Cancer loves to grow. In fact, that’s its deadliest trait.
At Indiana University School of Medicine, scientists are searching for ways to halt cancer in its tracks. Whether finding new targets for treatment, discovering pathways to prevention or testing new therapeutics, three researchers at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center and the Herman B Wells Center for Pediatric Research are on the hunt for improved approaches to the most common type of cancer in children: leukemia.
Reducing resistance
Cancer’s will to survive is so fierce that it will morph and spread even in the most poisonous terrain. When chemotherapy is used to treat patients with cancer, some cells alter their behavior in a way that will promote survival. This is called an adaptive response, and blood cancer is particularly good at it.
In pediatrics, the most common type of blood cancer is acute lymphoblastic leukemia (ALL), which accounts for about 75 percent of blood cancers in kids. One common chemotherapy, called L-asparaginase, works for many ALL patients by diminishing an amino acid called asparagine, which ALL cells need to survive. But that doesn’t work for everyone. Ji Zhang, PhD, wondered why.
In a recent study, published in the Journal of Biological Chemistry, his team demonstrated that the expression of the asparagine synthetase, or ASNS, gene dictates a cell’s response to the asparagine depletion triggered by chemotherapy.
This means that the adaptive response of some ALL tumors is determined by the status of the ASNS gene’s promoter—either methylated (repressed) or unmethylated (unrepressed). When the ASNS gene’s promoter is unmethylated, the gene produces more amino acid to combat the depletion caused by the chemotherapy, leading to tumor resistance.
“Determining ASNS status will be a good way to predict therapeutic response in patients with ALL,” said Zhang, who is an assistant professor in the Department of Pediatrics. “And a therapeutic agent that can target ASNS may help patients who would otherwise be resistant to chemotherapy.”
Finding that therapeutic agent is next on Zhang’s to-do list. He said that his team is actively working to identify the mechanisms that control the methylation status of the ASNS gene and target that gene in combination with chemotherapy to improve outcomes for people who are resistant to L-asparaginase.
Doorways to disease
But how can doctors prevent cancer from developing in the first place?
A large focus of research is not only identifying the what, but also the how. Clearly, mutations play a big role in cellular activity and can even impact disease development. If a mutation is a doorway to disease, what twists and turns lurk in the hallways between the mutation and cancer?
This has been a central question for Yan Liu, PhD, as he worked to identify the mechanisms of a common age-related condition called clonal hematopoiesis of indeterminate potential, or CHIP. CHIP occurs when mutated blood stem cells replicate very quickly, flooding the blood stream with mutated cells.
“Many people with CHIP don’t have any signs of disease, but they do have an increased risk of developing hematological malignancies, such as blood cancer,” said Liu, associate professor of pediatrics. “Our goal was to study the role of a specific mutated gene in the path from CHIP to blood cancer.”
That gene is called p53, and Liu said that many older adults with blood cancer possess p53 mutations. His team defined a number of mechanisms at work from mutant p53 on the path to blood cancer. In a study published in Nature Communications, Liu’s team identified one critical mechanism as another gene called EZH2, which interacts with mutant p53 to promote cell division and growth of the mutated cells.
Liu said that his team is now working on preclinical studies to collect more data on the effectiveness of blocking EZH2. He envisions future clinical use of therapies that target the gene to treat people with both CHIP and leukemia.
“Our research identifies EZH2 as an important therapeutic target for preventing CHIP progression and treating leukemia with the p53 mutation,” said Liu. “We hope that this will facilitate the clinical use of EZH2 inhibitors to treat patients with leukemia and improve outcomes.”
Treatments of tomorrow
Reuben Kapur, PhD, knows the value of target discovery. His lab has found new targets for treatment of the second most common type of pediatric blood cancer, acute myeloid leukemia (AML). And they might have a drug that can help.
“Many AML patients have a poor prognosis because they do not respond well to established therapies,” said Kapur, the Frieda and Albrecht Kipp Professor of Pediatrics. “In some of these patients, inherent treatment resistance is due to certain genetic mutation combinations. We’ve figured out how to target those co-existing mutations to prevent their downstream consequences and mitigate the spread of AML.”
AML is a rapidly progressive cancer. It accounts for about 1 in 4 childhood leukemias and is more common in adults. In all patients with AML, the 5-year survival rate is less than 30 percent.
In Kapur’s lab, a study led by Assistant Research Professor of Pediatrics Ruchi Pandey, PhD, found that a protein called SHP2 is key to the growth of mutated cells. They worked with a drug molecule from Novartis Pharmaceuticals, SHP099, to inhibit this protein and halt growth. In animal models, they’ve seen significant success.
Now, they’re ready to try it on human tumors. They’ll begin testing the drug on human tumors by growing leukemia cells from AML patients in animal models, an approach called patient-derived xenograft.
“Dr. Pandey and I worked closely to interpret our data, and we are very excited by the results,” said Kapur, who recently published their findings in The Journal of Clinical Investigation. “Relapse among AML patients is too high, and our work will help provide a more effective target for beating this thing for good.”
