Abstract
Simple SummaryDespite the enormous advance in biomarker discovery, many potential biomarkers of drug activity are unable to satisfy the clinical need due to inadequate sensitivity and specificity. The nucleoside transporter hENT-1 has been studied as a potential biomarker to predict the effect of the widely used anticancer drug gemcitabine in pancreatic cancer. However, several studies showed controversial results regarding the predictive value of hENT-1, prompting new analyses with larger cohorts of patients and standardized methodologies. Improved insights on molecular mechanisms underlying hENT-1 expression and activity should also help in the identification of subsets of patients who are more likely to benefit from specific treatments and improve their clinical outcome. The establishment of such biomarker is especially valuable in pancreatic cancer, which is frequently characterized by complex disease biology and high mortality.Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.
Highlights
In the story of “Ali Baba and the Forty Thieves” from the book One Thousand and One Nights,“Open sesame” is the magical phrase that opens the mouth of a cave in which the thieves have hidden a treasure
The human equilibrative nucleoside transporter represents a quintessential example of such a transporter. This protein is the main transporter involved in the entrance of nucleoside analogs and has attracted extensive attention for its potential role as predictive biomarker for the anticancer activity of gemcitabine [3], as well as for the development of drugs bypassing this transporter in order to overcome gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) [4,5,6]
In this study the expression of hENT-1 evaluated using the 10D7G2 antibody was predictive of both prolonged disease-free survival (DFS) and overall survival (OS) in Pancreatic ductal adenocarcinoma (PDAC) patients receiving gemcitabine adjuvant chemotherapy
Summary
“Open sesame” is the magical phrase that opens the mouth of a cave in which the thieves have hidden a treasure This statement has been commonly used to define something that allows a person to do or enter something or something that unfailingly brings about a desired end. The human equilibrative nucleoside transporter (hENT-1) represents a quintessential example of such a transporter. This protein is the main transporter involved in the entrance of nucleoside analogs and has attracted extensive attention for its potential role as predictive biomarker for the anticancer activity of gemcitabine [3], as well as for the development of drugs bypassing this transporter in order to overcome gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) [4,5,6].
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