Target5LO · Targeting 5-lipoxygenase in the context of Acute Myeloid Leukemia
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-03-01 → 2020-02-29
- EU contribution
- €195,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-CAR
Lines connect the coordinator with its partners.
Results in brief
Targeting 5-lipoxygenase in the context of Acute Myeloid Leukemia
Acute Myeloid Leukemia (AML), a cancer of the myeloid line of blood cells, is the most common type of leukemia in adults (~350.000 new cases yearly worldwide), yet continues to have the lowest overall survival rate of all leukemias (26.9%). Current AML management still relies largely on intensive chemotherapy and stem cell transplantation. Although some AML patients respond to these treatments, most patients that go into remission show disease relapse (up to and 70%). In addition, minimal advances have been made for patients unable to tolerate intensive treatment, for example, older patients. The main objective of this research project was to create a new treatment for AML that is (1) more effective and (2) tolerated by all patients. The fellow aimed to use the anticancer natural product beta-lapachone, an under-exploited drug, which has been shown to target the enzyme 5-lipoxygenase in an AML-specific mechanism to treat the cancer. The fellow developed a new targeting strategy for the drug to guarantee specific uptake of beta-lapachone by AML cells and, importantly, to minimize side effects of the drug on healthy cells. To achieve this goal, an antibody-drug conjugate was built to target the drug to cancer cells. The fellow showed that inhibition of 5-lipoxygenase by the drug beta-lapachone delivered as an antibody-drug conjugate leads to highly effective specific cancer cell death while sparing healthy cells, thereby yielding maximal efficacy while minimizing toxicity.
Data: CORDIS, © European Union
Project objective
Drug efficacy is cornerstone for successful drug discovery programs. Considering that, on average, FDA-approved drugs modulate dozens of off-targets it remains imperative to find strategies to overcome adverse drug reactions correlated with pernicious polypharmacology. In fact, several chemical entities displaying promising anticancer are discontinued from drug development pipelines due to narrow therapeutic windows in pre-clinical models. Here, we propose the development of antibody-drug conjugates exploring the unique bioactivity profile of the naphthoquinone natural product-lapachone (Lp) against acute myeloid leukemia (AML), an unmet medical need. Using a machine learning method, we disclosed Lp as an allosteric modulator of 5-lipoxygenase (5-LO), correlated its anticancer activity with 5-LO expression in blood cancers and showed its efficacy in a disseminated mouse model of AML.In this project, a comprehensive investigation of novel means for the targeted delivery of Lp to leukaemia cells is sought after, considering both the promising bioactivity profile but also the significant toxicity in untargeted dosage forms. We apply state-of-the-art synthetic medicinal chemistry to design and access cleavable linkers, and site-specifically conjugate Lp to an anti-IL7R antibody, a validated biomarker in AML and other leukaemia’s. We aim at employing biophysical and chemical biology approaches to validate quantitative and fast release of Lp with accurate spatiotemporal control in in vitro disease models. Finally, we will validate the deployment of the constructs through preclinical in vivo models of AML. We foresee broad applicability of the developed technology, which may have profound implications in drug discovery. Upon successful completion of this research program, we hope to yield a new targeted drug to treat AML patients with improved efficacy and reduced side-effects.
Original text from CORDIS.
Participants
- THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGECoordinatorUnited Kingdom
Links
- View on CORDIS
- DOI: 10.3030/792495
- https://arquivo.pt/wayback/20200205175644/https://gbernardeslab.com/
Data: CORDIS, © European Union