautioned. “In the lab, combinations often look good when you’re working with cells or animal models,” he said. “But it’s hard to give full doses of both drugs to patients because they can have overlapping toxicities.”
For example, in the first trial to test a MEK inhibitor in patients with lung cancer whose tumors have Kras mutations, patients who received selumetinib and the chemotherapy drug docetaxel lived longer than those who received docetaxel alone. But they were also far more likely to experience serious side effects.
So there is still a lot to learn from research with MEK inhibitors, Dr. Chen stressed.
In many of the cancers in which MEK inhibitors have been tested, “we’ve seen tumor response rates of between 10 and 20 percent and the response durations are usually short. Our challenge now is to better understand the resistance mechanisms and what combinations make the most sense,” she said. “These signaling pathways are complex … so we have to think carefully and do systematic laboratory and human studies to understand how they work together and how best to target them.”