Project 3 - Targeting Metabolic-Epigenetic Vulnerabilities to Overcome Treatment Resistance
Investigators: Gary Hammer, Zeribe Nwosu, Laura-Sophie Landwehr, Antonio Lerario & Johanna Werner (University of Michigan - Cornell University - University Hospital Würzburg)
Adrenocortical carcinoma (ACC) is a rare and aggressive cancer of the adrenal glands — small organs above the kidneys that produce essential hormones like cortisol. Most patients survive less than five years after diagnosis, and current treatments, including immunotherapy, frequently fail, highlighting an urgent need for new therapeutic strategies.
In most cancers, deadlier tumors look less and less like the tissue of origin. ACC breaks this rule: its most lethal subtype becomes strikingly similar to a normal adrenal gland, maintaining a specialized identity that the cancer depends on for survival. This identity drives the overproduction of stress hormones, which causes Cushing syndrome and, critically, suppresses the immune system — preventing it from recognizing or attacking the tumor. The cancer’s identity effectively becomes its shield.
Our research has identified an enzyme called ACLY as the essential fuel supply that keeps these cancer cells trapped in their aggressive state. Blocking ACLY creates a critical nutrient shortage inside the cells. This shortage disrupts the master program that maintains the cancer’s identity — the set of instructions that tell these cells to behave like hormone-producing adrenal tissue. Within 24–48 hours, the cells begin to lose that program, shedding not only their hormone-making ability but the very characteristics that make them cancerous.
Healthy cells can adapt by switching to alternative fuel sources. These cancer cells cannot. Once their identity program unravels, they become newly vulnerable.
This project pairs ACLY inhibition with immunotherapy to attack the tumor from two directions at once. By starving the cancer and dismantling its identity-based shield, we aim to open a window of vulnerability that existing treatments have been unable to create — ultimately offering new hope to patients facing one of oncology’s most challenging diagnoses.