T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer that occurs in children as well as adults. Despite intensive therapies, 25% of children and adolescents and 50% of adults with T-ALL will ultimately succumb to the disease. Moreover, the late effects of cancer treatment, including permanent organ damage, hormonal and reproductive dysfunction, and second cancers are a special concern in children as current therapies indiscriminately target all dividing cells. The goal of this proposal is to identify and therapeutically target a pathway that is essential for the growth and survival of T-ALL, the inhibition of which will be considerably less toxic than standard chemotherapy. Class I phosphoinositide 3-kinase (PI3K)/Akt signaling pathway has been reported to be activated in over 40% of cases of T-ALL. Although four distinct class I PI3K isoforms could participate in T-ALL pathogenesis, none have been implicated in this process. Using genetically altered animals and novel small molecule inhibitors, we have identified specific isoforms that appear to be essential for the development and survival of T- ALL. Based on these observations, we propose that it is possible to exploit the "addiction" of this hematological malignancy to these particular PI3K isoforms as a new therapeutic avenue for T-ALL. To achieve these objectives, we propose the following specific aims:
Aim 1. To determine the efficacy and to define the mechanism(s) of action by which 2 novel isoform specific PI3K inhibitors may impact on T-ALL pathogenesis. This will be accomplished by evaluating the effects of these inhibitors in an animal model of PTEN null T-ALL, on human T-ALL cell lines, and on primary patient samples. Emphasis will be placed on interrogating downstream pathways that regulate cell cycle progression, protein synthesis, and cell survival using a combination of biochemical and genetic approaches.
Aim 2. To uncover potential PI3K-dependent and independent mechanisms that may result in secondary resistance. This includes identifying resistance-conferring point mutations and alternative signaling pathways using in silico models of drug binding, chemical-induced mutagenesis, and drug-induced resistant disease in animals. Biochemical and genetic analyses will be performed, the latter including gene expression microarrays and array-based comparative genomic hybridization.
Aim 3. To determine the effects of isoform specific PI3K inhibitors on the development, peripheral expansion, survival and function of human T cells. This will be accomplished by evaluating drug effects in a unique human thymus/CD34+ stem cell xenograft model.

Public Health Relevance

The work outlined in this proposal will not only improve our understanding of the mechanisms that contribute to the development and survival of T-ALL, but will also lead to a less toxic strategy to treat this devastating disease, especially in our most vulnerable population: children. )

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA169162-02
Application #
8513283
Study Section
Special Emphasis Panel (ZRG1-BMCT-C (09))
Program Officer
Mccarthy, Susan A
Project Start
2012-08-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$312,080
Indirect Cost
$117,030
Name
Columbia University (N.Y.)
Department
Pediatrics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032