ISAL 2025 | A novel approach: targeting MYC for the treatment of acute leukemias

That’s a completely new field. MYC has not been investigated very much in heme malignancies except in lymphomas. We have established but there has never been an agent to target it. So we presented data today here at the conference for the first time of an agent that degrades MYC. And we investigated mechanisms, how this works. So it induces what’s called an integrated stress response, which then results in cell death. We established links between the protein translation machinery and MYC and links between MYC and P53. So as you know, P53 mutations are a major problem in leukemia therapy, cancer therapy. There’s essentially nothing that works. What we found is that P53 suppresses MYC. So when you have a mutation, MYC levels go up. And there is a direct correlation between levels of MYC and activity of this agent. So this agent was developed by us in collaboration with a group in China. It has a cereblon E3 ligase linker and the warhead is patterned after the MYC-MAX interaction protein structure. So this agent is active in very low nanomolar concentrations, 1 to 5 nanomolar. And we did extensive studies in vivo in mouse models and of course toxicology and so far we have seen very little toxicity, but this is a major concern and we need to do tox studies in other animals. But back to activity. So we found it degrades MYC, it degrades GSPT1. GSPT1 is involved in translation of proteins, very critical regulator. And the translation then was into Burkitt’s lymphoma which is driven by MYC. It’s the best tumor, the most MYC-dependent tumor and we have 100% survival in mice with a MYC rearranged Burkitt’s lymphoma. The second group was T-cell ALL lymphoblastic leukemias and T-cell PLL prolymphocytic leukemias which are very difficult to treat. They also have high MYC levels and we had some very nice in vivo data and then very importantly we found that venetoclax-resistant so BCL2 inhibitor-resistant patients overexpress MYC and then we treat patient samples and mouse models, PDX models from patients who are resistant to venetoclax. You get a tremendous increase in survival up to cures. So this has a potential of curing patients with AML that are sensitive to venetoclax, but even if they are resistant, it more than doubles survival. And then finally, we showed data that we can target p53 mutant leukemias, and we had doubling of survival in very complicated models that had more than the p53 mutation, like two p53 mutations plus others and nevertheless we got doubling of survival which in the field is considered probably very positive. So that’s the data I should discuss today. There is one agent in clinical trials. It’s a pseudoprotein a peptide and so far they have shown no side effects which is good but also no activity so it doesn’t help very much but so far this agent is not very active. There is a degrader for GSPT1 in clinical trials which may or may not degrade MYC what I know is that there’s a very short reduction in MYC but it’s not sustained and this degrader is in clinical trials so that’s the only drugs that I’m aware of that target MYC in one kind or another.

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