MedicalResearch.com Interview with:
Sudarshan Anand, PhD
Department of Cell, Developmental and Cancer Biology
Department of Radiation Medicine
Oregon Health and Science University
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Almost half of all cancer patients receive radiation therapy during the course of their disease.
While the impact of radiation on the cancer cells has been well studied in experimental models, its effects on the accessory cells that are present in the tumor are not well known. One of the major interests of our lab is studying these accessory cells of the tumor aka “the tumor microenvironment”. These group of cells consists of blood vessel cells, fibroblasts and immune cells that are normal cells that have been recruited by the tumor and generally support tumor growth.
The goal of this study was to understand the impact of radiation (and broadly DNA damaging agents) on the blood vessel cells in the tumor. We focused on a specific type of molecule called microRNAs (miRs) in these cells. miRs are small RNA molecules that bind to dozens of messenger RNAs and the production of proteins.
We discovered a group of microRNAs that was induced in blood vessel cells by radiation, a chemotherapy agent cisplatin and peroxide an agent that mimics oxidative stress that is often present in cancers. We found that the top candidate on this list was a microRNA that mimicked radiation by inducing DNA damage and eventually killing the blood vessel cells. Administering this microRNA, either within a tumor or using a specific nanoparticle that delivers cargo to the tumor blood vessels, decreased tumor growth in mouse models of breast cancer, brain cancer and colorectal cancer. We found that the efficacy of this agent was a result of its ability to suppress a protein TREX1, that is often mutated in human lupus.
In other words, this microRNA was able to create some of the immune and inflammatory features of lupus within a tumor and induce proteins that triggered cell death on tumor cells. Overall, our work illustrates how the tumor accessory cells respond to radiation and highlights the cross-talk between different accessory cells and the tumor cells.
MedicalResearch.com: What should readers take away from your report?
Response: The major message is that therapies that target the accessory cells in a tumor have the potential to synergize with the current standard of care treatments. While the immune checkpoint pathways are the major success story that highlights this message, there are also other agents targeting fibroblasts, blood vessel cells, specific tumor suppressor macrophages etc that are making their way through the research and clinical development pipeline that may offer benefits in specific cancer types.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Our work suggests that manipulating this TREX1 pathway using a microRNA was effective in mouse models. We would like to investigate whether we can target TREX1 using conventional small molecule drugs. We have developed an assay that can be used for rapidly screening libraries of compounds.
Another important area of work that would be useful is to test whether some of these microRNAs can serve as biomarkers for assessing effectiveness of radiation therapy. Currently, radiotherapy regimens can be 20-30 days of treatment and a month or two of waiting before we find out if the tumor has responded. But what if we can predict whether tumors will respond to radiation within the first week of treatment by measuring the levels of specific microRNAs? What if we are able to offer a blood test that can predict treatment responses and perhaps suggest a higher dose of radiation for some or alternative agents for some patients? We are now starting to look at this from patient tumor samples with some fantastic collaborators here at OHSU. These are some areas of potential utility in the clinic and we hope our work will enable other labs to explore some of these questions.
MedicalResearch.com: Is there anything else you would like to add?
Response: I want to emphasize that these studies are all in the research stage. While we use clinical samples to validate our findings etc, there is a long way to go before these discoveries will be of direct use to patient care. We and our collaborators will continue to work on these important problems to understand how cancers work with the goal of eventually bringing a diagnostic or therapeutic agent to clinical trials.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment
RaeAnna Wilson, Cristina Espinosa-Diez, Nathan Kanner, Namita Chatterjee, Rebecca Ruhl, Christina Hipfinger, Sunil J. Advani, Jie Li, Omar F. Khan, Aleksandra Franovic, Sara M. Weis, Sushil Kumar, Lisa M. Coussens, Daniel G. Anderson, Clark C. Chen, David A. Cheresh & Sudarshan Anand
Nature Communications 7, Article number: 13597 (2016)
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