Image-Guided, Ultrasound-Mediated Drug Delivery for Hepatocellular Carcinoma Treatment
Abstract
The proposed work addresses treatment of liver cancer, which is a critical problem for the general and Department of Veterans Affairs (VA) populations. Liver cancer is identified as a military-relevant risk factor and is recognized by the VA as related to hepatitis C virus (HCV) infection and ionizing radiation exposure during military service. Liver cancer is the third leading cause of cancer-related deaths worldwide with an estimated 750,000 new cases per year. Due to the advanced stage of disease at the time of diagnosis and the presence of underlying cirrhosis, transarterial chemoembolization (TACE) and systemic chemotherapy are the only treatment options for the majority of patients. Current systemic chemotherapies and TACE prolong median survival and time to progression by only a few months in patients with hepatocellular carcinoma (HCC). The poor results in treating HCC and with systemic or transarterial chemotherapy can be improved by combining strategies that enhance drug delivery to these aggressive and resistant tumors. We propose to use a technique called sonoporation in order to improve drug delivery and hence patient outcomes for liver cancer. In sonoporation, microbubbles similar in size to red blood cells, are injected intravenously and exposed to ultrasound so that they oscillate in ways that may help push drugs outside tumor vessels and towards cancer cells. Sonoporation, as the name suggests, may create pores in cancer cells so that drug molecules such as those of chemotherapy can enter the cells. In the present project, we will implement this technique in a diagnostic ultrasound scanner and perform all necessary animal experiments for drug efficacy and safety in order to lead this technique to clinical translation. We will evaluate (a) the effect of sonoporation on improving drug delivery to the tumor in mice with tumors very similar to human liver cancer and (b) the safety of this method in large animals (pigs) while examining both drug delivery improvement, safety, and tolerance. These are the necessary steps before trying this technique clinically in humans. At the completion of this project (in 2 years), we will be ready to proceed with a clinical trial of sonoporation for liver cancer patients that are undergoing chemotherapy. If successful, this technique may be used for enhancing locally chemotherapy for other cancer types. Our approach of using a diagnostic ultrasound machine to combine therapy and imaging will be tried in this work for the first time ever. Treatment of liver cancer is of great importance in the Department of Defense and VA populations where the condition has reached epidemic proportions. HCC is one of the fastest rising cancers in the VA. Liver cancer incidence increased by 2.5-fold and HCC mortality 3-fold from 2001 to 2013 in the VA nationally and is expected to continue to increase until at least 2020. Radiation and Agent Orange that may be associated with military deployments have also been identified as risk factors for HCC. Use of sonoporation clinically will lead to improved drug efficacy, reduced drug toxicity (by virtue of using lower drug doses), and improved patient outcomes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710188
Entities
People
- Michalakis Averkiou
Organizations
- United States Army
- University of Washington