Bench-to-bedside research at The Children’s Hospital of Philadelphia involves talented scientists who make discoveries in the lab that translate into investigations of clinical applications. CHOP experts studying T-cell acute lymphoblastic leukemia (T-ALL) are taking this model one step further — bench to bedside and back again — by turning around their findings from clinical studies to better inform new series of basic science experiments.
T-ALL is a cancer of a type of white blood cells called T-lymphocytes. Normally, T-lymphocytes help fight infections. When the bone marrow and thymus gland produce too many immature T-lymphocytes, the body’s ability to fight infections becomes compromised.
Despite advances in T-ALL treatment, between 15 and 20 percent of children and young adults who achieve an initial complete remission will have the disease return (relapse). They may need more intensive therapy or alternative approaches, but physicians do not yet have a reliable way of predicting which patients are at high-risk of relapse.
David Teachey, MD, an attending physician and researcher at CHOP with expertise in both oncology and hematology, is leading a study involving researchers from across the country who aim to develop new insights to improve risk stratification of T-ALL by increasing their understanding of its biochemical underpinnings. This work is being funded by the National Cancer Institute through an R01.
“This new grant is trying to tackle two problems,” Dr. Teachey said. “One is we don’t know how to identify the kids who relapse when they walk in the door — you don’t know until it’s too late. And two, we need to develop new therapies for the ones who do relapse.”
The study team will analyze patient samples collected from an international, phase 3 clinical trial called AALL1231 that Dr. Teachey chairs for the Children’s Oncology Group. AALL1231 includes approximately 1200 children and young adults from more than 200 hospitals, and the goal is to determine if standard chemotherapy with or without the drug bortezomib is more effective in treating T-ALL.
In the new study, the investigators will take a protein level approach to help identify subsets of patients with T-ALL who are likely to relapse. They will study participants’ leukemia cells and the proteins that they make, looking for patterns that clinicians could use as a high-risk molecular signature. Next, they will see if there is any correlation between these protein profiles and results from sophisticated next-generation sequencing that allows researchers to detect minute levels of cancer cells that remain after intensive, high-dose, multi-agent chemotherapy.
If the study team can figure out which proteins are abnormal in the patients who do poorly, then they could eventually test drugs that target those altered pathways. They will accomplish this by generating mouse models using the participants’ leukemia cell samples. Since the patients already are involved in the AALL1231 trial, the study team will know who did well and who went on to relapse, so they will be able to see how different therapies affect their prognosis.
For instance, the JAK/STAT signaling pathway is implicated in a high-risk subtype of T-ALL, according to a paper published in the journal Blood earlier this year by Dr. Teachey and colleagues. If drugs are available that can turn off that pathway, then they may be beneficial in combination with existing chemotherapy agents. The study team intends to identify other signaling pathways that are abnormally activated in T-ALL, which may give them clues to better predict chemotherapy response and resistance.
“In the big picture, the hope is the correlative biology performed in the lab will let us learn how to better diagnosis and treat children with T-ALL. Then, we can open a future trial using new drugs to treat children who we think aren’t going to do well and improve their chance of being cured,” Dr. Teachey said.
The project will involve researchers from Seattle Children’s Hospital; UCSF Medical Center, California; The University of Texas MD Anderson Cancer Center, and the University of Texas Southwestern Medical School, in addition to researchers from The Children’s Hospital of Philadelphia.