Abstract
Simple SummaryPancreatic cancer remains one of the most challenging malignancies to treat with standard approaches. Emerging treatment approaches incorporating innovative surgical techniques and novel systemic therapies may help to improve outcomes for pancreas cancer patients. Although immunotherapy has proven to be less effective for the treatment of pancreas cancer relative to more immunogenic tumor types, multiple immune system stimulating agents are under active investigation for pancreatic ductal adenocarcinoma, either alone or in combination with other therapeutic agents. The tumor microenvironment of pancreatic cancer is also an attractive therapeutic target given that it is believed to be highly immunosuppressive and encapsulated by a dense stroma. This review article aims to summarize pre-clinical and clinical studies, including ongoing clinical trials, which attempt to incorporate novel treatment approaches for pancreas cancer. Emerging treatment approaches may help to significantly improve outcomes for this tough to treat disease.Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest malignancies among all cancers. Despite curative intent, surgery and the use of standard cytotoxic chemotherapy and radiation therapy, PDAC remains treatment-resistant. In recent years, more contemporary treatment modalities such as immunotherapy via checkpoint inhibition have shown some promise in many other malignancies, yet PDAC still eludes an effective curative treatment. In investigating these phenomena, research has suggested that the significant desmoplastic and adaptive tumor microenvironment (TME) of PDAC promote the proliferation of immunosuppressive cells and act as major obstacles to treatment efficacy. In this review, we explore challenges associated with the treatment of PDAC, including its unique immunosuppressive TME. This review examines the role of surgery in PDAC, recent advances in surgical approaches and surgical optimization. We further focus on advances in immunotherapeutic approaches, including checkpoint inhibition, CD40 agonists, and discuss promising immune-based future strategies, such as therapeutic neoantigen cancer vaccines as means of overcoming the resistance mechanisms which underly the dense stroma and immune milieu of PDAC. We also explore unique signaling, TME and stromal targeting via novel small molecule inhibitors, which target KRAS, FAK, CCR2/CCR5, CXCR4, PARP and cancer-associated fibroblasts. This review also explores the most promising strategy for advancement in treatment of pancreatic cancer by reviewing contemporary combinatorial approaches in efforts to overcome the treatment refractory nature of PDAC.
Highlights
Pancreatic ductal adenocarcinoma, Pancreatic Ductal Adenocarcinoma (PDAC), which accounts for greater than 90% of pancreatic tumors, remains a dreadful disease characterized by poor prognosis
Current standard of care treatments including surgery, chemotherapy and radiation therapy remain incompletely effective treatment strategies as PDAC has proven to be highly resistant to these modalities whereas surgical resection has the potential of offering a curative treatment in early stages, nearly 80% of those who undergo surgery have disease recurrence, and PDAC typically presents in late stages as symptoms are non-specific
Traditional forms of therapy including chemotherapy, radiation therapy and surgery though commonly employed in a multimodal fashion still have significant limitations in therapeutic potential for pancreas cancer
Summary
Pancreatic ductal adenocarcinoma, PDAC, which accounts for greater than 90% of pancreatic tumors, remains a dreadful disease characterized by poor prognosis. Advances in the field of immunotherapy and targeted therapies have led to a shift in treatment paradigms for cancer care. Communication between cells, such as carcinoma associated fibroblasts or immunosuppressive myeloid cells or regulatory T cells of the TME possess the capacity to effectively silence immune response, contributing further to treatment resistance. Research into these cell types in the TME of PDAC have shed light on the failures of current treatment approaches in PDAC. Appropriate exploitation of these pathways or other well-known pancreas cancer potential molecular targets like KRAS, via a combinatorial, the TME can be leveraged to convert a tumor from ‘non-immunogenic’
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