JAK Inhibitors Used as Anti-inflammatory Therapeutics for Pancreatic Cancer

Ignacio Garrido-Laguna, MD, PhD
Published: Sunday, Aug 23, 2015
Abstract

Pancreatic cancer will be second only to lung cancer as the most common cause of death from cancer in US by 2030. Most patients are diagnosed with unresectable disease. In this setting, novel combinations of cytotoxics such as FOLFIRINOX and nab-paclitaxel plus gemcitabine have led to modest improvements in survival. At the time of disease progression, less than 50% of the patients will be fit to receive second-line therapy. Patients with advanced pancreatic cancer often develop debilitating cachexia. It is hypothesized that the disease induces a systemic inflammatory response following cytokine production mediated by cancer cells or stromal cells. Plasma levels of biomarkers associated with inflammation, such as C-reactive protein, have also been associated with poor outcomes in patients with advanced pancreatic cancer. The Jak/Stat pathway plays a key role in driving this inflammatory response. Janus kinases are the main signaling transducers for cytokine receptors. Activated Jak recruits and activates transcription factors (Stat) and different signaling pathways including Src, Ras, and the PI3K/Akt pathway. Jak inhibitors may inhibit cancer cell proliferation by disrupting these signaling pathways. Jak inhibitors may also impair the systemic inflammatory response underlying the development of cachexia. A randomized phase 2 trial recently failed to show a benefit in survival when ruxolitinib, a Jak2 inhibitor, was added to capecitabine in the second line. However, in a prespecified subset analysis, a modest improvement in survival was seen in patients with elevated C-reactive protein at baseline. Two randomized phase 3 trials are currently testing ruxolitinib in combination with capecitabine in patients with advanced pancreatic cancer. Patients must have elevated C-reactive protein at baseline to be eligible to participate in this study. In addition, a number of immune modulators are under development or have gained regulatory approval for different indications. This work will review ongoing clinical research with Jak inhibitors in advanced pancreatic cancer as well as some strategies for preclinical testing of vertical inhibition of the Jak pathway.


Introduction

Pancreatic ductal adenocarcinoma (PDA) is the fourth most common cause of death from cancer in the United States. It is projected that by 2030 it will be second only to NSCLC as the leading cause of cancer related mortality in US.1 In 2015, 48,960 new cases will be diagnosed in the United States, and 40,560 patients will succumb to the disease.2 The overall 5-year survival rate is less than 5%.3 Therefore, novel treatments are urgently needed in this disease. Recent data from a randomized phase 2 trial showed that a subset of patients with PDA may benefit from targeting the Janus kinase pathway.4 Janus kinases (Jak) are the main signaling transducers for cytokine receptors. Cytokines regulate immune response and inflammation. They also play a role in oncogenesis.5 Four different non-receptor tyrosine Jaks (Jak1, Jak2, Jak3 and Tyk2) have been identified.6 Jak family members contain seven conserved JAK homology (JH) domains. JH1 and JH2 are composed of almost identical phosphate transferring domains, a kinase and pseudokinase domain. The JH2, or pseudokinase domain, is catalytically active and can phosphorylate the kinase domain (JH1).7 JH3-7 are characterized by N-terminal regions or sites of interaction with cytokine receptors. Tyk2 was the first member of the JAK family to be isolated.8 Inactivation of Tyk2 in mice decreased response to interferon-alpha/beta (IFNÉ‘/β), IL-12 and led to defective Stat3 activation.9 Homozygous Tyk2 mutations cause autosomal recessive hyper-IgE syndrome, a rare primary immunodeficiency disorder characterized by repeated staphylococcal skin infections, respiratory infections, and elevated levels of IgE.10 Jak1 is a signal transducer for IFNÉ‘/β, IFN-γ, IL-2, IL-4, IL-6, IL-7, IL-9, IL-15, and IL-21. Mice that have a Jak1 deficiency die perinatally.11 Jak2 is critical for signaling by IFNÉ‘/β, IL-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), and growth hormone (GH). Its kinase activity, rather than its non-kinase status, is essential for mammalian development.12 The critical role of Jak2 in hematopoiesis was initially elucidated in Jak2-deficient mice models more than 20 years ago.13,14 In those models, Jak2-deficient embryos were characterized by an absence of red blood cells in the liver indicating impairment of liver hematopoiesis.


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Online CME Activities
TitleExpiration DateCME Credits
Oncology Briefings™: Integrating Novel Targeted Treatment Strategies to Advance Pancreatic Cancer CareNov 30, 20181.0
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