Gastrointestinal Stromal Tumors Already Proving to Be Treatable With Targeted Therapies

CUREGastrointestinal Special Issue
Volume 1
Issue 1

Identified only a decade-and-a-half ago, GIST is already treatable with several targeted therapies, and scientists are researching more.



When she was diagnosed with a metastatic gastrointestinal sarcoma nearly 20 years ago, Marina Symcox was 38, with a 2-year-old daughter and two sons, aged 6 and 8. Her doctors weren’t entirely sure of the exact type of sarcoma it was — there are more than 70, and only a few are well understood. Traditional chemotherapy and multiple surgeries did nothing to stop her disease.

Three years later, Symcox was in hospice care. She remembers often covering her head with a pillow, because it was so painful to listen to kids playing in the nearby schoolyard, and thinking how she would not live to see her youngest through kindergarten.

Then, through the wife of another patient in Pennsylvania, Symcox heard a rumor of a new drug that might work for patients like her. Her husband, a professor of chemistry at the University of Tulsa in Oklahoma, started trying to figure out if his wife might qualify for a trial, even though she was so sick. Her cancer turned out to have a mutation in a cell receptor — cKIT — that was the focus of research.

So Symcox and her husband traveled to Oregon Health & Science University in Portland. Symcox, who’s 5-foot-10, then weighed only 95 pounds.

“I basically was carried from Tulsa to Oregon,” Symcox remembers. “My tumors were huge, my belly was swollen with them. But it turns out that my cancer was a perfect match for Gleevec (imatinib), the drug they were testing. Within 48 hours, my tumors were liquefying and my belly was sagging as if I’d just had a baby. I knew it was working.”

Fifteen-and-a-half years later, it’s still working. Symcox has not only lived to see her daughter through kindergarten, but to see all her kids into college. In the 1990s, there really were no treatment options for patients like Symcox. Today, there is not only Gleevec, but two other FDAapproved drugs and more options on the way.

“The patient experience is radically different now,” says Robert Maki, professor of hematology and medical oncology at the Icahn School of Medicine at Mt. Sinai in Manhattan. “It’s changed the whole realm of how these tumors are treated.”


Symcox’s disease initially had been lumped into a group called leiomyosarcomas, but doctors now categorize her cancer as gastrointestinal (GI) stromal tumor, or GIST. These cancers start in special cells — “interstitial cells of Cajal” — that signal the muscles of the GI tract to repeatedly contract, pushing food through the system.

GIST is a rare cancer: It’s estimated that, in the United States, between 4,000 and 5,000 new cases occur each year. However, GIST is one of the most common kinds of GI sarcomas, cancers that start in connective tissue. Carcinomas, cancers that start in the epithelial cells that line the inside and outside of body cavities and organs, are much more common that sarcomas. GIST accounts for 80 percent of GI sarcomas. It can occur at any age, but it most commonly affects those older than 50.

GIST initially causes few symptoms. There are very rare cases of the disease being passed down through families, but in general, there are no known risk factors for it, and no definite ways to prevent it. The disease is often caught during scans for other conditions, such as a CAT scan or a colonoscopy. Sometimes these tumors are even unexpectedly found on autopsy. Approximately 50 to 70 percent of GISTs occur in the stomach and 20 to 30 percent in the small intestine, with the rest scattered in various other places, such as the esophagus or the rectum. The hallmark of most GISTs — 85 percent — are changes, or mutations, in the genes that code for a protein called c-KIT (CD117) and another protein, platelet-derived growth factor (PDGFRA). Gleevec, the drug that has made such a difference for Marina Symcox, targets the binding sites of KIT, PDGFRA and BCR-ABL — a gene prevalent in some blood cancers that is formed when parts of chromosomes 9 and 22 switch places — interrupting cell signaling and thus leading to cell death. Gleevec, along with next-generation drugs like Sutent (sunitinib) and Stivarga (regorafenib), which are also approved to treat GIST, make up a class of drugs called tyrosine kinase inhibitors (TKIs).

“These drugs block the signal from the surface into the interior of the cell,” explains Maki of Mt. Sinai. “The drug fits into the receptor like a key into a lock.”

Those GISTs that don’t have KIT, PDGFRA or BCRABL mutations, some 10 to 15 percent, are called “wild type.” These overwhelmingly account for GISTs found in children and young adults.


The story of TKIs is in a sense the origin story of GIST, or, at least, the origin of our understanding of this disease. In the mid-1990s, Gleevec was just sitting on a shelf at a Swiss drug company, with scientists unsure how to use it. Then a researcher at OHSU, Brian Druker, wondered if it might be useful in fighting chronic myelogenous leukemia (CML) by blocking BCR-ABL. Of the CML patients first treated with Gleevec, a large portion went into remission, proving the principle of Druker’s idea.

Not long after this, another researcher heard a talk about Gleevec and noted that not only did the drug block BCRABL, but it also blocked KIT. This researcher had a line of GI tumor cells with KIT mutations in his lab. When he dosed them with Gleevec, all the cell samples died. Then in 1998, a Japanese researcher wrote a breakthrough paper definitively linking the KIT mutations to increased expression of c-KIT proteins that led to GI tumors.

Word of this work started to percolate around the patient community. The wealthy husband of a patient in Finland sent a doctor to America to learn about the new developments, and, if possible, to get a sample of Gleevec. When the doctor returned to Finland and treated his patient with Gleevec, she went into remission. That positive result quickly led to clinical trials in America and Europe.

Over the next couple of years, sarcoma specialists would begin to group those GI tumors with KIT mutations under the name GIST. FDA approvals for Gleevec in GIST cases followed, in 2002 for metastatic patients and in 2008 for patients who’d had surgery to remove their tumors. It was the first targeted therapy for cancer.

“Before imatinib, metastasized GIST patients had a median survival of nine to 18 months, depending on what source you quote,” explains Anthony P. Conley, a sarcoma specialist at The University of Texas MD Anderson Cancer Center in Houston. “Now the expected median survival is about 60 months. About 40 percent of patients may live 10 years or more.”

Prognosis and treatment are generally determined by where the cancer occurs, how advanced it is and how actively the tumor cells are dividing. Because this cancer is more rare, and not as well understood, as more common cancers such as breast and lung, specialists emphasize that it’s important for patients to be treated at a large medical center with experience in GIST and access to a multidisciplinary team of specialists who can collaborate in care. These specialists can tailor drug doses and other treatments to each particular case.

“Multidisciplinary care is key,” Conley says. “GIST is rare. I hear doctors say they’ve never heard of it, or never seen one in person. This is a disease in which experience can help. For instance, a radiologist who looks at images of sarcomas all day long may key into something that a less experienced person could miss.”


The first-line treatment in many cases is surgery. GIST is resistant to conventional chemotherapy drugs and to radiation.

“If they’re caught early, we surgically resect, with a hope for cure,” says Joseph Ruggiero of Weill Cornell Medical College and New York Presbyterian Hospital.

However, since many GIST cancers have metastasized by the time they’re noticed, and may have grown very large, medical teams sometimes use a targeted drug like Gleevec to shrink the tumor or tumors before surgery, making these operations less risky. Surgeons say that rupture of large tumors is a common risk in GIST cases.

Risk of recurrence after surgery is high in most cases, specialists say. Approximately 80 percent of patients who have radical surgery may find that the tumor grows back or metastasizes to the liver and/or the peritoneum, the membrane that covers the abdominal cavity and internal organs.

So patients with the appropriate mutations in their tumors are usually then treated post-surgically with a targeted TKI agent like Gleevec. Recent studies recommend that this be done for three years, but in practice, physicians say, patients basically stay on Gleevec until it stops working. Eventually, all patients develop a resistance to Gleevec. How long that takes varies. In some patients, the drug may stop working after a year or two. Others may stay on it for a decade or more.

“There are different ways to develop resistance,” Maki explains. “The predominant mechanism is like when you break up with a boyfriend and change the lock, so you need a new key. The new drugs are the new key. But the new keys don’t fit into all the locks. And over time, none of the keys will fit into the locks. That’s why people still die of GIST.”

Most patients progress from taking Gleevec to trying Sutent. When Sutent stops working, they go on to Stivarga. These newer drugs not only block KIT but also angiogenesis (the development of blood vessels that supply the tumor) and other mutations in various locations as the cancer cells become ever more deranged.

Unfortunately, the newer drugs also come with more severe side effects. Gleevec commonly causes puffiness around the eyes, skin rashes, fatigue and muscle cramps. Sutent may cause skin and hair to blanch white, damage the heart and cause low white and red blood cell counts. Stivarga may cause painful neuropathy in the hands and feet (often described as feeling like a cross between a callous and a blister) and high blood pressure, among other problems.

“When I was on Sutent, I got terrible mouth sores and couldn’t eat,” says Lee Ann Lamb, co-founder, with Symcox, of GIST Support International. “After two years, Stivarga started eating up my intestines, causing fistulas and perforations (bulges and holes).”

Lamb spent all of last November in the hospital dealing with those complications. In some cases, patients at this stage may go back to Gleevec with some success, but this wasn’t possible for Lamb, who is now waiting to be admitted to a clinical trial.

“It’s scary to be at this point, when you don’t have anything more,” Lamb says.


There are currently at least a dozen phase 1 trials recruiting GIST patients, and 50-plus studies recruiting in various phases. Many of these are testing the FDA-approved drugs in combination with other agents, or trying to target more recently identified mutations in tumors.

A couple dozen studies are exploring Tasigna (nilotinib), a TKI approved for the treatment of chronic myeloid leukemia, when used alone in metastatic cases of GIST, and also when used in conjuction with Gleevec. Half a dozen other studies are exploring the use of Votrient (pazopanib), an agent indicated for use in soft tissue sarcoma — but not GIST, due to lack of sufficient testing — that disrupts the development of blood vessels that supply tumor cells.

A 2012 Phase 3 study explored the use of another TKI, masatinib, showing that this drug was less toxic than Sutent (sunitinib) and improved overall survival. Other Phase 3 masatinib studies may soon be recruiting patients: One compares masatinib to Gleevec as a first-line treatment in patients who’ve had successful surgery but also have a high risk of the cancer returning.

“There are lots of options to be tried,” says Ruggiero. “In the near future, I believe there will be more targeted therapies, more anti-angiogenic agents, more tyrosine kinase inhibitors.”

“Even within GIST, it’s a lot of diseases: KIT mutation, PDGFRA mutation, BRAF, KRAS, NF1, succinate dehydrogenase, glucose metabolism (how cells convert sugar into energy) — numerous different genes,” says Jason Sicklick, a surgeon-scientist at the University of California San Diego. “And there are others that we’re just learning about.”

Sicklick is hoping to use tumor genomics — study of a tumor’s entire genetic code — to find new targets for treatment. “We are now tearing GIST apart in terms of genetics,” Sicklick says. “We’re getting a better understanding as to next steps.”

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