Project duration:
Investigators: Gary Hammer, Zeribe Nwosu, Laura-Sophie Landwehr, Antonio Lerario & Johanna Werner
Institutions: 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 responsible for producing 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. Unlike most aggressive cancers, the deadliest subtype of ACC becomes increasingly specialized over time, overproducing stress hormones in a state of addiction to its own identity. This hormone excess 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 keeping these cancer cells locked in their aggressive state. Blocking ACLY triggers a rapid nutrient crisis: within 24–48 hours, cancer cells begin losing their identity and hormone-producing programs. Unlike healthy cells, which can adapt by switching to alternative fuel sources, these cancer cells cannot — rendering them newly vulnerable.
This project combines ACLY inhibition with immunotherapy to hit the tumor from two directions simultaneously. By starving the cancer and dismantling its hormonal defenses, 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.