Project 3: Targeting Stress-Induced MK2 as Novel Strategy in Pancreatic Cancer

Research Overview

Targeting Stress-Induced MK2 as Novel Strategy in Pancreatic Cancer

To date, combination chemotherapies remain the mainstay treatment of pancreatic cancer. FOLFIRINOX is a combination chemotherapy regimen with the best track record for treatment of pancreatic cancer that cannot be treated with surgery; however, even with the best treatment, the majority of the patients will still succumb to the disease within one to two years of diagnosis. This is largely due to the extreme resistance of pancreatic cancer cells to chemotherapeutics. Using an unbiased protein array analysis, we now made a new discovery that found that pancreas cancer cells dramatically upregulate MK2 enzyme and its partnering molecule Hsp27, when exposed to FOLFIRINOX chemotherapy. Both MK2 and Hsp27 protect pancreas cancer cells from cell death when their DNA is hit by chemotherapy. When MK2 was blocked by a new inhibitor ATI-450, pancreatic cancer cells became much more vulnerable to chemotherapy-induced death. In an aggressive cancer mouse model (KPC mice), the combination of ATI-450 plus FOLFIRINOX potently ablated the cancer, an observation that to our best knowledge, is rarely reported. Equally importantly, ATI-450 appeared to mitigate the intestinal damages incurred by chemotherapy, which is a major challenges in the clinic. Importantly ATI-450 is now already in clinical trial for patients with moderate to severe rheumatoid arthritis, has mild side effects and is overall very well tolerated. Therefore, ATI-450 not only has the potential of augmenting the efficacy of chemotherapy but also could mitigate chemotherapy-related side effects. More detailed analyses of mouse pancreatic tumors treated with ATI-450 showed that the immune cells surrounding the cancer cells are converted to the types that were more susceptible to immunotherapy, paving the way for development of an immunotherapy regimen in the future, which we will further test using human tumor samples and mouse models in this proposal.

Specific Aims: Based on our exciting preliminary data, we propose the following three Aims:

Aim 1. To conduct a phase I study to evaluate the safety and preliminary efficacy of ATI-450 in combination with FOLFIRINOX for patients with locally advanced or metastatic PDAC. We will assess the safety and tolerability of ATI-450 in combination with FOLFIRINOX, determine a recommended phase 2 dose and the preliminary efficacy of this combination in treatment-naïve patients with inoperable PDAC.

Aim 2. To conduct correlative analyses of tumor and blood samples obtained from trial participants to understand the immunological impact and resistance mechanism of ATI-450 plus FOLFIRINOX. We will collect pre- and post-treatment tumor and blood samples from enrolled patients to conduct multiple analyses.

Aim 3. To develop an effective immunotherapy regimen with ATI-450 in mouse models. We will mechanistically determine the immunomodulatory impact of MK2 inhibition on PDAC and develop a potent immunotherapeutic combination that can be tested in future clinical trials.