Texas MPN Workshop 2021 | Targeting dysregulated signaling networks for the treatment of MPNs
Stephen Oh, MD, PhD, Washington University School of Medicine, St. Louis, MO, gives an overview of how dysregulated signaling networks can be leveraged for the treatment of myeloproliferative neoplasms (MPNs). Dr Oh specifically talks on nuclear factor kappa-B (NF-kB) signaling, which is observed to be overactive in the case of myelofibrosis, and how this has been targeted therapeutically with the drug pevonedistat. Pevonedistat has yielded promising results in pre-clinical studies and is currently under investigation in combination with ruxolitinib in a clinical trial. Dr Oh further discusses the use of gene expression profiling to identify dysregulated gene expression with the prospect of developing disease-modifying strategies, in particular highlighting upregulated expression of DUSP-6. This interview took place at the Texas MPN Workshop: Second Annual Workshop and Meeting in 2021.
Transcript (edited for clarity)
So, certainly JAK inhibitors, such as ruxolitinib provide important clinical benefits for the treatment of patients with myeloproliferative diseases. It’s also, I think well-established that these drugs as a class, while they do provide symptom benefits, spleen volume reduction, their ability to eradicate the underlying malignant clone is relatively minimal. And so, we have really taken the approach that we need to better understand the signaling networks more broadly in cells from patients with these diseases so that we can identify vulnerabilities that may be targeted either alone or in combination with JAK2 inhibition...
So, certainly JAK inhibitors, such as ruxolitinib provide important clinical benefits for the treatment of patients with myeloproliferative diseases. It’s also, I think well-established that these drugs as a class, while they do provide symptom benefits, spleen volume reduction, their ability to eradicate the underlying malignant clone is relatively minimal. And so, we have really taken the approach that we need to better understand the signaling networks more broadly in cells from patients with these diseases so that we can identify vulnerabilities that may be targeted either alone or in combination with JAK2 inhibition. And to do so, we’ve utilized a technology called CyTOF or mass cytometry, which enables us to profile signaling broadly in actual MPN patient samples, and over the course of several years of work, we’ve utilized this approach to identify a dysregulated activation of the NF-kappa B signaling pathway. In particular, in patients with myelofibrosis, we found that this pathway was hyperactivated and we also identified that the NF-kappa B pathway is really central to the abnormal production of inflammatory cytokines in these diseases.
As a result of this work we have focused on targeting the NF-kappa B pathway therapeutically, and we’re doing so with a drug called pevonedistat. This is a NEDD8-activating enzyme inhibitor that inhibits NF-kappa B signaling. And we have found in our preclinical studies that pevonedistat does block NF-kappa B signaling in MPN patient cells. It very potently blocks inflammatory cytokine production, and it also has activity in vivo in animal models of MPNs. And from this work, we have initiated a clinical trial combining pevonedistat with ruxolitinib. So, this is a Phase I dose-escalation study with pevonedistat treatment for patients who are taking a stable dose of ruxolitinib and that clinical trial is currently ongoing.
The other part of my talk also related to aberrant signaling, but more specifically has been focused on looking at mechanisms of disease progression in MPNs, and utilizing a gene expression profiling approach we identified up-regulate expression of DUSP-6, which is a phosphatase that regulates the MAP kinase signaling pathway and exploring the impact of increased DUSP-6 expression in MPNs we found specifically that the gene is increased in patients who had transformed to acute leukemia and that aberrant signaling through DUSP-6 is transmitted downstream through RSK! And S6, and the signaling access can be targeted pharmacologically. And we found that in our animal models targeting this pathway also provides a benefit in terms of MPN disease features. So, this is also a pathway that is potentially translatable to the clinic with clinically available compounds.
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