Exploiting synthetic lethality of hematopoietic lineage cells to develop novel ta

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 2R44CA141848-02
Agency Tracking Number: R44CA141848
Amount: $1,865,575.00
Phase: Phase II
Program: SBIR
Awards Year: 2011
Solicitation Year: 2011
Solicitation Topic Code: NCI
Solicitation Number: PA10-050
Small Business Information
CELLECTA, INC.
320 Logue Avenue, MOUNTAIN VIEW, CA, -
DUNS: 780594185
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 KYLE BONNEAU
 (650) 938-3915
 kbonneau@cellecta.com
Business Contact
 KYLE BONNEAU
Phone: (650) 938-3915
Email: kbonneau@cellecta.com
Research Institution
 Stub
Abstract
DESCRIPTION (provided by applicant): Targeted therapies have the ability to specifically interact with and block proliferation of cancer cells by interfering with targeted gene products required for the malignant phenotype. Unlike conventional cancer chemotherapies, targeted therapies do not harm normal cells of the body. This class of therapeutic has been met with considerable clinical success indicating that there is a great need for new targeted therapies that block progression of other types of cancerfor which no targeted therapy exists. We hypothesize that all hematopoietic cells (normal and cancerous) express genes responsible for maintaining the blood lineage and blood cancer phenotypes, and that the products of these genes can be exploited by newtargeted therapies. Identification of these hematopoieitc-specific lethal genes would allow for the development of novel targeted therapies for combating diverse blood cancers, and for developing tissue-specific, targeted conditioning regimens for hematopoietic stem cell transplantation with greatly reduced morbidity and mortality. We tested this hypothesis in the course of Phase I studies, and demonstrated that pooled shRNA genetic viability screens could be successfully used to identify novel lethality drug targets specific for hematopoietic cancer cell types. We also identified small molecule agents that exhibited hematopoietic-specificity closely correlating lethality profiles of the shRNAs identified in genetic screens. In order to translate this researches into the future development of novel classes of targeted therapies, we propose in the Phase II studies to concurrently apply genome-wide RNAi-based genetic screening and small molecule library high-throughput (HT) screens to identify lethality genesand cytotoxic small molecules specific for members of a diverse panel of hematopoetic cell lines. The hematopoieitc-specific lethal shRNAs, and small molecules targeting lethality genes will be further validated using a wide panel of hematopoietic and non-hematopoietic cell lines and normal PBMC. Similar toxicity/lethality profiles will allow us to prioritize cytotoxic compounds based on their mechanism of action and simultaneously identify their specific drug target(s). These studies will be extended to the lead compounds for targeted therapy of hematological cancers in Phase III of the project in a joint drug development project between Cellecta and Tartis, Inc. PUBLIC HEALTH RELEVANCE: The relevance of the proposed research to public health is that it may identify new drugs or biomolecules targetable by drugs, for treatment of blood cancers such as leukemia, or for new, reduced toxicity ablative drugs for stem cell transplantation conditioning.

* information listed above is at the time of submission.

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