Abstract Introduction: Most cases of myelofibrosis (MF) arise from constitutive activation of the JAK/STAT signaling pathway in hematopoietic stem cells (HSCs) with resultant activation of bone marrow stromal cells driving fibrosis. Treatment options are limited to approved Janus kinase (JAK) inhibitors that produce minimal reductions in fibrosis or malignant HSCs, the primary drivers of disease. Overall five-year survival remains ~40%, underscoring the dismal plight of patients with MF. Aberrant JAK/STAT signaling activates downstream PI3K/AKT/mTOR pathway and MAPK/ERK pathways with interconnections between these pathways regulating outputs such as gene expression, proliferation, and survival. Due to considerable signaling crosstalk, we posited that combined targeting of both upstream (JAK/STAT) along with downstream (MEK and PI3K/mTOR) signaling effectors would increase treatment efficiency compared to current, single agent JAKi's. Methods 0.001) compared to vehicles. LP-182 treatment alone or in combination with MMB revealed normalization of pAKT and pERK was achieved. Clinical Implications: Jaki's such as MMB and ruxolitinib are unable to down modulate oncogenic driver signals such as PI3K/mTOR and MAPK necessitating development of an improved therapeutic strategy. LP-182 was demonstrated to have potency as single agent and in combination with MMB for down-modulating proliferative and survival signals. As LP-182 was demonstrated to provide therapeutic potency in combination with MMB, clinical evaluation of this combination strategy appears warranted. LP-182 has been demonstrated to be absorbed through the lymphatic system which provides a unique opportunity to establish an efficacious, less toxic combination approach towards development of an efficacious MF treatment strategy for ultimately improving patient outcomes.
Ross et al. (Mon,) studied this question.
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