Targeting cancer vulnerabilities in acute leukemia

Informations projet

ONCODESTROYER

N° de convention de subvention: 883552

DOI

10.3030/883552

Date de signature de la CE 26 Juin 2020

Date de début 1 Octobre 2020

Date de fin 30 Septembre 2026

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 3 200 000,00

Contribution de l’UE

€ 3 200 000,00

Coordonné par

THE HEBREW UNIVERSITY OF JERUSALEM
Israel

Periodic Reporting for period 3 - ONCODESTROYER (Targeting cancer vulnerabilities in acute leukemia)

Période du rapport: 2023-10-01 au 2025-03-31

Résumé du contexte et des objectifs généraux du projet

The overall objective of the ERC project (ONCODESTROYER) is to evaluate the therapeutic potential of a new class of anti-cancer drugs in acute myeloid leukemia (AML), using clinical study samples and mouse models. Acute myeloid leukemia accounts for 2 percent of all cancer death. Despite some recent remarkable developments in treating certain AML types, the standard therapy of the disease hasn’t changed much in the past 50 years. AML, like many cancer types, harbors distinctive vulnerabilities, prominent among which are cell death resistance control and transcriptional addiction. Our project is centered around a new type of experimental leukemia drug developed in our lab, taking advantage of critical AML vulnerabilities. We proposed to: 1) Diversify our original drug candidates, particularly by developing Proteolysis Targeting Chimeras (PROTACs), possibly expanding the therapeutic window of the drug in AML; 2) Elucidate the mechanisms of action with emphasis on disruption of oncogene-driving super-enhancers; 3) Figure out the basis of an observed cooperation of the immune system in the therapeutic effect of the drug in AML models; 4) Explore translational aspects of the drug treatment by identifying mechanisms of drug resistance and relapse; 5) Study the clinical potential of the drug in MDS and AML patients undergoing phase 1a/b clinical trial; and 6) Predict a patient response to the drug, based on clinical and genomic parameters.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

1. We have studied several PROTACs based on a major oncodestroyer molecule, A51. Whereas these PROTACs demonstrated signaling and cell killing effects in leukemia cell lines and primary AML cells in vitro, none of which showed the desired activity observed with A51 in vivo in our mouse models. We concluded that possible structural constrains of the PROTACs was incompatible with achieving a therapeutic response, a notion which is currently shared by many recent PROTAC studies.

2. A well-recognized property of oncogene-driving super-enhancers is an operation within a liquid-liquid phase separation condensates within the nucleus. We examined the drug effect on AML nuclear condensates and found that a short-term ex vivo treatment was sufficient to disrupt these condensates. Our next effort will be to understand the basis for the condensate disruption.

3. We previously speculated that one of the reasons for our observed cure of leukemic mice following the drug treatment was immune support, as in immune-deficient strains or in T cell-depleted AML mice, we have not observed leukemia cure. A major progress in these investigations was the demonstration of immune memory to the leukemia generated in the course of treatment, sufficient to prevent re-engraftment of the cognate leukemia. Further work is being planned to identify specific T cell clones behind the immune property.

4. We have developed a system to observe emerging drug resistance by prolonged treatment of AML cells in vitro. These studies yielded the notion that a major route of resistance is the emergence of presister state, at which AML cells become temporarily resistant to drug effects and resume responsiveness after some weeks in culture without the drug. As these states are being recognized now in multiple cancer patient treatment regimens, we are studying now cellular and molecular parameters associated with drug tolerant persisters and ways of preventing or delaying the emergence of this state. A significant finding in this direction is the role of epigenetic modifications in establishing the persister states, possibly indicating options of drug combination treatment to increase the therapeutic efficacy.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

One of the major aims of our ERC project was to assess an “oncodestroyer” drug in a phase I clinical trial. This was recently completed successfully, showing a satisfactory safety profile and a therapeutic effect of A51 (the first oncodestroyer molecule approved for clinical trials) in a large subset of patients harboring a particular, common AML mutation - patients who had been heavily pre-treated before by many AML drugs with no response. In light of the clinical data, we are developing now new mouse models for understanding the vulnerability value of the observed human mutation and improving the efficacy of the drug by combination treatment. Likewise, we continue our effort to predict and mitigate drug therapy resistance. In light of realizing the possible role of epigenetic modifications associated with emerging drug persistence, we started examining combination therapy of A51 with epigenetic modifying drugs in mouse AML models, with encouraging preliminary results. We previously speculated that periodical treatment with A51 of patients bearing clonal hematopoiesis (CH) and being at high risk of developing myelodysplastic syndrome (MDS) and AML may block or delay clonal evolution in CH and disease progression to AML. We have thus established new mouse models of CH to AML progression to test effects of periodical A51 treatment. At this time, we presume that data to be derived in the second term of the ONCODESTROYER project may be highly valuable in improving AML therapy.

The ONCODESTROYER ERC project: Graphical Abstract