The proposal addresses the potential of targeting the binding of DEPTOR to mTOR in TORC complexes in multiple myeloma cells. The preliminary results support the hypothesis that compounds can be identified in a yeast-hybrid high throughput screen that inhibit this binding. Once inhibited, we anticipate a subsequent dampening of the PI3-kinase/AKT pathway and induction of myeloma cell apoptosis. DEPTOR function is critical for survival of a subset of multiple myeloma clones consisting of approximately 30% of patients. This specific subset of patients can be identified by readily available clinical testing on their marrow malignant plasma cells. Thus, we part from the premise that identified compounds that inhibit DEPTOR-mTOR binding could be developed for effective targeted therapy for these patients. To further address DEPTOR as a therapeutic target, we will test the screening positive 'hits'for molecular effects in myeloma cells as well as anti-myeloma efficacy in vitro and in vivo in xenograft models.

Public Health Relevance

The goal of the proposal is to identify new therapies that can improve the management of multiple myeloma patients. Multiple myeloma is a malignant disease of plasma cells. It is incurable with a median survival of 4-5 years. Thus, new therapies are sorely needed. We believe we can identify new agents with efficacy in the disease through our novel screening procedure where >150,000 chemicals are tested rapidly by a robotic assay. We have already several such drugs with great potential in this serious disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA168491-01A1
Application #
8442174
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
2013-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$133,763
Indirect Cost
$25,013
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
197170756
City
Los Angeles
State
CA
Country
United States
Zip Code
90073