Abstract
Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States. It has a very low five-year survival rate (< 5%) in the United States as well as in the world (about 9%). The current gemcitabine-based therapy soon becomes ineffective because treatment resistance and surgical resection also provides only selective benefit. Signature mutations in pancreatic cancer confer chemoresistance by deregulating the cell cycle and promoting anti-apoptotic mechanisms. The stroma-rich tumor microenvironment impairs drug delivery and promotes tumor-specific immune escape. All these factors render the current treatment incompetent and prompt an urgent need for new, improved therapy. In this review, we have discussed the genetics of pancreatic cancer and its role in tumor evolution and treatment resistance. We have also evaluated new treatment strategies for pancreatic cancer, like targeted therapy and immunotherapy.
Highlights
Pancreatic cancer is a fatal disease that currently ranks third in the list of cancer-related deaths in the United States after lung cancer and colon cancer[1]
Overcoming gemcitabine resistance has been the focus of many conventional therapies, including adjuvant therapy, neoadjuvant therapy, targeted therapy as well as immunotherapy[124]
The patients treated with gemcitabine/nab-paclitaxel had an overall survival of 5.5 months compared to 3.7 months for the gemcitabine alone group[75], and patients treated with 5fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) survived for 6.4 months compared to 3.3 months survival of gemcitabine alone group[125]
Summary
Pancreatic cancer is a fatal disease that currently ranks third in the list of cancer-related deaths in the United States after lung cancer and colon cancer[1]. Gemcitabine was approved by FDA in 1996 on the basis that it increased survival in five-fold more patients over 5-FU (5-Fluorouracil), the previously used drug for pancreatic cancer chemotherapy[46]. The first category involves mechanisms like downregulation of CNT1 and ENT1 transporters in pancreatic cancer cells to decrease the uptake of gemcitabine[50,51]. Overexpression of cytidine deaminase (CDA) is observed in pancreatic cancer cells along with MRP-1 (multidrug resistance-associated protein) transporter responsible for causing an efflux of clinically relevant drugs[52].
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