Abstract 1958: Repotrectinib increases effectiveness of KRAS-G12C inhibitors inKRAS-G12Cmutant cancer modelsviasimultaneous SRC/FAK/JAK2 inhibition

2020 ◽  
Author(s):  
J. Jean Cui ◽  
Dayong Zhai ◽  
Wei Deng ◽  
Laura Rodon ◽  
Nathan Lee ◽  
...  
Keyword(s):  
Jak2 Inhibition

scholarly journals Therapy for myeloproliferative neoplasms: when, which agent, and how?

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 277-286 ◽  
Author(s):  
Holly L. Geyer ◽  
Ruben A. Mesa
Keyword(s):  
Quality Of Life ◽  
Disease Burden ◽  
Myeloproliferative Neoplasms ◽  
Jak Inhibitors ◽  
Symptom Profiles ◽  
Risk Of Progression ◽  
Life Threatening ◽  
Jak2 Inhibition

Abstract Myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia, and myelofibrosis (MF) (both primary and secondary), are recognized for their burdensome symptom profiles, life-threatening complications, and risk of progression to acute leukemia. Recent advancements in our ability to diagnose and prognosticate these clonal malignancies have paralleled the development of MPN-targeted therapies that have had a significant impact on disease burden and quality of life. Ruxolitinib has shown success in alleviating the symptomatic burden, reducing splenomegaly and improving quality of life in patients with MF. The role and clinical expectations of JAK2 inhibition continues to expand to a variety of investigational arenas. Clinical trials for patients with MF focus on new JAK inhibitors with potentially less myelosuppression (pacritinib) or even activity for anemia (momelotinib). Further efforts focus on combination trials (including a JAK inhibitor base) or targeting new pathways (ie, telomerase). Similarly, therapy for PV continues to evolve with phase 3 trials investigating optimal frontline therapy (hydroxyurea or IFN) and second-line therapy for hydroxyurea-refractory or intolerant PV with JAK inhibitors. In this chapter, we review the evolving data and role of JAK inhibition (alone or in combination) in the management of patients with MPNs.

scholarly journals THE JAK2V617F POINT MUTATION INCREASES THE OSTEOCLAST FORMING ABILITY OF MONOCYTES IN PATIENTS WITH CHRONIC MYELOPROLIFERATIVE NEOPLASMS AND MAKES THEIR OSTEOCLASTS MORE SUSCEPTIBLE TO JAK2 INHIBITION

2018 ◽  
Vol 10 ◽  
pp. e2018058
Author(s):  
Emmanouil Spanoudakis ◽  
Menelaos Papoutselis ◽  
Ioanna Bazntiara ◽  
Eleftheria Lamprianidou ◽  
Xrisa Kordella ◽  
...  
Keyword(s):  
Point Mutation ◽  
Genomic Dna ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Cellular Level ◽  
Hemopoietic Stem Cell ◽  
Jak2 Inhibitor ◽  
Chronic Myeloproliferative Neoplasms ◽  
Cell Niche ◽  
Jak2 Inhibition

JAK2V617F is a gain of function point mutation that occurs in Myeloproliferative Neoplasm (MPN) patients and deranges their hemopoiesis at cellular level. We speculate that hyperfunctioning JAK2 can modify osteoclast (OCL) homeostasis in MPN patients. We studied 18 newly diagnosed MPN patients and four age-matched normal donors (ND). Osteoclast forming assays started from selected monocytes also and under titrated concentrations of the JAK2 Inhibitor AG-490 (Tyrphostin). Genomic DNA was extracted from the formed osteoclasts, and the JAK2V617F/JAK2WT genomic DNA ratio was calculated. OCLs formed from monocytes derived from heterozygous (Het) for the JAK2V617F mutation MPN patients, were three times more compared to those from JAK2 wild type (WT) MPN patients (p=0,05) and from ND as well (p=0,03). The ratio of JAK2V617F/JAK2WT genomic DNA was increased in OCLs compared to the input monocyte cells showing a survival advantage of the mutated clone. In comparison to ND and JAK2 WT MPN patients, OCLs from patients JAK2V617F (Het) were more susceptible to JAK2 inhibition. These alterations in osteoclast homeostasis, attributed to mutated JAK2, can deregulate the hemopoietic stem cell niche in MPN patients.

Anti-arthritic activity of ferulic acid in complete Freund’s adjuvant (CFA)-induced arthritis in rats: JAK2 inhibition

2019 ◽  
Vol 28 (2) ◽  
pp. 463-473 ◽  
Author(s):  
Lijuan Zhu ◽  
Zhenshan Zhang ◽  
Nannan Xia ◽  
Weifeng Zhang ◽  
Yanlin Wei ◽  
...  
Keyword(s):  
Ferulic Acid ◽  
Complete Freund’S Adjuvant ◽  
Freund’S Adjuvant ◽  
Complete Freund's Adjuvant ◽  
Freund's Adjuvant ◽  
Jak2 Inhibition

scholarly journals JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial

2018 ◽  
Vol 33 (11) ◽  
pp. 1950-1959 ◽  
Author(s):  
Katherine R Tuttle ◽  
Frank C Brosius ◽  
Sharon G Adler ◽  
Matthias Kretzler ◽  
Ravindra L Mehta ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Controlled Clinical Trial ◽  
Phase 2 ◽  
Randomized Controlled Clinical Trial ◽  
Diabetic Kidney ◽  
Randomized Controlled ◽  
Jak2 Inhibition

Abstract B32: JAK2 inhibition blocks STAT3 signaling and enhances drug delivery and therapeutic response in pancreatic cancer.

2012 ◽  
Author(s):  
Nagaraj Nagathihalli ◽  
Yugandhar Beesetty ◽  
Michelle Reyzer ◽  
Chanjuan Shi ◽  
Richard Caprioli ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Pancreatic Cancer ◽  
Therapeutic Response ◽  
Stat3 Signaling ◽  
Jak2 Inhibition

scholarly journals Decrease of Store-Operated Ca2+ Entry and Increase of Na+/Ca2+ Exchange by Pharmacological JAK2 Inhibition

2016 ◽  
Vol 38 (2) ◽  
pp. 683-695 ◽  
Author(s):  
Jing Yan ◽  
Zohreh Hosseinzadeh ◽  
Bingbing Zhang ◽  
Mirjam Froeschl ◽  
Klaus Schulze-Osthoff ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Abundance ◽  
Transcript Levels ◽  
Migratory Activity ◽  
Jak2 Inhibitor ◽  
Whole Cell Patch Clamp ◽  
And Migration ◽  
The Impact ◽  
Powerful Mechanism ◽  
Jak2 Inhibition

Background/Aims: Cell proliferation and migration are regulated by cytosolic Ca2+ activity ([Ca2+]i). Mechanisms modifying [Ca2+]i include store-operated Ca2+-entry (SOCE) accomplished by the pore-forming ion channel unit Orai1 and its regulator STIM1, as well as Ca2+ extrusion by Na+/Ca2+ exchanger NCX1. Kinases participating in the orchestration of cell proliferation include the Janus activated kinase JAK2. The present study explored the impact of pharmacological JAK2 inhibition on SOCE and Na+/Ca2+ exchange. Methods: MCF-7 breast carcinoma cells were studied in the absence and presence of the JAK2 inhibitors TG101348 (250 nM - 1 µM) or of AG490 (20 - 40 µM). Transcript levels were quantified with RT-PCR, protein abundance with immunoblotting, [Ca2+]i with Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarcoendoplasmatic Ca2+-ATPase (SERCA) inhibitor thapsigargin (1 µM), and Na+/Ca2+ exchanger activity from increase of [Ca2+]i as well as Ca2+ current in whole cell patch clamp following extracellular Na+ removal. Migratory activity was determined by a wound healing assay. Results: JAK2 inhibitor TG101348 (1 µM) decreased Orai1 and STIM1 protein abundance, increased NCX1 transcript levels, decreased Ca2+ release from intracellular stores, decreased SOCE, increased Ca2+ entry as well as Ca2+-current following extracellular Na+-removal, and decreased migration. Similar effects on Ca2+ release, SOCE, and Ca2+-entry following extracellular Na+-removal were observed following treatment with AG490. Conclusion: The present observations disclose a novel powerful mechanism regulating intracellular Ca2+ release, cellular Ca2+ entry, cellular Ca2+ extrusion and cell migration.

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