Dr. Abha Agarwal is a Research Fellow in Surgery at Brigham and Women’s Hospital in Boston, Massachusetts. Her research focuses on drug testing using bio-markers and metabolic inhibitors to develop adjuvant therapies for anaplastic thyroid cancer. We sat down with Dr. Aggarwal to discuss her research and general developments in the field.
How would you describe your current role and research?
I currently work at Brigham and Women’s Hospital as a Research Fellow in Surgery under the guidance of Dr. Matthew Nehs. Dr. Nehs is an endocrine surgeon who is interested in studying anaplastic thyroid cancer, which is one of the most fatal and aggressive forms of thyroid cancers. It is very rare, accounting for only 1 to 2% of all thyroid cancers. After diagnosis, the median survival rate for patients is approximately 6 months.
How is anaplastic thyroid cancer treated currently?
Current therapies for anaplastic thyroid cancer are surgery, chemotherapy, radiation and targeted therapies. Unfortunately, the current medical therapies become ineffective due to evolved tumor resistance and complete tumor resection is seldom possible. Therefore, new therapies for anaplastic thyroid cancer are urgently needed.
What has been your approach for developing these new therapies?
Right now our research is in metabolism and cancer, mainly the Warburg effect. The Warburg effect refers to the observation that cancer cells favor metabolism via glycolysis rather than the oxidative phosphorylation pathway. This means that cancer cells exhibit increased glucose uptake and fermentation to lactate. This altered metabolism is known to aid in tumor cell growth and metastasis.
We can see this effect when we observe PET scans images on patients injected with radiolabeled fluorodeoxyglucose, which is readily absorbed by the anaplastic tumor cells. That’s what honed us in to examine this metabolic pathway more closely.
Was this heightened glucose uptake what led you to study low glucose diets?
Since we knew about the Warburg Effect and the anaplastic tumor PET images indicated that glucose was going straight to the tumors, we started off by testing the effects of a low glucose in vitro. We also treated the cancer cells with the antioxidant N-acetylcysteine (NAC), because increased glycolysis results in oxidative stress. Two combinations were used to treat the cancer cells: (1) low glucose and (2) low glucose + NAC. We observed decreased tumor cell growth in both groups, but we saw a significant decrease in cellular proliferation in the low glucose + NAC group.
To move the studies in vivo, we needed to select a low glucose diet to feed our mouse model. We chose the ketogenic diet, which is a low carbohydrate diet with moderate protein and high fat content. We injected the mice with an anaplastic thyroid cancer cell line and split them into four groups. Group one was fed a standard diet, group two was fed a ketogenic diet, group three was fed a standard diet supplemented with NAC, and group four was fed a ketogenic diet supplemented with NAC. We found that tumor size and volume were greatly reduced in the group four mice, and that two of the six mice showed no tumor at all. We were thrilled that we could recreate our results in vivo. It was a surreal moment for us to see no tumors in a third of the mice that were in the Ketogenic diet plus NAC group. We confirmed our results with histology.
What are your next steps?
Our future research will focus on expanding the cell lines used to vary the mutational profile of the tumors to look for consistent or disparate effects. We also plan to compare a heterotopic flank tumor injection with an orthotopic model, and assess the role of the ketogenic diet on an orthotopic mouse model with lung metastases.
Thank you for taking the time to discuss your research with us, Dr. Aggarwal! We wish you the best of luck with your future endeavours!
