In vivo imaging to monitor anti-angiogenesis and re-oxygenation on radio-sensitivity in pancreatic cancer xenografts

Ning Cao, Purdue University

Abstract

Over the past decade, little progress has been made to improve the extremely low survival rates observed in patients diagnosed with pancreatic cancer (overall 5-year survival rate is less than 5%). Late diagnosis, aggressive invasion, early and extensive metastasis, and chemo-radiotherapy resistance are the major characteristics of pancreatic cancer leading to poor patient survival. Treatment failure occurs due to an inability to control the spread of this highly aggressive cancer and an acquired resistance to therapy, which results in a high recurrence rate. Given that tumor hypoxia and angiogenesis are two strong prognostic factors associated with poor treatment outcome, targeting these two factors can greatly enhance therapeutic efficacy and extend overall survival rates. Two novel methods were developed to sensitize pancreatic tumor cells to radiotherapy: 1) Improvement of the abnormal tumor vasculature through anti-angiogenic drug (AAD) treatments (DC101, anti-VEGFR2 monoclonal antibody; Avastin, anti-VEGF monoclonal antibody); 2) Re-oxygenation of the tumor by stimulating oxygen production through the implantation of a novel medical device developed at Purdue University, the Implantable Micro Oxygen Generator, IMOG. To assess and validate changes in the oxygen microenvironment of pancreatic tumors, molecular and dynamic imaging of tumor hemodynamics using Photoacoustic Computed Tomography Spectroscopy (PCT-S) and Dynamic Contrast-Enhanced CT (DCE-CT) were used to longitudinally monitor the changes in the vascular physiology and oxygenation status after treatment with DC101 or Avastin. A temporary vascular normalization window was identified in DC101 treated tumors, during which the application of combined radiotherapy significantly reduced tumor growth rate. In vitro and in vivo tests, both invasive and noninvasive diagnostic imaging techniques, demonstrated that IMOG, upon stimulation by wireless ultrasonic power, was able to quickly and efficiently generate oxygen. Radiotherapy was applied immediately after a suitable time of IMOG stimulation, resulting in significantly better tumor local control. Thus, our imaging methods are used to evaluate the effects of AADs and IMOG, develop a suitable time window for further combined radiation therapy, and identify key prognostic factors of therapeutic efficacy in pancreatic cancer. The overall goal is to investigate new therapeutic strategies utilizing these prognostic factors for individualized radiation therapy plans in the clinic.

Degree

Ph.D.

Advisors

Ko, Purdue University.

Subject Area

Medical imaging|Oncology

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