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.

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 Io,ooo patients a year who can benefit from drugs targeting ALK.

ALK mutations found in many cancers

The ALK gene is a member of a family of genes known as the cluster of differentiation (CD) molecules, a group of genes that provide the genetic blueprint for the surface proteins of blood cells and, in the case of ALK, play a role in cellular communication and the development of the immune system. Mutations in ALK have been implicated in several cancers, such as neuroblastoma, non-small cell lung cancer, and inflammatory myofibroblastic tumors.

The company Pfizer developed crizotinib, and had studied it in hopes of treating a different mutation, when a team ofJapanese 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 known as the cluster of differentiation (CD) molecules, a group of genes that provide the genetic blueprint for the surface proteins of blood cells and, in the case of ALK, play a role in cellular communication and the development of the immune system. Mutations in ALK have been implicated in several cancers, such as neuroblastoma, non-small cell lung cancer, and inflammatory myofibroblastic tumors. 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 bodies’ cells.

When the results of the Phase I 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 IO 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.”

ALK mutations can trigger uncontrolled growth, leading to the formation of cancer

Mutations in the ALK gene can lead to cancer by turning on important signaling pathways at improper times. When the ALK gene is mutated or altered, it can enter a state where it no longer requires stimulation from outside the cell to initiate the cell signaling cascade for growth and maturation of the cell. This state, known as constitutive activation, means that the downstream signaling pathway it selectively controls becomes constantly turned on (activated), which may increase the proliferation of immature nerve cells. This constant signaling can lead to the kind of uncontrolled growth that typifies cancer.

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.” 1-Iowever, few drugs are truly wonder drugs-therapies typically involve a combination of drugs. So, as Shaw and Engelman explain, understandingwhat 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, that 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 20I2, to preliminary Food and Drug Administration (FDA) approval as a breakthrough therapy in March 20I3, to full FDA approval in April 20I4. About half the I63 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 20I3, 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.

ALK mutations may change treatment course

Checking for changes in the ALK gene in tumor tissue may help to plan cancer treatment, particularly for people with NSCLC or anaplastic large cell lymphoma.

For example, people with NSCLC who test positive for an ALK mutation may benefit from treatments, called ALK inhibitors, that specifically target the gene. The U.S. Food and Drug Administration (FDA) recently approved a drug called crizotinib (marketed as Xalkori) for people with advanced lung cancer and an ALK mutation. Xalkori has been shown to improve outcomes in such patients when compared with conventional, platinum-based chemotherapy. Although these drugs can help after chemo has stopped working, they are often used instead of chemo in people whose cancers have an ALK gene mutation.

Testing for an ALK mutation can also influence treatment for people with anaplastic large cell lymphoma. Patients with an ALK mutation usually respond well to standard chemotherapy, putting most patients in long-term remission. However, although most people without an ALK mutation initially respond to standard chemotherapy, many will relapse within five years. Because of this, people with anaplastic large cell lymphoma who do not have an ALK mutation are sometimes treated more aggressively, often with a stem cell transplant after remission.

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 I6o adults and I20 children are diagnosed with ALCL in the US 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 “CI-IOP” is effective in treating these ALK­ positive anaplastic large-cell lymphomas; 5-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 US each year, with half occurring in children under two. Neuroblastomas are very difficult to diagnose, and also behave unpredictably after diagnosis. About IO 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 20I4, 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.)

Testing tor ALK mutations

The most common way to test for an ALK mutation is through FISl-1 (fluorescence in situ hvbridization). ALK mutations can also be detected through molecular testing. Several organizations worked together to develop guidelines on who should be tested for an ALK mutation. They came to the consensus that patients with lung adenocarcinoma (or mixed lung cancers with an adenocarcinoma component) should be tested for ALK mutations (as well as EGFR mutations) regardless of characteristics such as smoking status/history, gender, race, and other risk factors.

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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