JAK Inhibitors Used as Anti-inflammatory Therapeutics for Pancreatic Cancer

Ignacio Garrido-Laguna, MD, PhD
Published: Sunday, Aug 23, 2015
The portfolio of drugs targeting inflammation is increasing rapidly and, therefore, various opportunities to develop combinations of targeted anti-inflammatory drugs are now available (Table 2). Early clinical trials with targeted therapy have recently shown that horizontal inhibition of different pathways is unlikely to be successful due to increased toxicity, which limits achieving optimal biological doses.50,51 In contrast to this, vertical inhibition of different signal transducers in a single pathway have proven successful.52,53 Vertical inhibition of the JAK/Stat pathway needs to be tested in preclinical models. This can include a combination of monoclonal antibodies against IL-6 or its receptor plus Jak inhibitors (Table 2). In addition, monoclonal antibodies against colony stimulating factor 1 receptor (CSF1R) are undergoing clinical evaluation and offer additional opportunities to test vertical inhibition of the Jak pathway. Some cytotoxic agents (5-FU) inhibit MDSC and are currently being tested in combination with JAK inhibitors. Monoclonal antibodies against CXCR4 inhibit recruitment of immature myeloid cells to the tumor and could also be tested in preclinical models in combination with JAK inhibitors.

Table 2. Potential Partners for Preclinical Testing of Vertical Inhibition in Combination With Jak Inhibitors

mAb indicates monoclonal antibody

Lastly, novel strategies including testing drugs in patients at earlier stages of disease also need to be evaluated. In this regard, a recent phase 1b dose escalation study showed that testing immunotherapies in the neoadjuvant setting is feasible and safe.54 In this trial, patients were treated with FOLFIRINOX in combination with PF- 04136309 (a monoclonal antibody against CCR2, which depletes tumor-associated macrophages [TAM]). The high response rate (52%) was encouraging.

In conclusion, several lines of evidence support a role for inflammation in oncogenesis in PDA. This inflammatory response seems to be driven by JAK/STAT pathway. Jak inhibitors hold promise in a subset of PDA patients with elevated CRP. Additional preclinical work is needed to test whether vertical inhibition of the pathway will be an effective strategy.

About the Author

Author affiliation: Departments of Internal Medicine (Division of Oncology) and Center for Investigational Therapeutics, Huntsman Cancer Institute, University of Utah, Salt Lake City.

Corresponding author: Ignacio Garrido-Laguna, MD, PhD, Assistant Professor, GI Oncology/Phase 1 Program, Department of Internal Medicine, Oncology Division, University of Utah School of Medicine, Huntsman Cancer Institute, 2000 Circle of Hope, Suite 2100, Salt Lake City, UT 84112, Phone: 801-585-0255, Fax: 801-585-0124. E-mail: ignacio.garrido-laguna@hci.utah.edu.


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