Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer and there are significant unmet therapeutic needs in the management of this malignancy. PDAC accounts for 3% of all new cancers and is the 4th leading cause of cancer-related death in men and women in the United States (US) [1]. A future projection suggests that if the mortality rate of PDAC continues in the current direction, it will be the second leading cause of cancer-related death in the US by 2030.[2] At the current time, key therapies for metastatic PDAC are cytotoxic-based approaches, including FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin)[3] and gemcitabine and nab-paclitaxel [4], and both regimens improve survival compared to single-agent gemcitabine; however median survivals remain less than a year.[3]
With progress in the understanding of the molecular underpinnings of cancer biology and development, targeted therapies and immunotherapy have led to dramatic improvements in survival outcomes of selected solid tumors.[5] However, unfortunately, these approaches including immunotherapy have achieved limited success in the management of PDAC due in part to its distinct molecular behavior.[6, 7] For example, immune checkpoint inhibitors have been shown to be effective in patients with mismatch repair deficient (MMR-D) PDAC[8], which accounts for about one percent of PDAC cases.[9, 10] Recently, a phase III trial of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, reported improvement in progression-free survival (PFS) in BRCA-mutant metastatic PDAC patients when administered as maintenance therapy following platinum-based treatment, compared to placebo.[11] Notably, BRCA gene mutations are also relatively uncommon and seen in about ~ 5–7% of unselected PDAC patients [12–14] making PARP inhibitors, a promising therapeutic strategy, applicable to a minority of patients with metastatic PDAC.
The PDAC microenvironment, which is a focus of interest for the development of therapeutic agents, carries very sophisticated biologic features.[15] Stromal desmoplasia is a complex connective tissue reaction leading to dense stroma and hypoxic tumor microenvironment. Clinical and preclinical studies have suggested that desmoplasia in the PDAC microenvironment is driven mainly by the sonic hedgehog pathway (SHH)[16] which led to a series of clinical trials targeting this pathway. Unfortunately, studies of SHH inhibitors have not shown benefit and notably, one of the SHH inhibitors led to detrimental outcomes in PDAC patients.[17, 18] These disappointing findings have resulted in significant loss of interest in SHH inhibitors and most recently, other stroma modifying agents including PEGPH20, a pegylated version of hyaluronidase, was investigated in metastatic PDAC patients. The combination of this agent with FOLFIRINOX and gemcitabine nab-paclitaxel chemotherapies did not result in any survival benefit and led to detrimental outcomes in patients who received PEGPH20 with concurrent FOLFIRINOX, [19–21].
Pancreatic cancer stem cells (PCSC) are enriched with SHH signaling which is one of the signaling pathways that induces of desmoplastic reaction in PDAC. Notably, a preclinical study identified a 46-fold increase in SHH signaling in PCSC as compared to normal pancreatic epithelial cells.[22] However, the dual interaction between tumor stroma and PCSC has not been well-investigated and it is unclear if PCSC may have a role in defining the composition of tumor stroma and disease behavior. In this study, we investigated the relationship between the PDAC stem cells and tumor stroma and evaluated the site of first recurrence pattern by stroma characteristics in PDAC patients who underwent surgical resection. We also examined the potential impact of stroma type and PCSC on survival outcomes in our cohort.