10P - In vivo evaluation of combertestatin A-4 phosphate for lung cancer by bioluminescence imaging and multispectral optoacoustic tomography

Date 07 May 2017
Event ELCC 2017
Session Poster Display Session
Topics Lung and other Thoracic Tumours
Pathology/Molecular Biology
Presenter Li Liu
Citation Annals of Oncology (2017) 28 (suppl_2): ii1-ii5. 10.1093/annonc/mdx090
Authors L. Liu1, S. Kumari1, J. Campbell1, R.P. Mason1, L. Zhang2
  • 1Radiology, University of Texas Southwestern Medical Center at Dallas, 75390 - Dallas/US
  • 2Biology, University of Texas at Dallas, 75080 - Richardson/US

Abstract

Background

Vascular disrupting agents (VDA) promise significant therapeutic efficacy against solid tumors by selectively destroying tumor vasculature. Combretestatin A-4 phosphate (CA4P) is a well-characterized VDA that inhibits microtubule polymerization by binding to the colchicine-binding site of beta-tubulin [1,2]. This disruption causes a decrease in blood flow, leading to ischemia and cell death. Photoacoustic tomography (PAT) is a non-invasive technique which allows for high-resolution (∼100μm) spectral imaging. The iThera Multispectral Optoacoustic Tomography inVision 256-TF (MSOT) system allows for high throughput, in vivo imaging of small animals. The MSOT has access to a range of frequencies (680-980nm) with 1nm resolution and so is able to differentiate between numerous different contrasts agents simultaneously.

Methods

Female and male nude mice (each group n = 6) were implanted with 2x106 H1299 lung cancer cells subcutaneously. Ten days after implantation, the mice image were acquired in transaxial sections through the tumor region using nine wavelengths ranging from 700-880 nm by MSOT device and bioluminescence images (BLI) were taken by IVIS Spectrum at different time points. Images were reconstructed and processed using manufacturer’s software. Percentage of hemoglobin saturation (%SO2) was calculated as %SO2 = [HbO2/(HbO2+Hb)]*100.

Results

VDA caused significant perfusion reduction and hypoxiation at 1 and 3 hours post VDA and mostly recovered at 24 hours. The %SO2 of tumor peripheral vessels was decreased from 42.5% at baseline to 33% and 28% at 1 and 3 hours respectively. The %SO2 of the tumor core reduced from 43% at baseline to 27% and 12% at 1 and 3 hours respectively. There was no change in %SO2 of normal tissue (spine). Similarly, BLI signal was reduced by > 90% within 3 hours after administration of CA4P indicating vascular disruption which was confirmed by histology.

Conclusions

We demonstrated the feasibility of MSOT to detect changes in oxyhemoglobin and deoxyhemoglobin based on their unique absorption spectra in order to further elucidate the mechanism of action. CA4P caused significant reduction of perfusion and oxygenation within the tumor. The results indicate strong rationale for further development, particularly in combination with additional therapies.

Clinical trial identification

Legal entity responsible for the study

Li Liu

Funding

CPRIT RP160617

Disclosure

All authors have declared no conflicts of interest.