Children and young adults with Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) who have a poor prognosis may benefit from treatment with tyrosine kinase inhibitors that are already approved by the US Food and Drug Administration (FDA).
Children and young adults with Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) who have a poor prognosis may benefit from treatment with tyrosine kinase inhibitors that are already approved by the US Food and Drug Administration (FDA). These results were presented at the American Association for Cancer Research (AACR) conference: Hematologic Malignancies: Translating Discoveries to Novel Therapies, held September 20-23, 2014, in Philadelphia.
Ph-like ALL is a B-cell ALL subtype that has a similar gene expression profile to that of BCR-ABL1 mutated ALL and is associated with a poorer outcome. But rather than harboring the BCR-ABL fusion, it has genetic aberrations within other tyrosine kinase genes. According to the authors, the risk of Ph-like ALL rises from 10% in standard risk childhood ALL to a more than 25% risk in young adults diagnosed with ALL. The study, by Kathryn Roberts, PhD, postdoctoral research associate in the Department of Pathology at St. Jude Children’s Research Hospital in Memphis, and colleagues developed the first mouse model of Ph-like B-ALL.
Roberts and colleagues had previously sequenced more than 150 cases of Ph-like ALL and identified genetic alterations in 18 kinase or cytokine kinase receptor genes. The current study developed a mouse model to test the potential efficacy of already available targeted agents on these subtypes of Ph-like ALL.
Speaking at a teleconference, Dr. Roberts said that the current study focused on two subgroups of Ph-like ALL that are sensitive to either ABL inhibition or to inhibition of the JAK2 pathway.
“We show for the first time that the kinase alterations we tested contribute to the development of Ph-like ALL, and that Ph-like ALL can be treated effectively with tyrosine kinase inhibitors in animal models,” said Roberts in a statement.“ These findings provide a strong rationale for treating Ph-like ALL patients with targeted therapies to improve their survival.”
The researchers introduced tyrosine kinase fusion mutations into non-tumor, normal mouse blood cells and found that these alterations resulted in a Ph-like ALL phenotype and independent growth without the need for additional growth factors that's typically needed for these blood cells to divide. This indicates that the genetically altered cells have some transformation potential.
Transplanting these Ph-like ALL tumor cells into mice resulted in the development of ALL-functionally linking these kinases to the development of B-ALL. Each gene fusion resulted in distinct signaling pathway activity. For example, ABL1 kinase fusions resulted in activation of the STAT pathway.
Treating the mice with dasatinib, a tyrosine kinase inhibitor that blocks the BCR/ABL oncogene, resulted in a lower tumor burden and reduced splenic weight compared to untreated mice in which the activity of the STAT pathway was blocked.
The mice with fusions involving the JAK2 gene (ATF7IP-JAK2 and PAX5-JAK2), as well as the IGH-EPOR fusion, were sensitive to ruxolitinib, a JAK2 inhibitor.
“Despite the diversity of rearrangements in this tumor type, these Ph-like ALL tumors can be grouped into several classes for which we can use a relatively small number of already approved kinase inhibitors," said Roberts during the teleconference. Roberts and colleagues have already treated 12 patients with Ph-like ALL as part of a compassionate use study, and the patients continue to respond to the therapy, according to Roberts.
The research team is currently designing a clinical trial to assess the efficacy of dasatinib in a subset of Ph-like ALL patients.