Stroma-targeting strategies in pancreatic cancer: Past lessons, challenges and prospects

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is projected to emerge as the second leading cause of cancer-related death after 2030. Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC. To date, combination chemotherapy remains the mainstay of treatment for most PDAC patients. Compared to other cancer types, treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorter-lived. Aside from typically harboring genetic alterations that to date remain un-druggable and are drivers of treatment resistance, PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance. However, emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes. These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression. The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells, stromal fibroblasts, and immune cells. This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease. Here, we provide a concise review on lessons learned from past stroma-targeting strategies, new challenges revealed from recent preclinical and clinical studies, as well as new prospects in the treatment of PDAC.

Keywords: Cancer-associated fibroblasts; Clinical trials; Pancreatic cancer; Stroma; Treatment resistance.

Figure 1

Illustration of the complex pancreatic ductal adenocarcinoma tumor microenvironment that consists of various cell types and acellular extracellular matrix proteins and proteoglycans. Therapeutic strategies that have recently been tested or are being tested in clinical trials are highlighted in red. PDAC: Pancreatic ductal adenocarcinoma; ATRA: All trans retinoic acid; apCAF: Antigen-presenting cancer-associated fibroblasts; iCAF: Inflammatory cancer-associated fibroblasts; myCAF: Myofibroblast-like cancer-associated fibroblasts; IL: Interleukin; TGF: Transforming growth factor; TGFBR: Transforming growth factor β receptor; PEGPH20: Pegylated PH20; NF-κB: Nuclear factor-κappa β; ECM: Extracellular matrix; FAK: Focal adhesion kinase.