Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumor entities with a very poor 5‑year survival rate of less than 5 %. One of the reasons for therapeutic unresponsiveness is the highly immunosuppressive tumor microenvironment (TME) which mostly consists of dense stroma and fibrotic tissue.
We are evaluating different drugs and drug combinations in order to beneficially modulate this harsh TME and determine new effective therapy options with long term durable responses. Our study focuses on the anti-tumor effects of the receptor tyrosine kinase (RTK) inhibitor Regorafenib (Rego). Rego’s mode of action is mainly based on depleting MΦ, inhibiting tumor angiogenesis, and potentially modulating ECM components. Clear single-agent anti-tumor impact by Rego as well as synergy with a MEKi could be shown in both transplantable and autochthonous mouse models for PDAC. Especially the physiological more relevant autochthonous mouse model reflects the clinical situation quite well and indicates the suitability of the Rego + MEKi combinational therapy for the clinical treatment of PDAC patients.
Our studies will now focus on deciphering Rego’s mode of action in more detail, especially its effects on myeloid cells, angiogenesis, and ECM components. Additionally, we will determine drug exposure levels in the tumor (PK analyses) and the impact on drug delivery after TME-modulation by Rego. Furthermore, the proposed hypothesis for the Rego + MEKi combinational therapy will be consolidated with the overall aim to translate our findings into the clinic.