Novel Therapies: Close but not close enough

One question that always comes up when Bob and I talk is this: “Why don’t we have new drugs for the MPNs?” It is a difficult question for me to answer. Is it for lack of trying? No, I’m sure that’s not it. Basic and clinical researchers are working harder than ever to identify new targets and develop new therapies. Is it that the best researchers are working on other diseases? Certainly not. No, I think it is the usual challenge of translating discoveries into therapies that work not just in animal models, but also in humans. Let’s consider the mainstay of therapy, JAK inhibitors. We are fortunate to have ruxolitinib available for PV and PMF patients. Despite its shortcomings, which include myelosuppression at higher doses and limited activity in some individuals, it has helped so many people. Why don’t we have a second JAK inhibitor in our arsenal to treat those who are intolerant or resistant to ruxolitinib? There are a few reasons, such as the challenge of accruing large numbers of patients to studies and severe side effects in a small percentage of patients. With respect to the latter, it isn’t for me to say whether the benefits outweigh the risks, but it’s a critical issue for patients and their advocates to consider. 

Where is the field headed? Perhaps the therapy with the most potential is a JAK2V617F selective inhibitor. This would be a drug that inhibits the mutant kinase while leaving the normal (or wild-type) protein alone. Although such a drug would be effective in only the 50 percent of PMF patients with the V617F driver mutation, it would be applicable for nearly all patients with PV who need therapy. It is likely that this drug would be more active in patients than ruxolitinib, as the doses could be increased with less toxicity than drugs that inhibit both the mutant and wild-type versions. JAK2V617F selective inhibitors are not in the clinic, but it is likely that companies and academics are aggressively searching for these. If they aren’t, they should be. Finally, type II JAK inhibitors, which target the kinase in a slightly different way from ruxolitinib, are under investigation. I expect that we will see one or more of these novel JAK inhibitors in patients in the future. 

There are a number of other targets that are being investigated in clinical studies. These include inhibitors of aurora kinase, a protein that regulates the cell cycle; histone deacetylases, factors that regulate gene expression through modifications of DNA associated proteins; and heat shock proteins, factors that regulate the stability of other proteins. I’m, of course, most excited about the aurora kinase inhibitor, which my laboratory has shown leads to maturation of abnormal megakaryocytes in pre-clinical models of PMF. 

Other promising “out of the box” therapies include imetelstat and PRM-151, which target telomerase or cells that contribute to fibrosis, respectively. Both of these drugs have shown promise in clinical trials and are enrolling patients in phase 2 studies. Finally, new therapeutic agents under investigation include PARP and BET inhibitors, which alter DNA damage and epigenetic factors, respectively. 


Why don’t we have new drugs for the MPNs? Bob, with more research and your support, we will.  

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