Current Limitations and Novel Perspectives in Pancreatic Cancer Treatment

SIMPLE SUMMARY: This review article presents a synopsis of the key clinical developments, their limitations, and future perspectives in the treatment of pancreatic cancer. In the first part, we summarize the available treatments for pancreatic cancer patients according to tumor stage, as well as the most relevant clinical trials over the past two decades. Despite this progress, there is still much to be improved in terms of patient survival. Therefore, in the second part, we consider various components of the tumor microenvironment in pancreatic cancer, looking for the key drivers of therapy resistance and tumor progression, which may lead to the discovery of new potential targets. We also discuss the most prominent molecules targeting the stroma and immune compartment that are being investigated in either preclinical or clinical trials. Finally, we also outline interesting venues for further research, such as possible combinations of therapies that may have the potential for clinical application. ABSTRACT: Pancreatic cancer is one of the deadliest cancers worldwide, largely due to its aggressive development. Consequently, treatment options are often palliative, as only one-fifth of patients present with potentially curable tumors. The only available treatment with curative intent is surgery followed by adjuvant chemotherapy. However, even for patients that are eligible for surgery, the 5-year OS remains below 10%. Hence, there is an urgent need to find new therapeutic regimens. In the first part of this review, we discuss the tumor staging method and its impact on the corresponding current standard-of-care treatments for PDAC. We also consider the key clinical trials over the last 20 years that have improved patient survival. In the second part, we provide an overview of the major components and cell types involved in PDAC, as well as their respective roles and interactions with each other. A deeper knowledge of the interactions taking place in the TME may lead to the discovery of potential new therapeutic targets. Finally, we discuss promising treatment strategies targeting specific components of the TME and potential combinations thereof. Overall, this review provides an overview of the current challenges and future perspectives in the treatment of pancreatic cancer.