Despite improved outcomes for acute lymphoblastic leukemia (ALL), particular subsets of high-risk ALL, such as hypodiploid B-precursor ALL still have very poor outcomes.  Our identification of Bcl-2 as a promising therapeutic target has led us to test specific classes of targeted Bcl-2 inhibitors (ABT-199, ABT 263) in cell lines and patient derived xenografts from hypodiploid ALL. We are currently conducting early phase clinical trials to validate our early in vitro Bcl-2 data, and test our hypothesis that inhibiting Bcl-2 will provide therapeutic efficacy. 

Neurofibromatosis Type 1 (NF1) is a dominant cancer predisposition syndrome. Children with NF1 are predisposed to a variety of malignancies including low grade gliomas, plexiform neurofibromas and juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm that is incurable with conventional chemotherapy. We are now primed to carry out a phase II clinical trial using Trametinib, a best in class MEK inhibitor in children with JMML. 

Hypodiploid ALL

MEK inhibition

While cure rates for childhood acute lymphoblastic leukemia (ALL) approach 90% in the current era, relapse remains the most common cause of treatment failure and death. Advances in cancer genetics have recently made several important discoveries, such as the identification of a particular group of patients who display a “genetic signature” similar to that of Philadelphia (Ph) chromosome positive ALL; hence, known as Ph-like ALL. It has also been shown that these patients respond to a special group of chemotherapy agents called “tyrosine kinase inhibitors” (TKIs) such as imatinib and dasatinib. We hope that combining TKIs with chemotherapy will cure most of these patients but we anticipate that some may still relapse as a result of developing resistance to these TKIs, similar to how certain infections can become resistant to antibiotics. Therefore, the objective of our study is to identify how this resistance happens and to further identify new medicines that can be used to treat patients with relapsed Ph-like ALL. 

PH-like ALL

 

JMML

Juvenile myelomonocytic leukemia (JMML) is a type of blood cancer that affects children and is very difficult to treat. Currently available treatments cure only half of the patients with some children experiencing aggressive disease while others get better with very little treatment. No one knows why this happens. This project will use the latest breakthroughs in scientific technology to determine how we can distinguish one group from the other at diagnosis so that patients can receive the appropriate amount of therapy. 

 

doi:10.1038/ng.2532

doi.org/10.1182/blood-2009-09-245944

imagebank.hematology.org/