Mechanisms and prospects of a novel CDK9 inhibitor for DLBCL

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Published: 25 Apr 2018
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Dr Susan Galbraith - AstraZeneca, Cambridge, UK

Dr Galbraith speaks with ecancer at AACR 2018 about a novel CDK9 inhibitor for diffuse large B cell lymphoma (DLBCL).

She discusses the mechanism of action of the investigatory treatment, and its effectiveness in combination with other treatment types to deliver targeted damage, growth control and cell death in tumours.

Clinical trials are ongoing.

We had a presentation in the New Drugs on the Horizon session for our CDK9 kinase inhibitor, AZD4573. This is part of our cell death portfolio. You may be aware that venetoclax has already got approval now in chronic lymphocytic leukaemia, that’s a selective BCL2 inhibitor so that gives clinical validation to the principle that you can by targeting proteins in the apoptotic family you can trigger cell death and enhance therapies. So there are other members of that family, one of which is MCL1 and we’ve got two different mechanisms of targeting MCL1: we have a direct inhibitor, AZD5991, and the drug we were talking about today is a CDK9 inhibitor. The way that that works is it inhibits the phosphorylation of phosphatidylserine 2 on RNA polymerase, so it basically inhibits transcription. We’ve designed a short-acting CDK9 inhibitor that produces short inhibition of transcription for a few hours dosed intermittently and that showed activity in particularly hematologic malignancies. We’ve also shown that by combining with our BTK inhibitor, acalabrutinib, you can basically prime some of these cells for cell death and then when you come in with the CDK9 inhibitor you can enhance the level of activity that you’ve seen. So we’ve seen prolonged and durable complete remissions for the combination of a CDK9 inhibitor and acalabrutinib.

There are other mechanisms, as well, of enhancing the activity you can see for acalabrutinib in B-cell malignancies and another one that we’ve got a poster on today is the combination of our ATR inhibitor, AZD6738, with acalabrutinib. That combination also enhances the level of cell kill but does it by a different mechanism. ATR is part of our DNA damage response portfolio; by inhibiting ATR you inhibit the ability for cells to repair DNA because what you do is you get separation of the DNA helicase that unwraps DNA and the polymerase that is polymerising behind it. So you get potential for conversion of single strand breaks into double strand breaks. By combining the ATR inhibitor with acalabrutinib, particularly in the subsets of hematologic malignancies perhaps that have either got other impairments in DNA damage repair, so for example if you’ve got ATM loss might be one example, p53 mutation is another, you may sensitise those cells to an increased level of DNA damage and that triggers cell death. What we’ve shown in the poster in diffuse large B-cell lymphoma models is that you can enhance the activity by putting these two drugs together. We’ve now got a clinical trial ongoing in hematologic malignancies looking at the combination of our ATR inhibitor and acalabrutinib.

What are the main challenges involved?

One of the challenges in diffuse large B-cell lymphoma is it’s quite a heterogeneous disease. The two mechanisms I’ve talked about may be important in different sub-segments of diffuse large B-cell lymphoma. What’s starting to happen is you’re starting to see sequencing of patients’ tumours and identification of the different mechanisms that are driving the tumour. One of the things we’re doing is we’re actually getting a platform-based study called the PRISM trial which will use molecular sequencing to select subgroups and look at different combinations with the different subgroups within diffuse large B-cell lymphoma. Because beyond the drugs I’ve talked about today we have others that might be relevant in that setting and that mechanism of a platform-based study will enable us to work out which combinations are working well in which patient subgroups. Then we can do the most appropriate late phase development programmes for the ones that are looking promising.