Hunger Laboratory Research Overview

Acute lymphocytic leukemia (ALL) is the most common type of childhood cancer. It is important to understand the genomics of ALL so that more effective therapies can be developed.

The Therapeutically Applicable Research to Generate Effective Therapies (TARGET) high-risk ALL initiative is a collaborative, international project sponsored by the National Cancer Institute. The goal of this initiative is to understand the genetic processes that cause ALL to develop.

The Hunger Lab is leading the efforts in TARGET to identify the specific genes responsible for the development of high-risk subsets of ALL, with a focus on identifying potential new therapeutic targets.

In the first phases of this project, investigators focused on a subgroup of pediatric ALL patients who were at high risk for treatment failure. Targeted sequencing was performed on approximately 125 genes in several hundred patients characterized as high risk at diagnosis based on clinical characteristics. Researchers wanted to see what the genetic correlates were to clinical characteristics.

In the first phase, the genes chosen for targeted sequencing were genes that were either known to be involved with leukemia or other subtypes of cancer. In the second phase, comprehensive sequencing of several hundred cases was performed, including sequencing DNA from normal cells (germline) and leukemia cells obtained at the time of initial diagnosis and relapse. Several different sequencing technologies were used: whole exome sequencing, whole genome sequencing, and RNA sequencing or transcriptomic sequencing.

This combination of sequencing technologies has successfully identified abnormalities that occur consistently in different patients, and offers a potential target for different therapeutic interventions. One major new subtype discovered is called Philadelphia chromosome-like (Ph-like ALL), and several new precision medicine clinical trials are being developed for this subtype.

Acute lymphocytic leukemia (ALL) is the most common childhood cancer. Approximately 70% of children with ALL in the United States are treated on clinical trials conducted by the Children’s Oncology Group (COG).

Until the early 1960s, childhood ALL was incurable. Since then clinical trials have shown steadily increased cure rates and survival for children with ALL. The most recent combined data from these trials (patients enrolled between 2006 and 2009), have shown a five-year survival rate of approximately 92%.

One trial for which enrollment has been recently completed evaluated different chemotherapy regimens in T-cell ALL, a high-risk subset of ALL. This trial included more than 1,000 patients and has shown an almost 90% survival rate — an outcome previously unheard of in this subtype of leukemia.

Using existing chemotherapy drugs, Dr. Hunger's research team at the Center for Childhood Cancer Research, in concert with COG, are refining existing chemotherapeutic regimens to improve outcomes and decrease side effects by comparing previous standard-of-care chemotherapeutic regimens with modified regimens.

Modifications may include the addition of new or different drugs, eliminating drugs, creating specific new combinations of drugs, changing dosing schedules (i.e., more or less frequent dosing of a drug), or changing the dosing of drugs. As survival rates improve, results are translated into newer, improved standard-of-care chemotherapeutic regimens.

More than 2,000 children per year have been and are being treated in these clinical trials, resulting in significant improvements in survival for children with ALL.

A small subset of children with ALL possess the Philadelphia chromosome (identified more than 50 years ago in Philadelphia). Patients with ALL who possess this chromosome are at a higher risk for poor outcomes than children who have ALL without this chromosome.

The Philadelphia chromosome produces a tyrosine kinase protein called BCR-ABL1, and until recently this was considered the highest risk subset of pediatric ALL. Adding medications such as imatinib and dasatinib that specifically inhibit the BCR-ABL1 tyrosine kinase (tyrosine kinase inhibitors or TKIs) to chemotherapy led to dramatic improvements in cure rates for children with Philadelphia chromosome positive ALL.

When a recent study on the genomes of children with high-risk ALL was performed, a new subset, called Philadelphia chromosome-like (Ph-like) ALL was identified. The abnormalities present in leukemia cells of patients with Ph-like ALL are highly similar to those of patients with Philadelphia chromosome positive ALL, but these cases do not contain BCR-ABL1 fusion. Research led by Dr. Hunger and his collaborators determined that one major subtype of Ph-like ALL had abnormalities in the Abl protein itself or in closely related proteins and showed that, as with Philadelphia chromosome-positive ALL, these abnormalities were very responsive to imatinib or dasatinib.

Dr. Hunger and collaborators are now taking the next step after identifying specific genomic mutations in children with high-risk ALL. A national clinical trial is being launched to screen ALL patients for the Ph-like subset and to characterize the genetic abnormalities present in these cases. If Abl class lesions are present, patients will have the opportunity to enroll in a trial where conventional chemotherapy is augmented with tyrosine kinase inhibitor therapy (dasatinib) to see if this improves cure rates.

Identification of the specific genetic characteristics of ALL subsets has contributed significantly to more options for precision medicine therapies and is anticipated to improve survival rates in children with Ph-like ALL.