Preclinical development of Dendrogenin A, an innovative molecule with an original mechanism of action, for the treatment of Acute Myeloid Leukemia – DAML

Acute myeloid leukemia (AML) are the most widespread acute leukemia in adults. Despite a high rate of complete remission after treatment with genotoxic agents (anthracyclines and Ara-C), relapse rates are very high resulting in a poor outcome in most cases (40 % overall survival in younger adults, 15% for elderly patients). In opposition to other hematological malignancies, there was no key development in AML treatment during the last decades. Leukemia stem Cells (LSC) are thought to play a central role in the pathogenesis of acute leukemia and likely contribute to both disease initiation and relapse. Several retrospective studies have correlated the percentage of CD34+CD38--cells to patient prognosis. This population is the most enriched in drug-resistant leukemic cells. Therefore, identification of agents that target LSCs is an important consideration for the development of new therapies.

Dendrogenin A (DDA) is a natural molecule discovered in mammals that exhibited strong anticancer effects against different tumor models in vitro and in vivo. Preliminary data from the partners of the project showed that DDA had remarkable anti-cancer activity against samples from leukemic patients and leukemic immature cells which are resistant to cytotoxic agents (anthracyclines and Ara-C). DDA alone at low doses (IC50 around 1 micromol/liter) eradicated either chemo-resistant CD34+CD38-CD123+ cells and the leukemic bulk, properties that make this compound an attractive and original agent against leukemic cells. Interestingly, DDA development is supported by an original mechanism of action targeting several aspects of AML biology and the discovery of a companion biomarker.

In this context, DAML project was designed to optimize and complete the pre-clinical development of DDA in order to reach a phase I clinical trial for AML treatment at the end of the project.