Chemoradiation induces epithelial-to-mesenchymal transition in esophageal adenocarcinoma.

Multimodality treatment has advanced the outcome of esophageal adenocarcinoma (EAC), but overall survival remains poor. Therapeutic pressure activates effective resistance mechanisms and we characterized these mechanisms in response to the currently used neoadjuvant treatment against EAC: carboplatin, paclitaxel and radiotherapy. We developed an in vitro approximation of this regimen and applied it to primary patient-derived cultures. We observed a heterogeneous epithelial-to-mesenchymal (EMT) response to the high therapeutic pressure exerted by chemoradiation. We found EMT to be initiated by the autocrine production and response to transforming growth factor beta (TGF-ß) of EAC cells. Inhibition of TGF-ß ligands effectively abolished chemoradiation-induced EMT. Assessment of TGF-ß serum levels in EAC patients revealed that high levels after neoadjuvant treatment predicted the presence of fluorodeoxyglucose uptake in lymph nodes on the post-chemoradiation positron emission tomography-scan. Our study shows that chemoradiation contributes to resistant metastatic disease in EAC patients by inducing EMT via autocrine TGF-ß production. Monitoring TGF-ß serum levels during treatment could identify those patients at risk of developing metastatic disease, and who would likely benefit from TGF-ß targeting therapy.

Amide chemical exchange saturation transfer at 7 T: a possible biomarker for detecting early response to neoadjuvant chemotherapy in breast cancer patients.

BACKGROUND: The purpose of this work was to investigate noninvasive early detection of treatment response of breast cancer patients to neoadjuvant chemotherapy (NAC) using chemical exchange saturation transfer (CEST) measurements sensitive to amide proton transfer (APT) at 7 T. METHODS: CEST images were acquired in 10 tumors of nine breast cancer patients treated with NAC. APT signals in the tumor, before and after the first cycle of NAC, were quantified using a three-pool Lorentzian fit of the z-spectra in the region of interest. The changes in APT were subsequently related to pathological response after surgery defined by the Miller-Payne system. RESULTS: Significant differences (P <  0.05, unpaired Mann-Whitney test) were found in the APT signal before and after the first cycle of NAC in six out of 10 lesions, of which two showed a pathological complete response. Of the remaining four lesions, one showed a pathological complete response. No significant difference in changes of APT signal were found between the different pathological responses to NAC treatment (P > 0.05, Kruskal-Wallis test). CONCLUSIONS: This preliminary study shows the feasibility of using APT CEST magnetic resonance imaging as a noninvasive biomarker to assess the effect of NAC in an early stage of NAC treatment of breast cancer patients. TRIAL REGISTRATION: Registration number, NL49333.041.14/ NTR4980 . Registered on 16 October 2014.

Taxanes: old drugs, new oral formulations.

Oral administration of anticancer drugs is most often preferred over intravenous administration, as it is convenient for patients, prevents hospitalisation and reduces costs of the therapy. However, the oral route is often hampered by low oral bioavailability, for instance of the taxanes paclitaxel and docetaxel. Limited oral bioavailability can be due to pharmaceutical as well as pharmacological reasons. Taxanes are poorly water-soluble drugs and do not sufficiently dissolve when administered in their crystalline form. Furthermore, affinity for drug transporters highly expressed in the epithelial layer of the gastro-intestinal tract, such as the drug efflux pump P-glycoprotein (P-gp, ABCB1), and presystemic elimination by the cytochrome P450 (CYP) metabolic enzymes, especially CYP3A4, present in liver and gut wall, further hamper oral application of these important anticancer drugs. Preclinical studies with knockout mice lacking functional Pgp and CYP3A4 metabolic enzymes show a significant increase in the bioavailability of orally applied taxanes. Enhancement of oral bioavailability of both taxanes was shown also in wild-type mice using P-gp and CYP3A4 blockers such as cyclosporine A (CsA) and ritonavir (RTV). Subsequently, in clinical studies enhancement of the oral bioavailability of paclitaxel and docetaxel was established when administered orally in combination with CsA or ritonavir. Initially, in preclinical and clinical studies drinking solutions based on the intravenous formulations were applied for oral administration of taxanes. Because these solutions had several disadvantages, solid pharmaceutical formulations of paclitaxel and docetaxel were developed. Clinical studies with these novel formulations in combination with ritonavir are currently ongoing at our Institute.