Through his work at the University of Michigan Cancer Center, Rally Researcher Dr. Mark Chiang discovered a novel protein that sticks to a leukemia cancer gene called Notch. This discovery could potentially pave the way for anti-Notch drugs—drugs without the harsh, harmful side effects of traditional acute leukemia treatment.
We sat down with Dr. Chiang to discuss acute leukemia in children, what this new discovery could mean, and why research (along with funding) is so important when it comes to pediatric cancer.
What is Acute Leukemia?
Acute leukemia is a very aggressive type of blood cancer that is quickly fatal if left untreated. It is the most common cancer in children and is a leading cause of cancer-related death. These cancers originate from primitive progenitor cells in the bone marrow. They can also originate from the thymus or lymph nodes and form tumors in related diseases. The thymus is an immune organ that lies just above the heart.
Both adults and children can develop this cancer. The major subtypes of acute leukemia are acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). ALL and AML are treated very differently. In children, ALL is far more common than AML. In contrast, in adults, AML is much more common than ALL. The cancer-causing genetic changes in pediatric acute leukemia are often shared with adults. However, based on three seminal studies published this year, we are starting to realize that in pediatric acute leukemia, like in other forms of pediatric cancers, there are many genetic changes that are not shared with adult cancers.
Acute Leukemia in Children
Children with acute leukemia can have many kinds of symptoms. In contrast to the symptoms of chronic leukemias that develop slowly, the symptoms of acute leukemias develop rapidly over a short period of time. It can be an emergency situation. Children with acute leukemia generally feel very weak. They play less and eat less. They lose weight. They can also have headaches, fevers, rashes, swelling of the glands, and bone pain. The leukemia cells crowd out normal blood cells that are important for many bodily functions. Because of this, children with leukemia have fewer normal blood cells. Normal blood cells are necessary to carry oxygen in the blood, prevent bleeding, and fight infections. Frequently, children with acute leukemia will go the emergency room with life-threatening infections.
Treating Pediatric Acute Leukemia
The typical treatment is a protocol consisting of multiple phases over 1-2 years with complicated cocktails that can include radiation and drugs like chemotherapy, steroids, and others. The details of the treatment plan depend on the type of acute leukemia and its genetic makeup. Doctors figure this out by performing tests on a bone marrow biopsy sample, which is obtained by inserting a needle into the hip bone to retrieve the leukemic cells. The first phase of treatment is the most intense. The goal is to get the patient into a remission by wiping out almost all of the leukemia cells. Drugs are given in the veins, in the brain fluid, under the skin, and by mouth. We measure for side effects and response to treatment by testing the blood, bone marrow, and brain fluid.
These children are considered so sick that they need to be hospitalized. The main reason is that both the leukemia and the treatment itself have unpleasant effects. They damage the blood and immune systems. To survive, the children need blood transfusions and antibiotics until their blood and immune systems recover. There is a lot of other important supportive care that can improve nutrition and reduce pain and anxiety. After the first phase, the other phases can be done with outpatient doctor visits, scheduled procedures like bone marrow biopsies and spinal taps, lab work, transfusions, scheduled admissions for infusions, and possibly emergent admissions for serious complications like infections.
Why We Need to Fund Research
The genetic changes in pediatric acute leukemia cells differ from patient to patient. Some patients will have genetic changes not found in adult leukemia. Some types of acute leukemias like the one associated with Down Syndrome are mainly or exclusively found in children. If research were only conducted on adult acute leukemias, then we might never understand the biology of a large subset of pediatric-specific leukemias or develop specific treatments tailored to combat them. Kids also have remarkable resilience to therapy. They can often tolerate higher doses of drugs or more aggressive treatments that adults could not. If we simply give kids the exact same treatments as adults, we would often be under-dosing them, leading to reduced chances for remission. In the past, the assumption was that treatments that work for adults will also work for kids. But now we are realizing that this assumption was flawed. It is important to develop clinical trials specifically tailored for kids with acute leukemia.
A Hopeful Prognosis
Overall, the outlook is relatively good compared to adults with acute leukemia. Kids usually respond better to conventional treatment than adults. However, some subsets of pediatric acute leukemia like infant acute leukemia have worse outcomes. Also, when the leukemia relapses, the prognosis is dismal. It is much harder to put these patients back into a remission. More so than in adults, kids cured of their acute leukemia have to deal with unfortunate long-term side effects like brain and heart damage and new cancers that were paradoxically caused by the treatment.
Changes in Treatment
Over the past 30 years, the backbone of the initial treatment has not changed much. It is still generally a combination of chemotherapies and radiation. They are a lot of side effects. There has been some progress in reducing the intensity of treatment to reduce long-term side effects. You might have read about fancy new targeted agents or so-called “magic bullets” that hone in on cancer cells and kill them by directly knocking out their inner machinery. Because of this, they have less side effects than conventional treatments. The option of using a particular targeted agent depends on the genetic changes in the tumor of a particular patient. This is often referred to as “personalized medicine.” Over the last year, many targeted agents were approved by the FDA for adult AML. We hope that these drugs might soon be found to be useful for pediatric AML. But for now, there are relatively few targeted agents on the shelf for pediatric acute leukemia. In contrast, there has been a lot of progress in harnessing the immune system to fight relapsed pediatric ALL like CAR T cells. Our immune system not only fends off dangers like viruses and bacteria, but can also fight cancer cells. It could use a little help to win the battle.
New Discoveries & Promising Projects
Discoveries in pediatric acute leukemia have also benefited adults with acute leukemia. Many genetic changes in pediatric acute leukemia are shared in adult acute leukemia. A good example are mutations in the Notch1 gene, which were originally discovered in a subtype of pediatric ALL called T-ALL in 2004. Notch1 is the most commonly mutated oncogene in T-ALL. In subsequent years, mutations were also commonly found in adult T-ALL. Because of this, anti-Notch1 therapies would be predicted to be effective in both kids and adults. As another example, CAR T-cell therapies were first tested in pediatric acute leukemia and are now being tested in adults with acute leukemia. Fortunately, adults seem to derive similar benefit from this novel treatment as kids do. Adult chemotherapy protocols have also learned a thing or two from pediatric treatment protocols. For a long time, we’ve known that pediatric oncologists do a better job in curing ALL than adult oncologists. Because of this, adult treatment protocols have shifted to incorporate some elements of pediatric protocols.
With regard to biology, we are seeing a bounty of new potential therapeutic targets from huge, recent studies from the Children’s Oncology Group and St. Judes that have been reading the DNA sequence of childhood cancers. In particular, we’ve learned about the genetic changes that cause relapse and how they might be countered. With regard to treatment, CAR-T therapies have become quite fashionable. However, more than half of the patients will relapse. One project to reduce relapse is to equip the CAR-T cells with two different weapons to kill leukemia cells instead of just one. Another promising new therapeutic approach are targeted agents that break up proteins that stick to each other. Scientists call the sticking together of two proteins a “protein-protein interaction” or PPI. Currently, targeted agents are generally drugs that knock out proteins called enzymes. That is because these types of drugs are easier develop. The problem is that most cancer-causing proteins are not enzymes. A lot of them cause cancer through PPIs. Just last year, the first anti-PPI drug was approved by the FDA for adult AML. Another anti-PPI drug in the pipeline looks very promising to treat infant ALL, which has dismal prognosis. Another class of anti-PPI drugs knocks out Ras, which is a huge driver of relapse in childhood leukemia. Ras drugs have eluded scientists for a very long time so it is exciting to finally see progress. Lastly, perhaps the most sexy new drug approach are Proteolysis-Targeting Chimera or “PROTAC” drugs. These drugs work by dragging cancer proteins to the trash compactor of the cell. They could be more effective than other drugs because they destroy proteins instead of just disabling them. Even more attractive, they could theoretically be designed to target any cancer protein.
Dr. Chiang’s Journey in Research
When I was an MD/PhD immunology student at the University of Pennsylvania, I was fascinated by how master genes called transcription factors controlled other genes to tell blood stem cells to mature into immune cells. If you take away these master genes from the stem cells, the cells stop maturing and arrest at a primitive stage. This maturation arrest is an important step in the transformation of a normal blood cell into an acute leukemia cell. Several years later, after the human genome was sequenced, we learned that these genes are often mutated and drive the development of pediatric acute leukemia. As a student, I was not aware of the clinical importance of these genes. I was tinkering and intrigued by how a single gene could have a profound impact on an entire lineage of cells. After returning to the clinical phase of MD/PhD training, I learned how I could apply my training to improve public health. It was a natural transition to switch from studying the development of normal immune cells to the development of malignant immune cells.
As I mentioned earlier, NOTCH1 was found to be the most frequent cancer-causing gene in T-ALL. Unfortunately, in clinical trials, anti-Notch drugs had too much gastrointestinal toxicity, causing diarrhea. The reason is that Notch is very important for keeping normal tissues healthy. How can we knock out Notch only in cancer cells? We believe that the answer may be proteins called cofactors that stick to Notch in a PPI. Some cofactors tell Notch to drive cancer. Other cofactors tell Notch to keep organs healthy. Our idea is that inhibiting the cancer cofactors could combat Notch without intolerable side effects.
In support of this idea, we have showed that two cofactors Zmiz1 and Ets1 stick to Notch. When we turned off these cofactors in mice sick with human or mouse leukemia cells, the leukemia cells shrank and the mice lived longer. We saw similar effects when we separated these cofactors from Notch. While we did see some toxicities, the effects were relatively mild. When we looked inside the T-ALL cells, we found that inhibiting these cofactors had similar effects on genes as inhibiting Notch itself. We hit several “bad actors”. We also hit several other “bad actors” outside the Notch pathway. This might explain why blocking these genes sometimes had stronger anti-leukemic effects than Notch inhibitors. We are now figuring out how these proteins that stick together in order to find a practical way to “unstick” these proteins. Based on our work, we believe that it might be possible to combat Notch in leukemia cells without intolerable toxicities.
How Rally’s Funding Makes a Difference
Without the help of Rally, I might not be performing lab-based research today. I would be working in private practice. I joined the University of Michigan as a junior faculty member during a recession. Dollars were very tight. My startup package was relatively meager—$375,000 and a lab as small as a college dorm room. I could not afford to hire experienced scientists or accept graduate students. I was tempted to switch the focus of my research given the very competitive paylines at the National Cancer Institute (NCI). However, the support from the Rally helped keep me focused on pediatric cancer.
Out of 24 scientists on the Cancer Research Committee of the University of Michigan Cancer Center, I am the only one who studies pediatric cancer. With help from Rally, I can do the kind of science that I feel will move my field forward. In my opinion, clinical researchers have been too narrowly focused on disrupting all Notch functions. It is becoming clear that we need to consider more specific anti-Notch therapies to avoid toxicities. In theory, we can target Notch cofactors to safely target Notch. With the help of Rally, we have shown that this might be possible and have acquired NCI-funding to study this more deeply.
Rally’s childhood cancer research grants are made possible by generous donors like you. This December, donations are being matched and you can have DOUBLE the impact for researchers like Dr. Chiang.
Give today #ForTheirFuture, and help us continue to fund lifesaving childhood cancer research.