Cristina R. Antonescu, MD Physician biography: http://www.mskcc.org/prg/prg/bios/559.cfm
Recent work in the Antonescu laboratory has revealed that 10-14% of breast angiosarcomas are caused by genetic mutations in the KDR receptor (VEGFR2). Dr. Antonescu summarizes this work by saying, “These findings open new avenues for specific therapeutic targeting with KDR inhibitors in a tumor characterized by an aggressive clinical course and limited management options and may have implications as pertains to angiogenesis in other cancers as well.”
The complete manuscript is available here: http://cancerres.aacrjournals.org/content/69/18/7175.long
Dr. Antonescu has drafted a budget based on a large scale genomic analysis of angiosarcoma tumors. Her current work has revealed that certain genes are upregulated in angiosarcomas even though there are no genetic mutations associated with the DNA that encodes those genes. The genes of interest are described in the manuscript linked above, many of which are involved in what would be considered “normal” angiogenesis. The fact that she has found them to be differentially regulated in angiosarcoma tumors has led to the hypothesis that there are epigenetic regulators of these genes that have yet to be identified through the genomic profiling applied to these studies thus far. In an effort to define what is causing these aberations in gene expression, she will be employing microRNA as well as methylation array analysis of the tumors. These studies will be aimed at defining the molecular underpinnings of angiosarcoma which will hopefully reveal more tailored options for therapies in the future. Your contributions will fuel this project, will hire the hands that will carry out these experiments and will give us a unique opportunity to delve into the nature of angiosarcoma.
The title of her project and the techniques used therein are listed below:
Mechanisms of upregulation of angiogenic regulators in angiosarcoma using genomic approaches to investigate dysregulation in miRNAs and whole genome methylation
- Whole genome methylation with individual gene methylation validation
- miRNA expression Agil…ent platform
- miRNA sequencing and validation
Broad scale implications of this research:
All solid tumors need a blood supply and recruit blood vessels through angiogenesis. In cancer, this is an aberrant process with misregulation of angiogenesis. Angiosarcoma IS aberrant angiogenesis, if we unlock the processes that drive angiosarcoma, we may be able to apply that knowledge to targeting the aberrant process of angiogenesis associated with tumor initiation in other cancers. The development of therapies that inhibit angiosarcoma may then be of benefit in fighting other solid tumors. In addition, the use of microRNA and methylation array platforms for studying the epigenetics of cancer is an emerging field using cutting edge technologies. This project will be at the forefront of cancer research allowing others to gain knowledge that can be applied to the overall field of cancer genomics.
Daniel A. Vallera, Ph.D.
Lion Scholar and Director
Section on Molecular Cancer Therapeutics
Professor of Therapeutic Radiology – Radiation Oncology
University of Minnesota Cancer Center
Jaime F. Modiano, V.M.D., Ph.D.
Perlman Professor of Oncology/Comparative Medicine
College of Veterinary Medicine and Masonic Cancer Center
University of Minnesota
Hemangiosarcoma (angiosarcoma) is a highly aggressive cancer that has a very poor prognosis. Alternative therapies are desperately needed. Our group has developed a new type of therapy that may help fight angiosarcoma. Instead of using traditional chemotherapy, we have developed what is called a targeted toxin. This type of therapy specifically targets a toxic substance to the tumor itself, which is different from conventional chemotherapy, where the drug is not targeted and therefore has affects throughout the body. We have designed this therapy to specifically act on molecules that are highly abundant on sarcomas and on newly made blood vessels, which is the hallmark of angiosarcoma. We have tested this therapy on mice with brain tumors and have found that we can induce long term survivors. In addition, this therapy shows high activity against angiosarcoma cells that have been grown in culture. One of the major problems in developing this type of therapy has been that the immune system can reduce the effectiveness of it over time. We have made discoveries that enable this therapy to be masked by the immune system, while retaining the ability to fight the cancer. Our intentions are to test this therapy in an animal model that would mimic the course of the disease in humans. Because angiosarcoma is so rare, accounting for only 1% of sarcomas, which in turn account for only 1% of all types of cancer, we may never get enough people who get this disease in order to test if this therapy would work. Dogs get hemangiosarcoma, and we can develop a clinical trial for this therapy using dogs as a model system. If this therapy is shown to be safe and effective, we would then be in a position where we could bring it into human clinical trials.