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ASH 2025 | First-in-class dual BTK-MALT1 fusion inhibitors for treating resistant mantle cell lymphoma
In this interview, Vivian Jiang, PhD, The University of Texas MD Anderson Cancer Center, Houston, TX, provides insight into the development of first-in-class dual BTK-MALT1 fusion inhibitors for treating resistant mantle cell lymphoma (MCL). Dr Jiang highlights the potential of co-targeting BTK and MALT1, a downstream effector of BCR-BTK signaling that plays a key role in BCR-NF-κB activation, to overcome therapeutic resistance in patients with MCL. This interview took place at the 67th ASH Annual Meeting and Exposition, held in Orlando, FL.
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Transcript
This project, we focused on developing a first-in-class BTK motor-arm fusion inhibitors, which is designed to overcome therapeutic resistance in B-cell lymphoma, especially mantle cell lymphoma. Mantle cell lymphoma is an aggressive subtype of non-Hodgkin lymphoma. BTK has been a great clinical target – so far, multiple BTK inhibitors have been approved by the FDA to treat patients with mantle cell and other B-cell lymphoma as well...
This project, we focused on developing a first-in-class BTK motor-arm fusion inhibitors, which is designed to overcome therapeutic resistance in B-cell lymphoma, especially mantle cell lymphoma. Mantle cell lymphoma is an aggressive subtype of non-Hodgkin lymphoma. BTK has been a great clinical target – so far, multiple BTK inhibitors have been approved by the FDA to treat patients with mantle cell and other B-cell lymphoma as well. However, therapeutic resistance does develop, and the resistance becomes a major clinical challenge.
So our translational study, using patient samples and also preclinical models, we identified that critical vulnerability downstream of BTK called MALT1, which is an essential signaling molecule that mediates the BCR-activated NF-kappa B signaling. So this molecule was found to be highly expressed and hyperactive in these resistant cells. We believe it’s a co-driver in BTKi resistance.
So our hypothesis is that co-targeting BTK and its downstream MALT1 may overcome the resistance or at least improve the treatment efficacy. And this has been proven by our previous preclinical studies. So we co-targeted BTK and MALT1 with a combination of single target agents and we do see a synergistic effect in preclinical models. And in the clinic, there are also ongoing combination therapies that combine BTK inhibitors and MALT1 inhibitors. And in early clinical data, they do show some beneficial effect by combining them beyond the single agents.
So, in this particular study, we managed to develop a single molecule that targets both BTK and MALT1 simultaneously. And we hope that this approach will perform better than just a combination of single target agents. And this is what we do and we found this newly developed dual inhibitor mechanistically targets both BTK and MALT1. They outperform single agent target combinations, both in cell lines, in clinically relevant models, such as patient-derived organoid and xenograft models. So we have seen this product works both in vitro, in vivo, and ex vivo. So we are also working on the toxicity profiling to see how far this can go. We hope this can soon translate into clinical investigation.
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