Project 1 - Targeting TADA2B-SAGA activity to overcome immune cell evasion in ACC
Investigators: Kleiton Borges, David Breault, Vasileios Chortis & Cristina Ronchi
Adrenocortical carcinoma (ACC) is a rare but aggressive cancer of the adrenal gland with poor survival rates and few treatment options. In most patients, available treatments work for only a limited time before the cancer returns and spreads. Immunotherapy, which helps the immune system recognize and attack tumors, has transformed treatment for many cancers but has shown limited success in ACC. One reason may be that ACC tumors can hide from the immune system, although the underlying mechanisms remain poorly understood.
Using a new mouse model that closely mirrors aggressive, immunotherapy-resistant human ACC, we identified a protein called TADA2B that helps tumors evade immune attack. TADA2B is part of a larger protein complex known as SAGA, which helps control how genes are turned on and off. We found that removing TADA2B activates immune pathways and makes tumors more responsive to immunotherapy. Importantly, drugs that target other components of the SAGA complex can reproduce many of these effects, pointing to a promising new therapeutic strategy.
This project will investigate how targeting TADA2B-SAGA activity strengthens anti-tumor immunity and whether the same mechanisms operate in tumors from ACC patients. Our goal is to develop new ways to help the immune system recognize and eliminate ACC, ultimately leading to more effective treatments for patients with this devastating disease.
Project 2 - Targeting WNT5A-Mediated Crosstalk with the Tumour Microenvironment in ACC
Investigators: Kaitlin Basham, Stéphane Angers, Fiemu Nwariaku & Melissa Reeves
Disease information: Adrenocortical carcinoma (ACC) is an aggressive cancer with limited treatment options. For patients and families facing this diagnosis, the development of new treatments has been frustratingly slow. While immunotherapy has greatly improved outcomes for many other cancers, it has not yet delivered meaningful benefit for most patients with ACC. Fewer than 15% of patients respond, and even those responses are often short-lived. Understanding why immunotherapy does not work in ACC – and how to make it work – is one of the most urgent challenges in the field.
Background: Our research focuses on a major barrier to immunotherapy success – the tumor’s ability to shut down the immune system. ACC tumors create a local environment that prevents immune cells, especially cancer-fighting T cells, from entering the tumor and doing their job. We have identified a protein made by tumor cells, called WNT5A, as a key driver of this immune shutdown.
Using a laboratory model that closely resembles human ACC, we found that WNT5A acts like a gatekeeper to block protective immune cells from getting into the tumor. In both our model and human patient data, high levels of WNT5A are linked to weaker immune activity and worse outcomes. These findings suggest that WNT5A is a promising new treatment target. Our goal is to develop new ways to block WNT5A activity, restore immune function, and improve response to immunotherapy.
Key Objectives: Our long-term objective is to develop a drug that can be used in patients to block WNT5A. To achieve this goal, our project has three key objectives:
1. Identify which receptor WNT5A uses in adrenal tumors.
2. Understand how WNT5A inhibits immune cells.
3. Test whether blocking WNT5A can make immunotherapy more effective.
Expected results, knowledge utilization, and impact: We expect that inhibiting WNT5A will increase the recruitment of cancer-fighting immune cells into the adrenal gland and enhance the efficacy of immunotherapy. By identifying the precise receptor that WNT5A signals through, we will be able to test new drugs developed by our team that block individual receptors, thereby avoiding the serious side effects that have been previously observed with broad-acting WNT pathway inhibitors.
If successful, this work could lead to new combination treatments that make immunotherapy effective for more ACC patients. This will not only address an unmet need for new ACC therapies, but also provide insights that can inform other cancers where the immune system is impaired.
Project 3 - Targeting Metabolic-Epigenetic Vulnerabilities to Overcome Treatment Resistance
Investigators: Gary Hammer, Zeribe Nwosu, Laura-Sophie Landwehr, Antonio Lerario & Johanna Werner
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.