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“There is a single light of science, and to brighten it anywhere is to brighten it everywhere.”
The overall 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 preferential dependence on glycolysis (cytoplasmic) rather than oxidative phosphorylation (mitochondrial respiration) for the production of intracellular energy (e.g. ATP). The biological significance of such altered metabolic phenotype is underscored by its recent classification as one of the “Hallmarks of Cancer”. Although the German Scientist, Otto Warburg documented the altered metabolic characteristic of cancer cells more than 80 years ago, this mechanism has not yet been fully explored or exploited for the treatment of cancer.
Ever since the true 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 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 with targeting tumor metabolism, our group has adopted 3-Bromopyruvate (3-BrPA) as the first true anti-glycolytic agent for this purpose. Over the course of the last 10 years we have explored the mechanism of this molecule, identifying glyceraldehyde 3- phosphate dehydrogenase (GAPDH) as its main target within the cancer cell. The preferential uptake of 3-BrPA through the membranous monocarboxylate transporter (MCT), which is known to be overexpressed in cancer cells, grants 3-BrPA a level of selectivity which can then be explored for therapeutic purposes. The efficacy of 3-BrPA has been demonstrated by our group in several animal models (VX2 liver tumor model in rabbits and the athymic nude mouse models of orthotopic liver, pancreas, breast and brain cancers). Furthermore, we explored the use of 3-BrPA under real-life conditions in two clinical patients of primary liver cancer under the compassionate use protocol showing promising initial results. In 2013, the FDA has recently granted an IND (investigational new drug) approval for 3-BrPA facilitating its entry into Phase I clinical trial in 2014.
Translational research is a fast-evolving field in interventional oncology. Our group has a long-standing interest in translating cutting-edge technical innovations into clinical use. Over the last decade, we have developed an expertise and have had great success in bench to bedside translational projects. This includes testing new drugs (3-Bromopyruvate) as well as drug delivery systems (drug-eluting beads) for transarterial chemoembolization. Our main platform to develop translational research is the VX2 liver tumor rabbit model. The advent of drug-eluting beads-TACE (DEB-TACE) brought about the benefit of further minimizing systemic toxicity of the locally delivered chemotherapeutic agent. However, replacing the previously used iodized oil, Lipiodol, as a radio-opaque agent with the radio-lucent DEBs has significantly reduced intra-procedural feedback which, in return, may lead to non-targeted embolization and complications.
In a multi-institution partnership since 2010, we are working with a pharmaceutical company (BTG), Philips, and the NIH to develop imageable drug eluting beads (iDEBs). These iDEBs are similar to those that are currently used in the clinic but are fully radio-opaque and allows for intra-procedural feedback on x-ray imaging. This partnership leverages the competencies of specialized iDEB manufacturing from BTG and the NIH, x-ray imaging optimization from Philips, and experience in TACE from Johns Hopkins.
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 collaboration 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 will use to realize these goals is the x-ray C-arm cone-beam CT (CBCT).
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 for tumor response assessment, which will potentially replace out-dated techniques (i.e. Response Evaluation Criteria in Solid Tumors).
Clinical Trials Program:
The main mission of our Clinical Trials Program, which complements the Basic and the Clinical and Translational Research, is to provide new image-guided loco-regional therapies to treat patients with primary and secondary liver cancer. The main benefit of these therapies is to maximize the potency of the treatment while minimizing systemic toxicities. This is accomplished by using new imaging tools for image guidance to target and treat the tumors more effectively, and by using new delivery systems that increase drug concentration in tumors or small radiation spheres that can emit their radioactive effects within the tumors.
Our goal is to offer a number of new, previously incompletely tested or untested therapeutic options to our patients with liver cancer, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, and liver metastases from various sources (colorectal, neuroendocrine, sarcoma, breast and others). In addition, we aim to tailor a treatment algorithm for each patient, combining clinical trials and standard therapies, to maximize options throughout the disease 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 that have properties maximizing drug concentration within tumors through a unique drug-release mechanism, concurrent DEB-TACE with sorafenib, an agent given systemically with strong anti-angiogenic properties, and concurrent conventional chemoembolization (TACE) and bevacizumab, a biologic agent that targets the angiogenesis pathway in cancer. These treatments were tested in both primary and secondary liver cancer. Our data was published in various journals, including Journal of Clinical Oncology (JCO), Cancer, CVIR, JVIR and Radiology.
- Use of lipiodol as an imaging biomarker of tumor response and patient survival. Lipiodol is an oily product that is the key component of chemoembolization (TACE) because it can be mixed with chemotherapeutic drugs and therefore be used as a drug carrying agent and specialized contrast medium since it is retained in liver tumors. This study will assess the ability of lipiodol to be retained within primary or secondary liver tumors and thus be used as a marker of tumor cell death. (Single center study, NCT00730483)
- New treatment for HCC using micro-sized doxorubicin eluting beads. This is the first study of its kind specifically designed to study this new drug delivery system. Because of the small size of the beads, the hypothesis is that drug concentration within tumors will be even greater than the current doxorubicin-eluting microspheres. (Single center study, NCT02007954)
- New treatment for patients with liver metastases from colorectal cancer using irinotecan eluting beads. This study will establish technical criteria for the delivery of these microbeads. (Single center study, NCT02015754)
- Treatment of patients with HCC using TACE +/- sorafenib. This study is a cooperative group trial sponsored by ECOG and the NCI designed to compare the progression free survival of patients with HCC. (Randomized Phase III, NCT1004978)
- Radioembolization with and without systemic chemotherapy (2nd line chemotherapy) in patients with liver metastases from colorectal cancer. (Randomized phase III, NCT01483027)
Student Exchange Program:
The Charité – Johns Hopkins Research Exchange Program was initiated by Prof. Jeff Geschwind, Prof. Bernd Hamm, Prof. Bernhard Gebauer and Dr. Julius Chapiro in 2013 as a cooperation project of the Departments of Radiology at the Charité University Hospital in Berlin, Germany and the Johns Hopkins Hospital. This exchange gives medical students and radiologists in-training from Berlin a unique opportunity to work on their doctoral thesis at one of the most distinguished research institutions worldwide. The Division of Interventional Radiology at the Johns Hopkins Hospital provides worldwide renowned expertise in basic science as well as translational and clinical research. This environment ensures a comprehensive training and offers an outstanding starting point for academic careers for the next generation of physician-scientists.
Selected students are generously supported by the Rolf W. Günther Foundation for Radiology and Radiological Sciences (www.rwguenther-stiftung.de), which was founded in 2006 by Prof. Rolf W. Günther to support research in different fields of Radiology. Prof. Günther is the former chairman of the Department of Radiology at the University Hospital Aachen in Germany and after his retirement he is currently Distinguished Professor in R & D of Interventional Radiology at the Charité University Hospital in Berlin. His sponsorship and mentoring within the framework of this project are gratefully acknowledged while his life work in the field of interventional radiology continues to be a unique inspiration for generations to come.