Development of companion diagnostics for dasatinib-based personalized therapy for T-ALL - PROJECT SUMMARY
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and a leading cause
of cancer-related death during childhood. ALL can arise in both lymphoid lineages, with B-ALL and
T-ALL accounting for 85% and 15% of this cancer. T-ALL is associated with more aggressive
presenting features and historically inferior treatment outcomes compared to B-ALL. Current T-ALL
therapy largely relies on cytotoxic chemotherapeutic agents. In recent years, further intensification of
chemotherapy has led to incremental increases in the cure rate of T-ALL, but is likely to have
reached a plateau due to excessive toxicities (especially in the relapse setting). Moreover, in
relapsed T-ALL, leukemia is markedly resistant to cytotoxic drugs. Unlike high-risk B-ALL for which
cellular therapy such as CAR-T is highly effective, there are no immunotherapies available for T-ALL
and patients with relapsed disease have a dismal five-year survival rate below 25%. Therefore, novel
and molecularly targeted therapeutics are needed to improve both survival and quality of life for
children with T-ALL.
We have previously observed that in 64 T-ALL cases (43 children and 21 adults) profiled thus far
38% showed a striking sensitivity to dasatinib in vitro. In particular, the proportion of T-ALL sensitive
to dasatinib is markedly higher in children than in adults (49% vs 14%, respectively). Dasatinib LC50
(drug concentration that kills 50% of leukemia cells) in these T-ALL cases were on par with that
observed in BCR-ABL1 B-ALL. However, none of the dasatinib-sensitive T-ALL cases had ABL
fusion nor did they respond to a more ABL-specific inhibitor. We demonstrated that LCK activation
and phosphorylation level of its downstream targets are responsible for this sensitivity, and, more
importantly, can be used to predict the effectiveness of dasatinib treatment in T-ALL cases. During
this project, we will develop a companion diagnostic panel that can be used to predict sensitivity to
dasatinib and ponatinib in a personalized manner. The following aims will be completed in the
proposal: Aim #1. Comprehensive characterization of phosphorylation and activation state of LCK by
LC-MS in T-ALL cells. Aim #2. Development of the PRM-MS and immunoassay-based methods for
rapid quantitative analysis of p-LCK, p-CD247, and p-ZAP70. By the completion of this project, a
companion diagnostic panel will be developed and validated with cell culture samples. This feasibility
portion will enable a much more extensive validation of this personalized diagnostic test in PDX mice
models and patient samples in Phase II.
