Challenges ahead for the GIST community
Last month’s newsletter reviewed the exciting developments that have occurred in the GIST world in the past five years. This month, Jerry Call, Life Raft Science Coordinator, shares his views on the challenges the GIST world is likely to face in the future.
Writing about
the past is easier to discuss. It deals
with people, events, dates and facts.
The hard parts are emphasizing the most
important events and knowing that many
important
people were left out of the story,
either because I simply was unaware of
their role or because of limitations
about the level of detail possible in a
newsletter article.
Writing about the challenges that I think the GIST world will face in the future is a more difficult task. At the risk of appearing supremely arrogant, I will peer into my layperson’s crystal ball.
Understanding the GIST world is like looking through a prism. When you look through a prism, the whole picture (white light) is separated into distinct colors. Looking at GIST, each of us sees only a piece of the whole story as though we were looking through a prism but can see only
one color. I, as a caregiver, might see only the red; a patient might see orange, a researcher a blue color, someone from pharma a violet color. Within each group we must make further divisions, for no two people experience exactly the same circumstances.
So please understand that when you read my opinions on the challenges of the future, they are influenced by what I see through my prism; my insight into the GIST world.
SECONDARY RESISTANCE
Despite the large number of GIST patients who initially benefit from Gleevec, most have tumors that will eventually become resistant to Gleevec. This is a common problem with cancer treatments.
Resistance to Gleevec after having an initial response is called “secondary resistance.” Overcoming secondary resistance is one of the most important challenges facing GIST researchers.
In GIST patients, secondary mutations in the target gene, c-kit, are the largest known mechanism of resistance. Secondary mutations in GIST patients also occur in an alternate receptor, PDGFRA.
Several approaches to overcoming this resistance are possible. One strategy is to design drugs that bind to KIT just like Gleevec but that have a somewhat altered structure that fits better into the altered binding pocket of KIT. AMN107, for example, is a modified form of Gleevec that may inhibit some secondary mutations in KIT that are insensitive to Gleevec.
A variation of this would be to combine two (or more) inhibitors with activity against different mutations in an effort to inhibit a broad spectrum of mutations.
Another tactic may be to bypass the problem of drug binding to the many different conformations possible in KIT or PDGFRA, and inhibit these proteins using a different technology. Some possibilities include antisense technology, siRNA technology, or HSP90 inhibitors. Of these possibilities, HSP90 inhibition took the lead when a phase I trial for IPI-504, an HSP90 inhibitor by Infinity Pharmaceuticals, began this month (see article on Page 2). The antisense and siRNA technologies don’t appear to be very far along at present.
Targeting proteins downstream of KIT or PDGFRA is another direction considered to overcome Gleevec resistance.
Further defining and overcoming other methods of secondary resistance such as protein overexpression and activation of an alternate receptor also remain a challenge.
PRIMARY RESISTANCE
Initial resistance to Gleevec occurs in about 15 percent of GIST patients. Some of the problems dealing with primary resistance are similar to secondary resistance and some are quite different. One particular PDGFRA mutation, D842V, is insensitive to Gleevec. What’s needed is a drug that fits into the binding pocket of this mutation. While this mutation is rare, it’s still the most common PDGFRA mutation.
KIT exon 9 mutations don’t respond to Gleevec as well as the most common exon 11 mutation. Exon 9 mutations are somewhat of a problem from both the primary and secondary resistance aspects. While more research is needed to better understand exon 9 mutations, Sutent already offers some clinical relief, as it is effective in about 80 percent of Gleevec-resistant exon 9 mutations.
The third major type of primary resistance occurs with GIST tumors that don’t have KIT or PDGFRA mutations. These tumors are called “wild-type” (for) KIT/PDGFRA. Part of the “wild-type” mystery was solved when researchers discovered the PDGFRA mutations that occur in 5 to 7 percent of GISTs (see the “GIST and Gleevec: 5 years of progress” article in last month’s newsletter). More research is needed to find the “driver” for the remaining wild-type GISTs.
GIST AS A CHRONIC DISEASE
There is a lot of talk about moving away from the concept of curing cancer and moving towards treating cancer as a “chronic disease.” Gleevec is one of the best examples of how this may be possible.
Gleevec does not cure GIST (or chronic myelogenous leukemia), it just keeps it under control. About half the GIST patients who take Gleevec will have significant tumor shrinkage, while about a third will have less significant shrinkage, or stability.
Gleevec has been one of the most important milestones ever in the war on cancer. It marked the beginning of the molecularly targeted era. It is also a prime example of treating cancer as a chronic disease.
Treating metastatic GIST as a chronic disease is likely to continue for quite some time, and the historic gains made using this concept should be loudly acknowledged.
Despite this incredible success, treating GIST as a chronic condition should only be an intermediate goal. Research into ways to overcome secondary resistance is vital and should be supported to the best of our ability.
At the same time, I believe that it is possible to pursue a parallel path that tries to improve upon the effectiveness of Gleevec with an ultimate goal of curing GIST.
While many (perhaps most) GIST patients would be quite happy to take Gleevec or a similar therapy forever to control their disease, there are several concerns. The first is that Gleevec resistance (in GIST more so than chronic phase CML) is proving far too common.
The second concern with the “GIST as a chronic disease” philosophy is that while most GIST patients can maintain a reasonable quality of life, a few can’t, either because of side effects from Gleevec or the advanced stage of their cancer. Side effects such as fatigue, nausea and diarrhea can be difficult to live with if they continue long-term. One symptom that is difficult to manage in a chronic fashion is bleeding. Although rare, bleeding represents a significant challenge for some patients.
A third concern with treating cancer as a chronic condition is the cost. Gleevec has dramatically extended the survival of GIST patients with metastatic disease. But the cost is significant. Gleevec (most patients take other medications as well) and other targeted therapies such as Avastin (for colon cancer) and Nexavar (for kidney cancer) are very expensive. Then there are the CT scans, blood monitoring and visits to doctors. I’m not suggesting we throw away 30 years of (slow) progress in the war on cancer because treating cancer as a chronic condition is too expensive; that would be foolhardy. I merely acknowledge the fact that this philosophy is expensive.
The good news and an argument for the “treat as chronic disease” philosophy is that the mechanisms of resistance in GIST are becoming fairly well understood. The incredible focus that results from having a single target (either KIT or PDGFRA) being so important to the proliferation and survival of GIST, and having an effective inhibitor (Gleevec), is what allows the biology of GIST and the mechanisms of resistance to Gleevec to be dissected so thoroughly. Add to that the comparisons that can be drawn from the Gleevec for CML story and you end up with GIST, CML and Gleevec creating models for molecularly targeted cancer therapies.
As more progress is made in the war on cancer, we can expect that more common cancers will be increasingly treated with molecularly targeted therapies. As this happens, huge costs will be incurred as patients, governments and insurance companies try to fund these advances in treatments.
STABLE DISEASE
Most people consider stable disease to be a huge victory in the war on cancer. I do as well, but I also consider it a challenge. For many GIST patients, Gleevec kills many — perhaps even most — of their tumor cells. For some GIST patients, Gleevec kills few tumor cells but it does keep them from proliferating — resulting in “stable disease.” No matter what type of response patients have, Gleevec seldom, if ever, kills all of their cancer cells. This means that patients will have to continue taking Gleevec as long as it continues working.
Efforts to improve initial responses to Gleevec and responses in “stable patients” has the potential for gain in several areas. One is simply improved symptomatic relief. In a few patients this symptomatic relief could be substantial, even profound.
If we acknowledge that resistance arises in tumor cells that drugs don’t kill, then attacking stable disease may be beneficial. One question is whether the residual stable tumor cells are easier to kill than cells that become resistant to Gleevec. While intuition would suggest this is true, I’m not convinced it is. However, I am convinced that trying to understand and (eventually) target both gives the maximum chance of success.
The more we understand residual disease, the better chance we have of developing effective adjuvant therapies.
While acknowledging that residual/stable disease may turn out to be more complex (especially more heterogeneous) than we’d like, I still believe that the potential benefits justify research into this area. I was glad to see that researchers involved in The Life Raft Group resistance project seem to agree and have made “stable disease” one of their priority areas for research.
PEDIATRIC GIST
The primary cause of GIST is a mutation in c-kit (that affects the KIT protein) in 80 to 85 percent of adults, or PDGFRA in 5 to 7 percent of patients. Knowing the primary cause in adults provides the rational for therapy. And, thankfully, Gleevec is an effective therapy.
In pediatric GIST, the primary cause isn’t known. Hence understanding the biology of pediatric GIST and, specifically, finding the most important mutations is the most important challenge facing GIST researchers. Understanding pediatric GIST may also reveal clues that fill in some of the knowledge gaps in adult GIST.
The most difficult obstacle for pediatric GIST researchers is probably the scarcity of resources, specifically tumor tissue samples. Consolidating the limited resources and getting them to the right researchers is a top priority of the Life Raft Group, as is a dedicated pediatric tissue bank and basic research into finding the causes of pediatric GIST.
CLINICAL TRIALS
The
early and tremendous success of Gleevec
introduced GIST patients to the world of
clinical trials. Prior to Gleevec there
was no effective therapy for metastatic
or inoperable GIST. There was a window
of time — from July of 2000 until
February of 2002 — when Gleevec was only
available in clinical trials (although
it was available “off-label” in 2001).
With 85 percent of participants benefiting in the early clinical trials of Gleevec, GIST patients came to depend on these clinical trials for survival. Most of these responses were fairly long-lasting as well with a median time-to-progression of about two years.
By 2002, as some of the early GIST patients were becoming resistant to Gleevec, Sutent entered clinical trials for GIST. While Gleevec-resistant patients didn’t see the same spectacular results, they were still good (see Sutent below).
As GIST patients stopped responding to Gleevec, they sought out new clinical trials. These included AMG706, Gleevec plus RAD001, Gleevec plus PKC412, BMS-354825, Gleevec plus AMN107, Gleevec plus Perifosine, BAY 43-9006, CCI-779, and the latest drug, IPI-504.
SUTENT
Sutent (formerly known as SU11248) has won U.S. approval for Gleevec-resistant GIST, and it is a welcome addition to the GIST treatment arsenal. It is particularly nice that it seems to be most effective in patients that typically have primary resistance to Gleevec, specifically patients with KIT exon 9 mutations and “wild-type” patients.
Sutent seems to significantly benefit 60 to 65 percent of patients, most of whom experience stable disease. About half of Sutent patients will progress in slightly over six months. Many will have significantly more than six-months’ benefit.
THE ‘CURSE OF THE CURE’
There was a recent editorial in the journal, “Nature Clinical Practice Oncology” by Vincent T. DeVita Jr., titled “The curse of the cure.” He wrote: “We are in some ways victims of our own success in the management of childhood leukemia and advanced Hodgkin’s disease (HD). Leukemia was the first childhood malignancy to be cured by chemotherapy, and HD was the first tumor of a major organ system in adults, in its advanced stages, to be cured by chemotherapy. In both instances, as the majority of patients respond to chemotherapy, investigators are faced with the challenge of reducing the toxicity of treatment while still offering patients the maximum chance of cure.”
In other words, it was hard to make further progress in treating these diseases because the existing treatments were successful, but toxic.
In GIST, a potential “curse of the cure” looms, albeit a bit differently. While Sutent has been approved in the U.S., it is not a cure and only about half of the patients get more than six months’ benefit from it. We still need much better treatments for Gleevec-resistant GIST. These treatments must be proven in clinical trials.
Gleevec-resistant patients are harder to treat than patients who’ve never had Gleevec. Patients who are resistant to both Gleevec and Sutent are harder to treat than patients resistant only to Gleevec.
While it’s risky to generalize too much, my impression is that as you treat cancer with therapy after therapy, it becomes harder to treat with each failure.
It’s possible that a drug with good to excellent activity against Gleevec-resistant GIST might have marginal activity in Gleevec- and Sutent-resistant GIST. How would you know if you only tried it in Gleevec/Sutent-resistant GIST?
With Sutent’s approval, we have a new challenge: How do we maximize the patient’s therapy and at the same time maximize advances in GIST treatment in general? Should all patients try Sutent after failing Gleevec? Or should some patients go directly into other clinical trials? How do you choose? And will Sutent’s approval — clearly good news for patients — slow overall progress in the war on GIST? Can the GIST community avoid “the curse of the (not quite) cure?”
MOVING
TOWARDS
INDIVIDUALIZED THERAPY
When we hear the word cancer, we think of one disease, but cancer is really made up of many, many types of cancer, each of which could be thought of as a separate disease. Six years ago, most doctors and almost all patients thought of leiomyosarcoma (LMS) and GIST as the same disease or they thought of GIST as a subset of LMS. Today we know that GIST and LMS are quite different and require totally different treatments.
GIST itself can be subdivided in several different ways — by major gene mutation (KIT or PDGFRA), then by the location of the mutation within the gene (exons). These mutations can be analyzed in the lab. The process of determining the gene and exon mutation is called genotyping, and it may represent the next major method of subdividing GISTs.
Testing
tumors to see if they “stain positive”
for the KIT protein has been possible
(clinically) since approximately 2000.
This helped establish the diagnosis of
GIST and make GIST distinct from other
cancers such as LMS. In a way, we could
think of this as the beginning of
“individualized therapy” for LMS/GIST
patients. There was a good reason to
separate the two as there was a powerful
drug in clinical trials (Gleevec) that
targeted the mutant KIT receptors.
Mutations in different parts (exons) of the gene result in proteins that have a different shape than normal proteins. These changes in shape can result in “short-circuiting” the protein, causing it to be continuously activated. These activated proteins (receptors) continually provide an abnormal growth and survival signal to cells, resulting in GIST.
Mutations in some exons can change the way drugs bind to the target proteins (KIT and PDGFRA) and cause the drugs to be ineffective.
Mutations in different exons can also change the activation pattern of downstream signaling proteins. Some drugs work better against one type of mutation while other drugs work better against other types of mutations:
1. It is well established that mutational status (genotyping) can predict how well patients will respond to Gleevec:
• GIST highly sensitive to Gleevec
□ KIT
• Exon 11
□ PDGFRA
• Exon 12
• GIST with intermediate sensitivity to Gleevec
□ KIT
• Exon 9
• GIST with lower sensitivity to Gleevec
□ PDGFRA
• Exon 18
□ Wild-type for KIT and PDGFRA (no mutations)
2. Clinical trials have also defined the response rate (at least partially) of Sutent (in Gleevec-resistant GIST) by exon status including secondary mutations:
• Gleevec-resistant GIST highly sensitive to Sutent
□ KIT
• Exon 9
• Wild-type for KIT & PDGFRA
• Secondary exon 13 or 14
• Gleevec-resistant GIST less sensitive to Sutent
□ KIT exon 11
□ KIT secondary exon 17 mutation
If testing for KIT expression is the first step in individualized therapy for GIST patients, genotyping is clearly the second step. In addition to predicting response to drugs, genotyping can help diagnose GISTs that don’t express the KIT protein (KIT negative GIST) as most of these tumors do have either KIT or PDGFRA mutations. It could help in deciding whether to have surgery and whether a patient would be likely to benefit from neoadjuvant Gleevec (Gleevec before surgery).
The role of genotyping will continue to expand as sensitivity profiles are developed for more drugs. I believe any patient who has access to genotyping (through insurance, etc.) should strongly consider having this testing done.
The other step patients can take toward individualized therapy is simply finding the best GIST experts, preferably an institution with a multi-disciplinary team. For that matter, this may be the most important thing a patients can do. While we can make generalizations about treatments from details like KIT expression and genotyping, the details are all important. It takes a GIST expert to interpret all aspects of a patient’s care, from his or her general health to CT scans to surgery and many other details.
One challenge will be to extend the use of genotyping. Some possible questions/scenarios:
• A patient has a mutation that is known to be insensitive to Gleevec (such as PDGFRA D842A); should that person be required to fail Gleevec before being allowed to participate in a clinical trial? What if the trial drug has demonstrated in-vitro (test tube) activity against this mutation?
• Should patients be directed towards clinical trials based on matching their mutation to in-vitro activity of the drug?
Beyond genotyping exists the next generation of individualized therapy. How do we match the patient with the best therapy possible? Should we know the activation status of KIT and/or downstream signaling proteins? Given that GIST biology is extremely well understood, it seems logical the GIST should be at the forefront of individualized therapy.
FINAL THOUGHT
The introduction of Gleevec sparked a revolution in the way cancer is treated. The gains made by researchers and pharmaceutical companies are great, but there are challenges ahead — not just the ones I’ve mentioned, but ones we haven’t even dreamed of.
