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.
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.
OncLive®: What makes the JAK-STAT pathway such a promising target for anti-cancer therapy?
: 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
also are found in numerous patients with MPNs. These CALR
mutations also lead to the deregulated activation of the JAK-STAT pathway.
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.
What lessons have we learned from clinical experience with JAK-targeting drugs?
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.