The Story of ALK

GENE STORY

The Story of ALK

How breakthrough drugs such as crizotinib and ceritinib target the ALK mutation in lung cancer, non­ Hodgkin's lymphoma and other malignancies.

ALK Mutations at Glance
  • ALK mutations are found in several cancers, including inflammatory myofibroblastic tumors, anaplastic large cell lymphoma (ALCL), 10 percent of neuroblastomas, and 5 percent of non-small-cell lung cancers (NSCLC).

  • When mutated, ALK improperly signals cells to grow and divide, which can lead to cancer.

  • An ALK mutation diagnosis could change your treatment if you have lung cancer or anaplastic large cell lymphoma (ALCL). The ALK inhibitor crizotinib (marketed as Xalkori), has been approved to treat patients with advanced NSCLC. Patients with ALCL and an ALK mutation usually respond well to standard chemo. ALCL patients without an ALK mutation tend to relapse within five years, and may therefore be treated more aggressively.

  • There are many more treatments for ALK mutations that are presently in early phase clinical trials

  • Testing for ALK typically requires a tumor sample.

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ALK

This gene is also known as:

ALK, CD246, NBLST3, ALK Tyrosine Kinase Receptor

Sarah Broom’s second book of poetry, Gleam, came out a few months after her death. She lived for five years after being diagnosed with ALK-positive lung cancer, thanks to targeted gene therapies. She published her first book, Tigers at Awhitu, two years after her diagnosis. “The heat is its own desperate cure,” she wrote. In “holding the line,” a poem from Gleam, she continued:

when I feel feverish I take the full moon

and place it on my brow like a flannel

Although she was born and lived in New Zealand, about as remote from the epicenters of drug development as one can get, Broom was the third person to receive crizotinib, a remarkable drug that treats patients suffering from non-small-cell lung cancer who have a mutation of the ALK oncogene. Non-small-cell lung cancers account for about 85 percent of all lung cancers; there are about 200,000 new cases each year in the United States alone. While only about 5 percent of non-small-cell lung cancers have the ALK (anaplastic lymphoma kinase) mutation, that’s 10,000 patients a year who can benefit from drugs targeting ALK.

The company Pfizer developed crizotinib, and had studied it in hopes of treating a different mutation, when a team of Japanese researchers lead by Hirayuki Mano, then a professor at Jichi Medical University, some 30 miles north of Tokyo, discovered the ALK mutation in lung cancers in 2007. Mano found ALK fused with another gene called EML4 in non-small-cell lung cancers; his team also found that the fusion didn’t occur in a variety of other cancers they screened for the fused gene. Crizotinib targets the ALK protein produced by the ALK gene. Like many targeted anti-cancer drugs, it works by occupying a space on the protein that would otherwise be filled by ATP (adenosine triphosphate), the main source of energy within cells. The shape crizotinib takes means that, to the ALK protein, it looks like ATP, though it doesn’t look like ATP to other proteins. So it jams up the works for ALK, with only limited side effects. It helps that ALK does not appear in normal tissues (or if it does, only to a very limited extent). It only appears in tumors. And tumors that contain ALK aberrations depend very strongly on ALK activity to multiply and survive. So if you can block ALK’s function, you stand a chance of stopping the tumors in their tracks without harming the rest of the body’s cells.

When the results of the phase 1 trials for crizotinib were published in the New England Journal of Medicine in 201o, it was hailed as the “Latest Champion in the Cancer Wars.” Doctors had screened 1,500 tumor samples and found 82 patients with ALK mutations that made them eligible for the study. Over half of the patients responded favorably to the drug, compared to about 10 percent for standard chemotherapy.

The favorable responses were very favorable. As a New York Times Magazine article about Broom explains, though she had been diagnosed and given months to live, after she started on crizotinib, her “tumors shrank by half, and Broom led an almost normal life for two years. Then the cancer returned.”

Sadly, Broom’s case was typical. Crizotinib worked very well on many patients, but only for a short time. Some patients develop a resistance to the drug within months, while for others, like Broom, it takes a year or two. As Alice Shaw and Jeffrey Engelman wrote in the Journal of Clinical Oncology, “ALK-driven cancers invariably become resistant to crizotinib.” However, few drugs are truly wonder drugs—therapies typically involve a combination of drugs. So, as Shaw and Engelman explain, understanding what causes crizotinib resistance is now a very active area of research that searches for useful combinations. There are several reasons that ALK cancers develop resistance.

The first type of resistance comes from mutations either in or near the pocket where ATP binds to the ALK protein. Such mutations block crizotinib’s ability to bind to the protein while still allowing ATP—the fuel molecule—to interact with ALK. The other type of resistance arises when crizotinib continues to block the site where ATP normally binds, but mutations occur elsewhere in the protein that allow ATP to give it energy at an alternative location.

By better understanding how crizotinib resistance develops, researchers can develop new drugs that can be used either as an alternative to, or in combination with, crizotinib and might not be vulnerable to similar mutations. The second drug developed to specifically target ALK is called ceritinib (its trade name is Zykadia). It went from a proof of concept in May 2012, to preliminary Food and Drug Administration (FDA) approval as a breakthrough therapy in March 2013, to full FDA approval in April 2014. About half the 163 patients in the clinical study that led to FDA approval responded to ceritinib; these patients had either been intolerant to crizotinib or hadn’t benefited from it.

Alectinib, another ALK inhibitor, was also approved as a breakthrough therapy in 2013, as was brigatinib, in October 2014. According to a recent paper in Cancer, alectinib blocks ALK even when it has developed several of the mutations that cause crizotinib resistance, while brigatinib appears to directly inhibit ALK’s ability to fuse with other proteins. A number of other drugs are in early-phase clinical trials.

One further area of positive development is in a type of non-Hodgkin’s lymphoma called anaplastic large­ cell lymphoma (ALCL), from which the gene name ALK is derived. Only about 160 adults and 120 children are diagnosed with ALCL in the U.S. each year. When the gene coding for ALK was first discovered, it was by a group at St. Jude Children’s Research Hospital in Memphis, Tennessee, focusing not on lung cancer, but rather ALCL. A chemotherapy combination that goes by the acronym “CHOP” is effective in treating these ALK­-positive anaplastic large cell lymphomas; five-year survival rates are about 70 to 80 percent, so targeted drugs have not yet been widely applied to such lymphomas, because it isn’t clear they would work better than more conventional chemotherapy.

ALK signaling also plays a role in other rare cancers, including inflammatory myofibroblastic tumors, which typically show up in teenagers, and neuroblastoma, which is the most common cancer in infants. There are about 650 new cases of neuroblastomas in the U.S. each year, with half occurring in children under two. Neuroblastomas are very difficult to diagnose, and also behave unpredictably after diagnosis. About 10 percent of neuroblastomas have ALK mutations.

Ignyta, a biotech start-up dedicated to targeted cancer drugs, got orphan drug approval for entrectinib, a drug that blocks ALK, to treat neuroblastomas in December 2014, and for non-small-cell lung cancer in February 2015. (The orphan drug designation, for rare diseases, doesn’t mean the drug has been approved for use, but makes it easier for drug-makers to get that approval, through tax credits and assistance from the FDA with clinical trials.)

Many of the drugs targeting ALK are, broadly speaking, chemically similar. The trick is in getting them through clinical trials and seeing how small differences in chemistry might lead to bigger differences in their ability to fight cancer. One of the challenges of clinical trials is recruiting patients; many trials fail to get off the ground because they cannot find even a single eligible patient, while cancer patients may not know of trials that target the particular oncogenes they carry. By participating in the clinical trial exchange, it may be possible to overcome this gap.

Sarah Broom, as the Times magazine explains, managed to get a hold of ceritinib even before it had cleared clinical trials. It helped her, for a year, before her lung cancer resurfaced. She died on April 18, 2013. Her poem, “holding the line,” concludes:

when I feel that my heart is clapping out of time, I take it out and throw it up among the stars, who know all there is to know about holding the line.

 

 

 

 

 

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