Funding opportunities

Derivation and Characterization of Myeloproliferative Disorder Stem Cells from Human ES Cells

Funding Type: 
New Faculty II
Grant Number: 
RN2-00910
Principle Investigator: 
Funds requested: 
$3 065 572
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Statement of Benefit to California: 
Review Summary: 
The principal objective this proposal is to find out whether human embryonic stem cells (hESCs) can be used to generate leukemia-initiating cancer stem cells (CSC). The underlying problem this research addresses is the quiescent nature of cancer stem cells which allows them to escape destruction by agents that target dividing cells and also limits their utility to expand in vitro to the numbers needed to probe their characteristics and their response to anti-cancer agents. An incomplete understanding of the sequence and cellular framework of mutations that contribute to CSC production represents a critical barrier to developing therapies. Because hESCs have robust self-renewing capacity and can provide a potentially limitless source of tissue specific stem and progenitor cells they represent an ideal model system for generating cancer stem cells. Proposed work is based on recent discovery that a point mutation in a specific gene increases proliferation of cancer stem cells. The PI proposes three aims. First the PI will determine whether the introduction of two specific oncogenes into hESC and cord blood progenitors is necessary and sufficient to induce pre-leukemic changes in differentiation, survival and proliferation characteristic of myeloproliferative disease (MPD). Second, to learn whether self-renewal genes are required in addition to these oncogenes to endow these cells with oncogenic potential. And third, to learn whether single or combinations of the oncogene-selective drugs are required to target leukemic CSC with an ultimate aim of developing highly active anti-MPD stem cell therapy. Reviewers agreed that the scientific rationale is strong and the focus is on a valid biologic target. The proposal provides a much-needed experimental model system for myeloproliferative disorder (MPD) cancer stem cells, and may have ramifications for other cancer stem cells. Reviewers concurred that the proposal is very well written and organized, with specific aims and the experiments to accomplish these aims clearly described. The order of the aims and sub-specific aims are logical and follow from each other. Two minor weaknesses in the proposal were pointed out by one reviewer: first, the lack of details on the efficiency of hESC differentiation into CD34-expressing candidate HSC, and second reviewers questioned whether the bioluminescence assay to measure frequency of the engineered cells would be quantitative. Another reviewer questioned the use of two independent vectors for the oncogene transduction. In general, reviewers felt these to be minor issues with an otherwise excellent plan. Reviewers agreed that the applicant, a physician-scientist, has extensive experience with the techniques and has an impressive track record in the field. She/he has been a productive young clinician-investigator who is enthusiastically pursuing new therapeutic options for myeloproliferative disorders. The PI has included a thorough and convincing plan for career development as a physician-scientist. Moreover, PI has an excellent institutional support and mentorship of two outstanding clinician-researchers. In conclusion, the panel agreed that the generation and characterization of CSC from hESC is an important and much needed model system to study the biology and potential therapeutic options for targeting and elimination of cancer stem cells. Combined with exceptional track record of the investigator in translational research and institutional support, enthusiasm for this proposal was high.
Conflicts: 

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