Prognosis of children with leukemia, the most common pediatric cancer, has improved markedly. Yet, relapse still occurs in 15-40% of patients with a probability of survival of \<50%, which is unlikely to be boosted by intensification of standard chemotherapy due to overwhelming toxicity. The advent of effective and safe targeted therapies for high-risk cases is therefore imperative. This study constitutes two research projects aiming at driving therapeutic advances.
The first part of the study aimed to investigate genomics and drug sensitivity profiling of childhood leukemia and its potential application for precision medicine. The second part of the study aimed to develop novel antibody for treatment of childhood leukemia by animal model experiments. Design: Project 1: Whole-exome and RNA sequencing will be performed on children with leukemia (ALL, AML, MPAL, JMML, MDS) prospectively recruited in the Hong Kong Children's Hospital. Samples will be screened for their sensitivity to preselected, clinically accessible targeted agents in an ex vivo culture system. Results for the high-risk patients will be subjected to the tumor broad for evaluation. Project 2: Fully human antibody candidates identified by phage display will be engineered into therapeutic forms, and assessed for efficacy and safety in patient-derived xenografts of relapsed/refractory B-ALL and in transgenic mice. The mechanisms of action will be identified by single-cell RNA sequencing. Significance: Implementation of functional genomics could identify leukemia patients who will benefit from targeted therapies and enable tailoring of precision medicine. The invented antibodies could be moved forward into clinical trials for salvaging high-risk pediatric B-ALL. Immediate and long-term impact on therapy of childhood leukemia is foreseen.
Study Type
OBSERVATIONAL
Enrollment
300
Gene expression and fusion transcripts analysis
Genetic alternation analysis
Remission and relapse are monitored by cytogenetic analyses.
Hong Kong Children Hospital
Hong Kong, Hksar, China
RECRUITINGGenetic alterations of childhood leukemia
Association of mutation data with drug sensitivity profiles and disease-free survival /overall survival are analysed using standard statistical methods.
Time frame: Baseline
Gene expression profiles of childhood leukemia
Global transcriptome and fusion transcripts of leukemic blasts are identified by RNA-sequencing.
Time frame: Baseline
Drug sensitivity profiles
Drug sensitivity results of individual patient blasts-derived ex vivo culture are presented as IC50 and AUC values.
Time frame: Baseline
Antibody efficacy for treatment of childhood leukemia
In vitro biochemical and biological assays and invivo leukemic patient-derived xenografts are used to characterize the efficacy and toxicity of the novel human anitbodies.
Time frame: Up to 1 year
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