JAK Signaling Remains a Promising Target in Myeloproliferative Neoplasms

Srdan Verstovsek, MD, PhD

Although the development and clinical use of drugs that target JAK signaling have been challenging, novel agents and evolving treatment approaches should soon enhance their utility for patients with hematologic malignancies, according to Srdan Verstovsek, MD, PhD.

Verstovsek specializes in understanding the biology of and developing new treatments for myeloproliferative neoplasms (MPNs). His research helped pave the way for ruxolitinib (Jakafi), which became the first, and still only, FDA-approved JAK inhibitor in 2011. Ruxolitinib is indicated for treating patients with intermediate- or high-risk myelofibrosis (MF), including primary MF, postpolycythemia vera MF, and postessential thrombocythemia MF. It also is approved for patients with polycythemia vera who have had an inadequate response to, or are intolerant of, hydroxyurea.

OncLive^®: What makes the JAK-STAT pathway such a promising target for anti-cancer therapy?

In a recent interview with OncologyLive^®, Verstovsek discussed the rationale for targeting JAK signaling, new drugs under study for this pathway, and clinical challenges associated with these therapies. Verstovsek is a professor in the Department of Leukemia and director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms at The University of Texas MD Anderson Cancer Center in Houston.Vertovsek: The JAK pathway is integral in the control of cellular processes, including, but not limited to, hematopoiesis stem cell maintenance, proliferation, differentiation, apoptosis, and the signaling of cytokines and growth factors that regulate the inflammatory response. This signaling pathway is critical for the normal regulation of the bone marrow and immune cell functions. If there is either aberrant activation of the JAK-STAT pathway or JAK is constitutively active due to activating mutations, then this pathway confers malignant, or cancerous, properties on cancer cells.

MPNs provide a good example of the aberrant activation of the JAK-STAT pathway, with the identification of frequent JAK2 mutations. The predominant mutation, which is an activating mutation, in Philadelphia chromosome—negative MPNs is a single base substitution in the JAK2 gene that results in a JAK2 V617F mutation. Other mutations in CALR and MPL also are found in numerous patients with MPNs. These CALR and MPL mutations also lead to the deregulated activation of the JAK-STAT pathway.

What lessons have we learned from clinical experience with JAK-targeting drugs?

These findings led to the development of JAK inhibitors, such as ruxolitinib, which are used clinically in an attempt to normalize the activated JAK-STAT pathway. You can align this phenomenon by thinking of it in terms of operating a vehicle. In the vast majority of MPNs, the car is moving forward at an accelerated pace; however, the car will decelerate when the brakes are applied through the use of ruxolitinib.While JAK-targeting agents share the capabilities of reducing spleen size and constitutional symptoms, there is still a major obstacle of trying to hone in on optimal dosing regimens and concentrations of these drugs to maintain durable benefits and reduce myelo-suppression. It is interesting to note that JAK-targeting drugs are all ATP [adenosine triphosphate]—competitive, so they’re unable to discern the difference between targeting wild-type versus mutant JAK2. Therefore, clinically relevant therapeutic indices between patients may differ.

If JAK2 inhibitors were able to discern and specifically target mutated JAK2, then there wouldn’t be such a great effect on normal hematopoiesis and the malignant clone could potentially be better targeted. Unfortunately, the JAK2 V617F mutations in MPNs are often accompanied by other genetic modifications, and therefore combinatorial therapy may prove essential for eliminating these cancers. It has been found that other signaling pathways that may be affected include mutations in spliceosome factors and in epigenetic pathways involving DNA methylation and chromatin remodeling. These complications are challenging; however, they also provide opportunities to advance the personalization of medicine through additional drug discovery.

Beyond ruxolitinib, what are the most promising JAK-targeting drugs in the pipeline, in your opinion?

In MPNs, it is very important to weigh several factors when considering JAK2 inhibitor therapy for each patient. We need to consider not only whether a patient has deregulated JAK2 signaling but also disease stage and treatment goals, as well as adverse events that may occur in addition to ensuring an optimal outcome for our patients.Currently, the only FDA-approved JAK inhibitor for MPNs is ruxolitinib. Although fedratinib provided positive responses for patients with MF who were treated in an international phase III clinical trial, this agent was on clinical hold [not clinically developed] due to reports of an acute neurological condition known as Wernicke encephalopathy, which was indicative of a chronic vitamin B deficiency. This drug is now back in development.¹

Different JAK inhibitors target members of the JAK family differentially. In terms of targeting MPNs, where inhibition of the JAK2 protein is prevalent, another promising JAK2 inhibitor is NS-018. In small phase II study in patients with MF who were previously treated with ruxolitinib, it had good clinical efficacy,² and additional studies are planned in this clinical setting.

Do you think JAK inhibitors might have a role in solid tumors or other types of malignancies besides MPNs?

Pacritinib, a JAK2/FLT3 inhibitor, is a promising agent that is also being used to treat patients who did not benefit from ruxolitinib or were ineligible to receive ruxolitinib. We are eagerly awaiting the results from the ongoing PAC203 study of this agent [NCT03165734]. To summarize, I’m certain that we’ll see significant advances in combinatorial therapies and in JAK2 monotherapies for MPNs in the very near future.Deregulation of the JAK-STAT pathway is rare in hematological malignancies other than MPNs. In other solid tumors, such as in certain types of sarcomas, lung, breast, head and neck, ovarian, brain, hepatocellular carcinoma, and prostate cancers, targeting the JAK-STAT pathway has become a promising therapeutic strategy. In a poor prognostic subtype of pediatric acute lymphoblastic leukemia (ALL), except in those patients having Philadelphia chromosome—positive ALL, activating mutations in the JAKs were discovered that resulted in constitutive activation of the JAK-STAT signaling pathway. The next logical step would be to test JAK inhibitors for therapeutic intervention in JAK-mutated ALL.

In an aggressive leukemia, T-cell prolymphocytic leukemia (T-PLL), it has been shown that activating mutations in JAK3 and STAT5B genes were mutually exclusive and detected in 30% and 21% of the cases, respectively. The investigators concluded that, due to the constitutive activation of the JAK-STAT pathway in this cohort of T-PLL, therapeutic intervention may be favorable.

What are the most significant limitations or challenges to successful JAK targeting in cancer?

Numerous JAK inhibitors also are being tested in phase II and III clinical trials for various autoimmune diseases. Inhibiting the JAK signaling pathway appears to be effective for treating the pathogenesis of inflammatory bowel disease, rheumatoid arthritis, psoriasis, and other autoimmune diseases.The limitations and challenges to successful JAK targeting in MPNs are combinatorial. By targeting the JAK-STAT pathway, there is a risk of enhancing an immunosuppressive phenotype, which carries with it the propensity of acquiring infections, such as herpes zoster (± 8%), bronchitis (± 6%), and urinary tract infections (± 6%). Therefore, it is important for us to keep detailed notes on the challenges that arise with JAK2 inhibition in our patients, such that their associated risk factors can be carefully and effectively managed.

Additionally, JAK inhibitors may decrease neutrophil numbers, resulting in neutropenia; however, this can be reversed by withholding treatment until the patient has recovered. Other dose-related effects, such as thrombocytopenia, which is a condition where the body produces abnormally low levels of platelets, can also be managed by reducing the JAK inhibitor dose or providing the patient with a platelet transfusion. Accordingly, patients may develop anemia where blood transfusions or JAK inhibitor dose modifications would be called for. In some patients, low-density lipoprotein and high-density lipoprotein cholesterol levels may increase, which would also require intervening therapy.

It is very important that patients who are either on JAK inhibitor therapy or being tapered off let their physician know if they experience any adverse effects, regardless of the perceived degree. Overall, in my opinion, the benefits of treating those patients eligible for JAK inhibitor therapy, although it is a personal choice, far outweigh the risks. Challenges and limitations occur with all therapies; however, if there are personalized therapies available for qualifying patients, then the potential benefit needs to be carefully considered.

References

1. Celgene to acquire Impact Biomedicines, adding fedratinib to its pipeline of novel therapies for hematologic malignancies [news release]. Summit, NJ, and San Diego, CA: Celgene Corporation and Impact Biomedicines; January 7, 2018. ir.celgene.com/releasedetail. cfm?releaseid=1053509. Accessed March 18, 2018.
2. Verstovsek S, Talpaz M, Ritchie EK, et al. Phase 1/2 study of NS-018, an oral JAK2 Inhibitor, in patients with primary myelo brosis (PMF), post-polycythemia vera myelo brosis (postPV MF), or post-essential thrombocythemia myelofibrosis (postET MF). Presented at: 2016 American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 1936. bloodjournal.org/content/128/22/1936.