Project: STUDY OF EFFICACY OF ALDH INHIBITORS IN CANCER STEM CELLS
Acute myeloid leukemia (AML) accounts for about 30% of all leukemias (blood cancers, usually fatal) in adults (around 22, 250 new cases per year in Europe). AML is less common than chronic leukaemia in adults but is 5 times more frequent under the age of 50. AML accounts for 15-20% of childhood leukemia. AML starts in the bone marrow (the soft inner part of the bones, where new blood cells are made), but in most cases it quickly moves into the blood. _x000D__x000D_The American Cancer Society's estimates (2011) for leukemia in the US are about 44,600 new cases of leukemia (all kinds) and 21,780 deaths from leukemia (all kinds), about 12,950 new cases (30%) of acute myeloid leukemia (AML) and about 9,050 deaths (70%) from AML. _x000D__x000D_Current clinical treatments are based on the combination of radiotherapy with chemotherapy followed by either allogenic transplantation (Hematopoeitic stem cells (HSC) originating from an external donor) or autologous transplantation using frozen HSC taken from the patients before initiating the chemotherapy. _x000D_Such strategies increased the survival rates of patients but nevertheless rely on the finding of a compatible donor and continuous medication (COtenance phase) or the exclusive regeneration of healthy blood cells from the patient’s transplant (30% of cases). _x000D__x000D_Different populations of cancer cells co-exist within the same tumor; some have properties that closely resemble those of normal stem cells (SC), which gave rise to the concept of cancer stem cells (CSC) or cancer initiating cells (CIC). The cancer stem cell model predicts that, even if differentiated cancer cells can be killed, only the destruction of undifferentiated CSC allows full recovery. CSC are the only cells with tumorigenic potential. CSC are highly resistant to conventional therapies. In fact, most cancers likely recur because cancer SC escape treatment, survive and regenerate the tumor. This demonstrates the importance of treatments targeting CSC for patient outcome._x000D_In recent years the activity of the aldehyde dehydrogenases (ALDH) appears as an additional promising discriminatory marker. _x000D__x000D_The combination of cellular surface markers and ALDH has led to the identification of subsets of SC with high (ALDHhi) and low (ALDHlow) activities [Moreb 2008; Ma & Allan 2011 ; Quash et al. 2013]. Moreover, a recent consensus is essentially restricting the ALDHhi characteristic to CSCs in tissues with low or practically no ALDH activity [Ma & Allan 2011]. Therefore, the overepression of ALDH in CSC is likely to be involved in their resistance mechanisms towards chemotherapy._x000D_ _x000D_Di-methyl ampal-thiol-ester (DIMATE ; patents CNRS & ABD), a selective inhibitor of ALDH 1 and 3 isoforms, has been demonstrated in vitro and in vivo (Quash et al. 2013 (CNRS & ABD)] on murine and human cells to i) trigger apoptosis of ALDHhi cells (malignant cells) even when Bcl-2 is overexpressed and ii) to induce reversible cytostatic effect on ALDHlow cells (normal cells). _x000D_Targeting these mechanisms by taking advantage of potential differences in the biology of normal and cancer SC, such as differences in ALDH expression as well as in surface phenotype, self renewal/quiescence and stem cell-niche interactions, might allow successful CSC targeting and improve cancer treatment outcome._x000D__x000D_SEFALDIN approach will consist in assessing the potential of ex vivo DIMATE treatment to eliminate cancer stem cells in AML patient’s HSC fresh samples towards autologous transplantation (for which Transcure has an extensive expertise: )_x000D_Should this proof of concept be established, it will allow, in 2 years of time following the end of the project, i) running clinical investigations based on the purge of CSC from autologous AML cells with a view to re-injecting them to the patient and ii) undertaking DIMATE toxicity assays in animals to determine whether they meet the requirements for direct in vivo use (systemic or local) in a phase 1 clinical trial. In the latter case, the application spectrum of DIMATE could possibly be extended to solid cancers as an alternative therapeutic._x000D_This project is made possible by the unique design of ALDH specific isoforms inhibitors (Fournet et al 2006) that are protected by 2 US patents: 7,078,402 B2 & 8,026,231 B2 issued to the CNRS and 1 patent pending to ABD (ex vivo clinical use of DIMATE).
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Acronym
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SEFALDIN
(Reference Number: 8388)
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Duration
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02/09/2013 - 31/08/2016
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Project Topic
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Acute myeloid leukemia accounts for 30% of all leukemias in adults. SEFALDIN will try to establish proof of concept for first eradicating ex vivo cancer stem cells (CSC) and CSCs only from HSC samples using an aldehyde dehydrogenase inhibitor DIMATE before envisaging autologous transplantation.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 10
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Project partner
