Targeting p53 in the Treatment of Hematologic Malignancies With Matthew Davids, MD, MMSc
Tumor suppressor gene p53 is the most frequently mutated gene in human malignancy. Through a complex series of molecular events, p53 leads to malignant cell proliferation and plays a significant role in tumor formation. In the Presidential Symposium at the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition in Atlanta, Georgia, Dr. Matthew Davids of Harvard Medical School discussed the current therapeutic strategies used to inhibit or reactivate mutant p53 in the treatment of hematologic malignancies. In this interview with Oncology Data Advisor, Dr. Davids delves further into the latest research in p53-directed therapeutic strategies and the future of targeting this specific mutation.
Oncology Data Advisor: I'm Keira Smith with Oncology Data Advisor. Today I'm here with Dr. Matthew Davids.
Matthew Davids, MD, MMSc: Hello, I'm Matthew Davids. I'm an Associate Professor of Medicine at Harvard Medical School, and I direct the Clinical Research Program in the Division of Lymphoma at Dana-Farber Cancer Institute in Boston.
Oncology Data Advisor: When a patient is told they have a p53 mutation and they ask you about p53 biology, what are some of the most important points to counsel them on?
Dr. Davids: Across hematologic malignancies, when patients have either a deletion or mutation of p53, the prognosis is unfortunately not as good as for other patients. In particular, when we treat these patients with conventional chemotherapy, they tend to not do that well. Generally, when I'm meeting with a patient who has this abnormality, I first counsel them about the more aggressive nature of their hematologic malignancy. Second, I help them to understand that some of the more modern targeted therapies can actually be much more effective than the historical chemotherapy-based approaches for the disease.
Oncology Data Advisor: What has the latest research in p53-directed therapeutic strategies included?
Dr. Davids: In the Presidential Symposium at ASH, I reviewed five broad categories of ways to tackle this problem of therapy for hematologic malignancies. Basically, the first strategy is to just try to control the disease—so rather than trying to kill the cells through the p53 protein itself, to actually use other pathways to disrupt the survival of these cells. A great example of that is the Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, in chronic lymphocytic leukemia (CLL). It's a highly effective drug, even for patients with high-risk disease, but it doesn't necessarily need to kill the cell directly through p53.
The second approach is to actually target downstream of p53. An example of that is venetoclax. It's a BCL2 antagonist which can directly target the mitochondria, so it doesn't rely on signaling through p53. This is a highly effective strategy in CLL and is also a useful component of therapy in other leukemias, such as acute myeloid leukemia (AML). Then you can imagine the combinations of these types of approaches. In CLL, we and others have been doing studies of the combination of BTK inhibitors with the BCL2 inhibitor. In AML, there are combinations of venetoclax with hypomethylating agents such as azacitidine or decitabine.
Then a fourth strategy I discussed is immune-based approaches. The traditional one, of course, is allogeneic transplantation, which can be effective for certain patients with CLL who have high-risk disease. In AML, however, patients with high-risk p53 mutations do not tend to benefit as much from transplant. There are other strategies for AML in development—for example, magrolimab, which is an anti-CD47 antibody that can help harness macrophage-based immunity and increase phagocytosis, which can be very helpful in combination with other agents for AML.
Finally, the fifth strategy that I discussed was actually targeting p53 itself. In particular, the focus of my talk was on reactivating p53 with drugs like eprenetapopt. This drug can actually help convert improperly folded mutant p53 into a confirmation that can then bind DNA and restore the activity of p53. There are various studies now looking at combinations of eprenetapopt with azacitidine in AML and MDS. This does seem to be a very promising strategy. Fortunately, there are a lot of new approaches in development for this high-risk type of disease.
Oncology Data Advisor: That's great to hear. So will different therapeutic approaches be better for p53-mutant versus -deleted hematologic malignancies?
Dr. Davids: We don't know the answer to that question yet. I think it will depend to some degree on the specific therapeutic modality. For example, if you're talking about the drug ibrutinib, where it's kind of controlling the disease by working through other pathways, I don't think mutated versus deleted is going to be that important of a distinction. The drug should work well in patients with either deletion or mutation of p53.
On the other hand, if you think about patients who are treated with eprenetapopt, that's a drug that needs to reactivate mutant p53. If it's actually completely deleted, then it may not be there to be reactivated and the drug may be less effective; although often with deletion(17p), it's a deletion of only one allele, and you still have the other allele that's present and mutated. So that drug could still be effective in that situation.
Oncology Data Advisor: Lastly, is it better to focus on disease-specific therapeutic strategies, or are there strategies that could be broadly applicable across p53-mutant cancers?
Dr. Davids: I think this is really an open question in the field right now. I think that the disease control strategies are probably more disease-specific. Really, ibrutinib works in CLL because it's targeting the B-cell receptor pathway. That's obviously not going to work in a myeloid malignancy like AML. On the other hand, targeting mitochondria directly with venetoclax seems to work well in CLL and AML because it's such a basic mechanism of the cells. That's a strategy that could be more broadly applicable across cancers.
Similarly, immune-based therapies offer promise across cancers. Some of the discoveries that are being made now in hematologic malignancies could also have future implications for solid tumors, as well. Obviously the targets are a bit different, but some of these fundamental cellular processes are similar. I think there's a lot of opportunity to make progress across different cancers.
Oncology Data Advisor: Well, thank you so much for explaining all this, and it'll be really exciting to see how all this research plays out.
About Dr. Davids
Matthew Davids, MD, MMSc, is an Associate Professor of Medicine at Harvard Medical School and the Director of Clinical Research in the Division of Lymphoma at Dana-Farber Cancer Institute. He is also the Associate Director of the Chronic Lymphocytic Leukemia (CLL) Center at Dana-Farber. Dr. Davids specializes in the treatment of patients with leukemia and lymphoma. His research focuses on the development of novel treatments and therapeutic strategies for patients with hematologic cancers, including those who undergo hematopoietic stem cell transplant. He has authored or coauthored numerous peer-reviewed publications regarding the treatment and management of patients with hematologic malignancies.
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Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.