Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and a leading causeof cancer-related death during childhood. ALL can arise in both lymphoid lineages, with B-ALL andT-ALL accounting for 85% and 15% of this cancer. T-ALL is associated with more aggressivepresenting features and historically inferior treatment outcomes compared to B-ALL. Current T-ALLtherapy largely relies on cytotoxic chemotherapeutic agents. In recent years, further intensification ofchemotherapy has led to incremental increases in the cure rate of T-ALL, but is likely to havereached a plateau due to excessive toxicities (especially in the relapse setting). Moreover, inrelapsed T-ALL, leukemia is markedly resistant to cytotoxic drugs. Unlike high-risk B-ALL for whichcellular therapy such as CAR-T is highly effective, there are no immunotherapies available for T-ALLand patients with relapsed disease have a dismal five-year survival rate below 25%. Therefore, noveland molecularly targeted therapeutics are needed to improve both survival and quality of life forchildren with T-ALL.We have previously observed that in 64 T-ALL cases (43 children and 21 adults) profiled thus far38% showed a striking sensitivity to dasatinib in vitro. In particular, the proportion of T-ALL sensitiveto 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 thatobserved in BCR-ABL1 B-ALL. However, none of the dasatinib-sensitive T-ALL cases had ABLfusion nor did they respond to a more ABL-specific inhibitor. We demonstrated that LCK activationand phosphorylation level of its downstream targets are responsible for this sensitivity, and, moreimportantly, can be used to predict the effectiveness of dasatinib treatment in T-ALL cases. Duringthis project, we will develop a companion diagnostic panel that can be used to predict sensitivity todasatinib and ponatinib in a personalized manner. The following aims will be completed in theproposal: Aim #1. Comprehensive characterization of phosphorylation and activation state of LCK byLC-MS in T-ALL cells. Aim #2. Development of the PRM-MS and immunoassay-based methods forrapid quantitative analysis of p-LCK, p-CD247, and p-ZAP70. By the completion of this project, acompanion diagnostic panel will be developed and validated with cell culture samples. This feasibilityportion will enable a much more extensive validation of this personalized diagnostic test in PDX micemodels and patient samples in Phase II. PROJECT NARRATIVE
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological
malignancy in children and adults, and treatment is usually based on conventional
cytotoxic drugs with poor outcome. We previously found that dasatinib, a
well-tolerated treatment used for B-ALL, is also effective for a significant population of
T-ALL patients. This NIH SBIR Phase I project will support the effort to develop a new
companion diagnostic test to determine which T-ALL cases would be sensitive to
dasatinib and can be treated through this personalized medicine approach. Accounting ; Adult ; 21+ years old ; Adult Human ; adulthood ; Algorithms ; inhibitor/antagonist ; inhibitor ; Antibodies ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Cell Culture Techniques ; cell culture ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Child ; 0-11 years old ; Child Youth ; Children (0-21) ; youngster ; Cessation of life ; Death ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exhibits ; Feasibility Studies ; Future ; Human ; Modern Man ; Immunoassay ; Immunotherapy ; Immune mediated therapy ; Immunologically Directed Therapy ; immune therapeutic approach ; immune therapeutic interventions ; immune therapeutic regimens ; immune therapeutic strategy ; immune therapy ; immune-based therapies ; immune-based treatments ; immuno therapy ; In Vitro ; leukemia ; Acute Lymphocytic Leukemia ; Acute Lymphoblastic Leukemia ; Acute Lymphoid Leukemia ; Precursor Cell Lymphoblastic Leukemia ; Precursor Lymphoblastic Leukemia ; acute lymphatic leukemia ; acute lymphogenous leukemia ; acute lymphomatic leukemia ; Mixed B- and T-Cell Leukemia ; Acute B- and T-Cell Leukemia ; B- and T-Cell Acute Lymphoblastic Leukemia ; B- and T-Cell Acute Lymphocytic Leukemia ; Mixed-Cell Acute Lymphocytic Leukemia ; Mixed-Cell Leukemia ; Acute T Cell Leukemia ; Acute T-Cell Lymphoblastic Leukemia ; Acute T-Cell Lymphocytic Leukemia ; Acute T-Lymphocytic Leukemia ; Precursor T Lymphoblastic Leukemia ; T-Cell Type Acute Leukemia ; T-lineage acute lymphoblastic leukemia ; Methods ; Mus ; Mice ; Mice Mammals ; Murine ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Patients ; Phosphoproteins ; Phosphorylation ; Protein Phosphorylation ; Proteins ; Public Health ; Quality of life ; QOL ; Quantitative Evaluations ; Relapse ; Sensitivity and Specificity ; Signal Pathway ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Survival Rate ; T-Lymphocyte ; T-Cells ; thymus derived lymphocyte ; Testing ; Treatment Protocols ; Treatment Regimen ; Treatment Schedule ; Tyrosine ; Measures ; Treatment outcome ; Diagnostic tests ; base ; fusion gene ; improved ; Clinical ; Phase ; Childhood ; pediatric ; drug sensitivity ; Recurrent disease ; Relapsed Disease ; Adult Precursor T Lymphoblastic Leukemia ; Adult T cell acute lymphoblastic leukemia ; Adult T-ALL ; T-Cell Adult ALL ; T-Cell Adult Acute Lymphocytic Leukemia ; cell mediated therapies ; cell-based therapeutic ; cell-based therapy ; cellular therapy ; Cell Therapy ; Therapeutic ; Cytotoxic drug ; Cytotoxic agent ; Hematologic Cancer ; Hematologic Malignancies ; Hematological Malignancies ; Hematological Neoplasms ; Hematological Tumor ; Hematopoietic Cancer ; Malignant Hematologic Neoplasm ; Hematologic Neoplasms ; Dependence ; Reaction ; Inferior ; interest ; Lytotoxicity ; cytotoxicity ; Toxicities ; Toxic effect ; novel ; chemotherapeutic agent ; Adult Acute Lymphoblastic Leukemia ; Adult Acute Lymphogenous Leukemia ; Adult Acute Lymphoid Leukemia ; adult ALL ; Adult Acute Lymphocytic Leukemia ; Modeling ; Sampling ; response ; rapid method ; rapid technique ; Effectiveness ; 70 kDa zeta-associated protein ; Protein Tyrosine Kinase Zap70 ; SRK ; Syk-related tyrosine kinase ; ZAP-70 ; ZAP-70 Kinase ; ZAP-70 protein ; ZAP70 ; Zeta-Chain Associated Protein Kinase ; ZAP-70 Gene ; ABL1 ; Abelson Murine Leukemia Viral Oncogene Homolog 1 ; JTK7 ; c-Abl ; c-abl Genes ; c-abl Proto-Oncogenes ; ABL1 gene ; Dose ; Dasatinib ; cytotoxic ; Molecular Marker of Prognosis ; Prognosis Marker ; prognostic biomarker ; prognostic indicator ; Prognostic Marker ; in vivo ; Cancer Etiology ; Cancer Cause ; Leukemic Cell ; Lymphoid ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Tyrosine Phosphorylation ; Validation ; Monitor ; Development ; developmental ; Pathway interactions ; pathway ; Outcome ; Cancer cell line ; Population ; Resistance ; resistant ; Cell model ; Cellular model ; Network-based ; chemotherapy ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; high risk ; patient population ; treatment response ; response to treatment ; therapeutic response ; activity marker ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; genome-wide ; genome scale ; genomewide ; resistant strain ; resistance strain ; Regimen ; personalized medicine ; personalization of treatment ; personalized therapy ; personalized treatment ; personalized diagnostics ; personalized diagnosis ; precise diagnostics ; precision diagnostics ; leukemia treatment ; diagnostic panel ; companion diagnostics ; targeted agent ; biomarker panel ; marker panel ; molecular targeted therapies ; molecular targeted therapeutics ; molecular targeted treatment ; phosphoproteomics ; phospho-proteomics ; CRISPR screen ; CRISPR editing screen ; CRISPR-based screen ; CRISPR/Cas9 screen ; clustered regularly interspaced short palindromic repeats screen ; acute T-cell lymphoblastic leukemia cell ; T leukemia cell ; T-ALL cell ; acute T-cell lymphocytic leukemia cell ; patient derived xenograft model ; PDX model ; Patient derived xenograft ;
