Abstract
Circulating tumor cells (CTCs) are cells shed from solid tumors into circulation and have been shown to be prognostic in the setting of metastatic disease. These cells are obtained through a routine blood draw and may serve as an easily accessible marker for monitoring treatment effectiveness. Because of the rapid progression of pancreatic ductal adenocarcinoma (PDAC), early insight into treatment effectiveness may allow for necessary and timely changes in treatment regimens. The objective of this study was to evaluate CTC burden as a biomarker of response to treatment with a oral phosphatidylinositol-3-kinase inhibitor, BKM120, in patient-derived xenograft (PDX) mouse models of PDAC. PDX mice were randomized to receive vehicle or BKM120 treatment for 28 days and CTCs were enumerated from whole blood before and after treatment using a microfluidic chip that selected for EpCAM (epithelial cell adhesion molecule) positive cells. This microfluidic device allowed for the release of captured CTCs and enumeration of these cells via their electrical impedance signatures. Median CTC counts significantly decreased in the BKM120 group from pre- to post-treatment (26.61 to 2.21 CTCs/250 µL, p = 0.0207) while no significant change was observed in the vehicle group (23.26 to 11.89 CTCs/250 µL, p = 0.8081). This reduction in CTC burden in the treatment group correlated with tumor growth inhibition indicating CTC burden is a promising biomarker of response to treatment in preclinical models. Mutant enriched sequencing of isolated CTCs confirmed that they harbored KRAS G12V mutations, identical to the matched tumors. In the long-term, PDX mice are a useful preclinical model for furthering our understanding of CTCs. Clinically, mutational analysis of CTCs and serial monitoring of CTC burden may be used as a minimally invasive approach to predict and monitor treatment response to guide therapeutic regimens.
Highlights
Tumor cells that are present in peripheral circulation, or circulating tumor cells (CTCs), have been isolated from blood samples of patient’s with many solid cancers
While much work has been done to prove the prognostic value of CTC levels in breast, colorectal, prostate and lung cancers, little progress has been made in this area for pancreatic cancer due to the poor sensitivity of many CTC assays for patients with pancreatic ductal adenocarcinoma (PDAC) [1,2,3,4,5]
The highly sensitive microfluidic chip used in this study was capable of detecting and enumerating CTCs from only 250 mL of PDAC patient-derived xenograft (PDX) mouse blood
Summary
Tumor cells that are present in peripheral circulation, or circulating tumor cells (CTCs), have been isolated from blood samples of patient’s with many solid cancers These cells are an attractive target for staging and monitoring treatment effectiveness because they are obtained noninvasively through a routine blood draw and can be measured serially throughout the course of treatment. Promising therapies focus on targeting downstream effectors of Ras such as the Raf-MEK-ERK mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathways [10]. PI3K is an attractive therapuetic target as it is one of the main Ras effector signaling pathways, is involved in tumor growth and maintenance, and has been reported to be mutated in pancreatic cancers [11], [12], [13]. In vitro studies of various cancer cell lines have shown that BKM120 decreases phosporylated-Akt (p-Akt) levels, inhibits signaling pathways downstream of PI3K and p-Akt, and induces apoptosis [17]
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