Funding opportunities

Prostaglandin pathway regulation of self-renwal in hematopoietic and leukemia stem cells

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06036
Principle Investigator: 
Institution: 
Funds requested: 
$1 244 455
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Leukemias are cancers of the blood cells that result from corruption of the normal controls that regulate blood-forming stem cells. They are serious causes of illness and death, and are particularly devastating in children and the elderly. Despite substantial advances in treatment of leukemia, a significant proportion of cases are unresponsive to current therapy. Since more aggressive chemotherapy regimens provide only marginal improvements in therapeutic efficacy, we have reached a point of diminishing returns using currently available drugs. Thus, there is an urgent need for more targeted, less toxic, and more effective treatments. To this end, our studies focus on defining the defects that corrupt the normal growth controls on blood stem cells. The proposed studies build on our discovery of a key enzyme with an unexpected causative role in leukemia. We propose to further characterize its function using various proteomic approaches, and employ a cross-species comparative approach to identify additional pathways unique to cancer stem cell function. The proposed characterization of crucial growth controls that go awry in blood stem cells to cause leukemia will identify new drug targets for more effective and less toxic treatments against these devastating, life-threatening diseases.
Statement of Benefit to California: 
Leukemias are cancers of the blood cells that cause serious illness and death in children and adults. They result from corruption of the normal controls that regulate blood-forming stem cells. Despite many attempts to improve treatments with new drug combinations, this approach has reached a point of diminishing returns since intensified chemotherapies contribute only marginal improvement in outcome and are associated with increasing toxicity. The proposed characterization of crucial growth controls that go awry in blood stem cells to cause leukemia will identify new drug targets for more effective and less toxic treatments against these devastating, life-threatening diseases.
Review Summary: 
The applicant discovered that a protein, which is known to have tumor inhibiting functions in some cancers, is, unexpectedly, highly over expressed in the cancer stem cell population of a specific form of leukemia. Based on further evidence, the applicant proposes that this protein’s function in leukemia stem cell (LSC) self-renewal occurs through a mechanism different from its known enzymatic activity. The specific goal of this proposal is to define the novel biochemical and molecular mechanism by which this enzyme affects LSC function. Significance and Innovation - If the proposed studies are successful, greater understanding of the molecular pathways regulating self-renewal properties of LSCs could lead to the identification of unique biomarkers and facilitate efforts to selectively eliminate them in blood cancer to achieve more efficacious therapies; this would have a major impact in the field. - The proposal is focused on a type of leukemia that represents a significant clinical problem with unmet medical need. - Since the enzyme that is the subject of this study is also expressed in normal hematopoietic (blood-forming) stem cells (HSCs), it is unclear if the therapeutic approaches that may ultimately be derived from the proposed studies will have a negative impact on normal hematopoiesis. - This proposal is based on an interesting discovery, and the proposed approaches are innovative. Feasibility and Experimental Design - The proposed studies are logical and achievable within the given timeframe. The proposed approaches are technically and conceptually sound, the techniques are state of the art, and the experimental design is well reasoned. - Project feasibility is supported by very strong and compelling preliminary data. - Reviewers’ enthusiasm would have been even greater if the applicant had proposed to examine the role of the enzyme in question in normal HSCs. - The studies proposed under Aim 3 are tangential to the main focus of the project. Principal Investigator (PI) and Research Team - The PI is exceptionally well qualified with an outstanding record in leukemia stem cell research. - The research facilities available to the PI are outstanding. Responsiveness to the RFA - The proposed research is responsive to the RFA, as it utilizes human cancer stem cells and is focused on molecular mechanism.
Conflicts: 

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