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Discovery of New Targets and Pathways for T-ALL Therapy

T-ALL 治疗新靶点和途径的发现

基本信息

批准号：
8550035
负责人：
A. THOMAS LOOK
金额：
$ 35.63万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-24 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8550035
关键词：
Accounting Acute Acute T Cell Leukemia Adult Apoptotic Biological Assay Biological Models Cell Line Cells Child Childhood Clinical Collaborations DNA DNA Sequence Rearrangement Data Dependence Detection Development Diagnosis Disease remission Disease-Free Survival Exhibits Failure Funding Genes Genetic Genotype Goals Gray unit of radiation dose Growth Health Sciences Human Image Knowledge Mediating Medicine Modeling Molecular Molecular Target Mus Normal tissue morphology Oncogenic Oregon Outcome PI3K/AKT PTEN gene Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Protein Tyrosine Kinase Proto-Oncogene Proteins c-akt Relapse Repression Research Research Project Grants Resistance Role Sampling Staging Subgroup Synthesis Chemistry T-Lymphocyte T-Lymphocyte Subsets TYK2 Teenagers Testing Therapeutic Thymocyte Development Tumor Suppressor Proteins Tyrosine Universities Up-Regulation Work Zebrafish chemotherapy clinical application high risk human FRAP1 protein improved inhibitor/antagonist knock-down leukemia lymphoblast mTOR Inhibitor medical schools novel outcome forecast programs small hairpin RNA small molecule therapeutic target thymocyte

项目摘要

T-cell acute lynnphoblastic leukemia (T-ALL), which comprises 10% to 15% of ALL cases in pediatric patients, is especially common in teenagers and accounts for 25% of ALL cases in adults. Despite significant advances in long-term event-free survival, current treatments for T-ALL are often toxic to normal tissues, producing serious acute and delayed sequelae in a substantial fraction of patients. The central hypothesis for this research is that in-depth knowledge of multi-step pathways of molecular pathogenesis is needed to propel progress toward personalized medicine for T-ALL. An important long-term goal is to find genes encoding new targets and molecular pathways for the development of more specific and less toxic drugs for the treatment of T-ALL. This goal will be achieved through three specific aims. In Aim 1, we will build on work conducted during the last funding period of this project to identify oncogenic pathways and therapeutic targets in high risk T-ALLs with the absence of blallelic TCRy chain deletions (ABD subtype) and PTEN loss. We will conduct BH3-profillng to specifically target anti-apoptotic pathways and also test mTOR inhibitors to improve therapy for the high risk ABD subgroup. In Aim 2, we will build on our exciting new preliminary data to determine the mechanisms of TYK2 pathway dependence and analyze selective pathway inhibitors in T-ALL. We recently discovered that the majority of human T-ALLs depend on TYK2 tyrosine activity for growth an survival, and In this Aim we will interrogate this pathway in detail to develop potent inhibitors that specifically target T-ALL cells.. In Aim 3, we will pursue our discovery during the last funding period that LEF1 Is a tumor suppressor in T- ALL to define the mechanisms through which loss of LEF1 contributes to T-ALL using zebrafish and primagraft T-ALL models. Each of these Alms involves numerous opportunities to interact closely with other projects in this program, with the ultimate goal of bringing novel targeted therapies to the bedside for children and adults with T-ALL. RELEVANCE (See instmctions): The intensification of therapy for children with T-cell acute lymphoblastic leukemia (T-ALL) has improved clinical outcomes substantially, but first-line therapy continues to fail in approximately 25% of children and in more than 50% of adults, and after initial failure these patients have a very poor prognosis. In this research project, we will test inhibitors of the PI3K/AKT/mT0R axis and anti-apoptotic pathways, the TYK2 tyrosine kinase and pathways disrupted by the loss of LEF1 to develop new targeted therapies for high risk T-ALL.

t细胞急性淋巴母细胞白血病（T-ALL），占儿科ALL病例的10% ~ 15%