High Endothelial Venules and Pancreatic Ductal Adenocarcinoma: A potential game changer

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal disease anti-CTLA-4, anti-PD-1, Chimeric antigen receptor T cells (CAR-T) and with its annual incidence rate almost mirroring its mortality rate [1]. There were 55,440 new cases of PDAC and 44,330 deaths in the United States last year alone and it continues to be a growing problem worldwide [1]. Majority (N80%) of patients will present with unresectable disease and for those with metastases on diagnosis, the 5-year survival is a dismal 5% or less [2,3]. Even in patients with early or resectable disease, the surgery is plagued by complexity, complications and significant recurrence rate, even in high-volume expert centers [3,4]. Despite some advances in the understanding of the molecular and genetic basis of pancreatic cancer, the results and prognosis remains much to be desired. Nonetheless, exciting new therapeutics are in development and there is light for better outcomes in the future [2]. Our understanding of PDAC s biology has evolved, notably in various fields such as tumor microenvironment (TME), cancer immunology and genetics. One of the hurdles and central to the failures of cytotoxic-based regimens such as gemcitabine and FOLFIRINOX (folinic acid, 5-FU, irinotecan and oxaliplatin) is the notorious dense stroma composing a significant portion of the tumor and an intense desmoplastic reaction, serving as a barrier impairing drug delivery and supporting an immunosuppressive TME. [2]. It is clear that new strategies are necessary and some strides have been made in different aspects. Stromal modifying therapy using enzymes such as recombinant pegylated hyaluronidase enzyme to target tumor stromal hyaluronan have shown early promise in Phase I and II studies [2]. Another emerging method to tackle the immmuosuppressive TME is by targeting and/or inhibiting various chemokines. Targeted therapy has shown little efficacy in PDAC beyond erlotinib and gemcitabine. Most targeted therapy has been directed at the RAS pathway and/or platelet/epidermal-derived growth factor receptors (PDGFR/EGFR). Other downstream effectors such as MEK, ERK and ERK, various cell-cycle checkpoint inhibitors and novel kinase receptors are currently being studied as targets for inhibition as well. Other pronged approaches includes immunotherapy strategies such as