Cameron Brewer
Research Mentor: Yuanyuan Qiao
Mentor Department: Pathology – Ctr for Translational Pathology, Medicine
Author(s): Cameron Brewer, Alice Yin, Yi Zhao, Yuanyuan Qiao
Session: Session 1 (9:00 AM – 9:50 AM)
Presentation Type: Poster 75
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare malignancies arising from hormone producing cells in the gastrointestinal tract and pancreas. These tumors often grow slowly but can be difficult to treat once they spread, and current therapies are limited. GEP-NETs rely on a signaling pathway called mTOR, which helps cells regulate growth and metabolism. Drugs that block mTOR, such as everolimus, are commonly used to treat patients, but these treatments usually slow tumor growth rather than kill cancer cells, and resistance can develop over time. Previous research has shown that cancer cells treated with mTOR inhibitors become more dependent on lysosomes and autophagy, a process in which cells break down and recycle their own components to survive under stress. The goal of this study was to test whether blocking both mTOR and PIKfyve, a protein that helps lysosomes function, could improve treatment outcomes in GEP-NETs. The study employed a panel of validated human and murine GEP-NET cell lines (QGP-1, BON-1, GOT-1, and STC-1), along with normal control cells. Pharmacological inhibition of PIKfyve will be achieved using ESK981 or apilimod, and mTOR signaling will be inhibited with everolimus or Torin-1. Tumor cells were treated with mTOR inhibitors alone or in combination with PIKfyve inhibitors. Mechanistic studies include Western blot analysis, CellTiter-Glo assays, and qRT-PCR. Levels of ferritinophagy-related proteins and lipid markers will be evaluated in both in vitro and in vivo. While inhibition of mTOR alone slowed tumor growth, combined inhibition of mTOR and PIKfyve led to stronger anti-tumor effects and increased cancer cell death. Tumors treated with the combination therapy were significantly smaller and mice survived longer compared with those receiving either treatment alone. These results show that targeting PIKfyve can make mTOR inhibition more effective and suggest that combining these two treatments may be a promising strategy in GEP-NET patients.
