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Research

Summary

With our research in Interventional Oncology, we aspire to improve the detection, characterization, and treatment of neoplastic disease in the liver. This includes the full breadth of translational research in:



Basic Science:

The goal of our basic research team is to develop effective therapeutic strategies against cancer. Cancer cells have long been known to exhibit altered energy metabolism. This metabolic phenotype includes a dependence on glycolysis (cytoplasmic) rather than oxidative phosphorylation (mitochondrial respiration) for the production of intracellular energy (e.g. ATP). The biological significance of this altered metabolic phenotype is underscored by its recent classification as one of the hallmarks of cancer.


Since the advent of interventional oncology, a radiological discipline which uses image-guided procedures to deliver anti-cancer agents directly to the tumor, the search for new and effective agents for the treatment of cancer has been an organizing principle of research in this field. In an effort to combine minimally-invasive, image-guided approaches to target tumor metabolism, our team has demonstrated the efficacy of the first anti-glycolytic agent 3-Bromopyruvate (3-BrPA) in several animal models.

Translational Pre-clinical Research:

One of the highlights of our research work has been the awarding of an NIH RO1 grant in 2016 to our lab to improve liver cancer treatment. This 5-year project bridges basic, translational and clinical research aspects and will eventually result in an improved assessment of the tumor microenvironment with the ultimate goal of a better TACE procedure. As such, changes in the tumor energy metabolism are reflected in the pH of the tumor and its microenvironment; even slight deviations are believed to be early warnings signs of a premalignant state. Biosensor imaging of redundant deviation in shifts (BIRDS) is a highly innovative and unique imaging technique in magnetic resonance imaging (MRI) that can detect changes in temperature, pH, and metabolites. As part of both the NIH RO1 grant as well as our academic-industrial partnership with Boston Scientific, we are examining the change in pH variances in tumor microenvironment by applying BIRDS imaging and other molecular imaging methodologies to liver cancer.

Clinical Research:

Our clinical research focuses on improving intra and post-procedural imaging for intra-arterial therapies such as transarterial chemoembolization (TACE) and Yttrium (Y) 90 radioembolization (Y90). This happens in close partnership with Philips Research North America within the framework of an academic-industry partnership. One of the highlights is the awarding of an NIH RO1 grant to more optimally treat liver cancer. The goals of this partnership are to see, reach, and treat the tumor by 1) removing the subjectivity in catheter placement, 2) optimizing the drug delivery protocol, and 3) quantifying treatment success. The main tool that we use to realize these goals is the x-ray C-arm cone-beam CT (CBCT), to which based on our findings and development, helped with the adoption of CBCT into routine clinical workflow as standard of practice.


We have been greatly expanding the limited role CBCT currently plays in the TACE procedure. The methods have been developed and validated in pre-clinical and clinical environments and the results translated to commercial products. Specifically, we can provide intra-procedural assessment of tumor characteristics such as blood supply and localization, provide improved catheter navigation guidance through the use of image fusion and registration techniques, and most importantly, provide direct, immediate and quantitative feedback of embolization and drug delivery success. The activities include developing new 3D quantitative, modality-independent approaches (quantitative European Association of the Study of the Liver [qEASL]) for tumor response assessment, which will potentially replace out-dated techniques (i.e. Response Evaluation Criteria in Solid Tumors).

Machine Learning

 

Given the increasing amount of data gathered and processed with electronic health records, the field of interventional oncology must utilize this resource to create the next generation of medical technologies applied to cancer treatment. Our lab aims to be at the forefront of this movement, using machine learning to combine imaging and clinical parameters to create powerful predictive algorithms that can be applied to the diagnosis and treatment of liver cancer. Machine learning models use algorithms that self-improve by learning from patterns in large datasets. Current projects in our lab include the application of machine learning techniques to accurately diagnose primary hepatic liver cancers. Through our partnership with Philips Research North America, we are also developing a platform to process and visualize large volumes of data, advancing the research process of training and testing machine learning algorithms.

The following experimental calculator implements a machine-learning based algorithm for the prediction of tumor response after transarterial chemoembolization of patients with primary liver cancer based on the most predictive clinical and imaging parameters assessed before therapy (as published by Abajian A et al, JVIR February 2018). Follow the link to test the calculator with your own data: TACE response prediction

Clinical Trials:

The main mission of our Clinical Trials Program is to provide new image-guided loco-regional therapies to treat patients with primary and secondary liver cancer. Our goal is to offer a number of new therapeutic options to our patients with liver cancer, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and liver metastases from various sources (colorectal, neuroendocrine, sarcoma, breast, and others). We aim to develop a practice of care that tailors treatment for each patient and maximizes treatment options throughout the disease management process.


Our clinical studies range from collaborative, multicenter, federally (NCI) and industry-sponsored studies to independent, single site, physician-sponsored studies. Some of these studies are closely supervised by the FDA (IDE or IND).


Over the last decade, we have reported on the feasibility, safety, and efficacy of radioembolization (delivery of high doses of radiation to liver tumors), drug eluting bead chemoembolization (DEB-TACE) using beads designed to maximize drug concentrations, concurrent DEB-TACE with sorafenib (an agent given systemically with strong anti-angiogenic properties), and concurrent conventional chemoembolization (TACE) and bevacizumab (an anti-angiogenic biologic). These treatments were tested in both primary and secondary liver cancer, and the resulting studies have been published in various journals, including Journal of Clinical Oncology (JCO), Cancer, CVIR, JVIR and Radiology.

https://www.yalecancercenter.org/patient/trials/
  1. Doxorubicin-eluting LC Bead M1 (DEBDOX) for patients with hepatocellular carcinoma – HIC# 1507016214
  2. Irinotecan Drug-Eluting Bead (DEBIRI) Therapy for Patients with Liver Metastases from Colorectal Cancer – HIC# 1507016214
  3. Lipiodol as an imaging biomarker of tumor necrosis after transcatheter chemoembolization therapy in patients with primary and metastatic liver cancer – HIC# 1601017054
  4. Pharmacokinetics of doxorubicin in cTACE of primary and secondary liver cancer – HIC# 1506016008
  5. A Phase II Trial of Systemic Chemotherapy (Gemcitabine and Cisplatin) in Combination with Conventional Transarterial Chemoembolization (cTACE) in Patients with Advanced Intra-Hepatic Cholangiocarcinoma (ICC)