RSNA Grant Leads to Critical Research on RF Tumor Ablation

Four years ago, a single question posed by Muneeb Ahmed, M.D., led to a successful RSNA-funded research project on radiofrequency (RF) ablation, spawned a series of successive studies, and launched a promising line of research in interventional oncology.

“In tumor ablation, in which extreme heating or cooling is used to kill tumor cells around an ablation needle placed into the tumor with image-guidance, most research has focused on creating the largest ablation zone possible to treat larger tumors more completely,” Dr. Ahmed said. “But research has been limited to the effects of that procedure around the edges of the treatment area. My colleagues and I were interested in knowing: Can partial heating of tumor and normal liver cells at the margin of the RF ablation zone affect tumor cells that are present elsewhere in the body? We wanted to understand these reactions at a biological and mechanistic level with the hope of using this information to develop ways to direct and improve overall treatment.”

Dr. Ahmed, an associate professor of radiology and chief of vascular and interventional radiology at Beth Israel Deaconess Medical Center and Harvard Medical School, developed a 2012 RSNA Silver Anniversary Campaign Pacesetters Research Seed Grant into a study that helped characterize the effects of RF ablation on remote tumor growth and systematically identify dominant cellular and molecular pathways that activate to promote tumor growth.

In his RSNA research, Dr. Ahmed implanted breast adenocarcinoma tumors subcutaneously in animals. He then performed RF ablation in normal liver and kidney tissue in these animals to simulate everyday interventional oncology clinical practice, in which the normal tissue margin is ablated. He measured tumor growth in the animals before they were randomly assigned to the RF treatment group or to the control group. Then in all animals (treatment and control), he measured tumor growth and performed immunohistochemical (IHC) and western blot analysis for markers of inflammation and cell infiltration, cytokines, cellular proliferative indices and markers of neoangiogenesis. Findings demonstrated that RF ablation increased the expression of several key factors with known links to tumor growth stimulation, including hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6).

The initial study concluded that RF ablation of tissue can incite significant unwanted “off-target” tumor growth far away from the treatment zone. “This finding may have significant implications concerning the current use of RF ablation in clinical practice,” Dr. Ahmed said.

The findings were observed after RF ablation of two different organs and in two different animal tumor lines, suggesting that “off-target” RF-induced secondary effects may occur over multiple organs or ablation sites, and, therefore, may be more widespread than currently appreciated. In the next experiments, immediately after RF ablation, Dr. Ahmed administered different drugs that blocked HGF, VEGF or IL-6. He demonstrated that in the presence of these blocking agents, following ablation, levels of these factors and tumor growth remained at baseline and did not increase.

“Such strategies may have the potential to reduce post-RF ablation-induced tumor recurrence and new tumor growth while improving overall ablation efficacy,” Dr. Ahmed said.

Dr. Ahmed also found that not all tumors seemed to be susceptible to off-target effects of RF ablation, suggesting that tumor receptor positivity may hold promise as a biomarker to predict tumors that are more susceptible to cytokinetic responses following hepatic ablation.

RSNA Project Spawns Research

Results of this study were presented in two abstracts at RSNA 2013 and formed the core data for an invited refresher course at RSNA 2014 and 2015. Dr. Ahmed’s findings were also used as preliminary data for a follow-up pilot development grant from the Northeastern University Center for Translational Cancer Nanomedicine (CTCN), and for additional larger grant applications to the National Institutes of Health (NIH), which are currently under review. Dr. Ahmed’s research was also published online in Radiology in September 2015 and in PLOS ONE in July 2015.

As a result of the initial study, Dr. Ahmed was awarded the 2014 Gary J. Becker Young Investigator Award from the Society of Interventional Radiology (SIR). SIR also sponsored Erik Velez, a now fourth-year UCSF medical student for a 1-year joint Howard Hughes Medical Institute-SIR research fellowship in Dr. Ahmed’s lab. Six subsequent abstracts were presented at national meetings including RSNA, SIR, and Society of Thermal Medicine, and two additional manuscripts have been accepted for publication.

Dr. Ahmed said that the RSNA grant played a key role in his career as a researcher and in securing further research funding. “An RSNA Research Seed Grant provides an excellent starting point and opportunity to obtain pilot funding to gather preliminary data and develop research ideas,” said Dr. Ahmed, who was also awarded a 2006 Covidien/RSNA Research Resident Grant to study RF thermal ablation.

The RSNA grant laid the groundwork for a very promising research career, said S. Nahum Goldberg, M.D., director of the Applied Radiology Laboratory and professor of radiology at Hadassah Medical Center and Beth Israel Deaconess Medical Center and Harvard Medical School, who mentored Dr. Ahmed through his RSNA research project. Dr. Goldberg received an RSNA 1997 Cook Incorporated Research Fellow Grant to study RF ablation.

“Not only has Dr. Ahmed used this RSNA seed grant to explore one of the most important questions currently facing interventional oncology, but he has also parlayed this into peer-reviewed, NIH-sponsored funding,” said Dr. Goldberg. “His scientifically rigorous mechanistic-based approach to understanding how and why our local therapies can have systemic and sometimes negative effects holds substantial potential for markedly improving ablation and transcatheter therapies.”

Grants In Action

NAME:
Muneeb Ahmed, M.D.

GRANT RECEIVED:
RSNA Silver Anniversary Campaign Pacesetters Research Seed Grant (2012)

STUDY:
“Elucidating the Extent and Causes of RF Ablation-induced Cell Growth”

CAREER IMPACT:
“The RSNA Research & Education Foundation seed grant allowed me to obtain preliminary data that has already led to additional grant funding and has formed the core basis for several additional grants,” Dr. Ahmed said. “RSNA has been very supportive of me during the early stages of my career.”

CLINICAL IMPLICATION:
“The studies supported by this RSNA research seed grant have generated very exciting, provocative and clinically relevant results – namely that RF ablation of tumor and different normal organs can stimulate variable growth in distant tumors, far away from the ablation site,” Dr. Ahmed said.

Web Extras

• Access the Radiology study by Dr. Ahmed and colleagues, “Hepatic Radiofrequency Ablation–induced Stimulation of Distant Tumor Growth Is Suppressed by c-Met Inhibition,” at RSNA.org/Radiology