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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Targeting Aryl Hydrocarbon Receptor for Breast Cancer Treatment and Improved Immunotherapy

Alternative title: Målretting mot Aryl hydrokarbonreseptor for behandling av brystkreft og forbedret immunterapi

Awarded: NOK 12.0 mill.

Breast cancers, like many other cancers, develop through a complex set of events, including DNA mutations and changes in the way the immune system fights cancer. The immune system plays an important role in protecting us from cancer, but these protective mechanisms are lost when tumours are formed. Targeting the immune system by increasing the ability of immune cells to recognize and kill tumour cells, in an approach known as immunotherapy, has led to unprecedented clinical benefit for many patients. However, not all patients respond, and those that do, experience relapse. Therefore, there is urgent need to find new therapeutic targets to improve this treatment. The aryl hydrocarbon receptor (AHR) is a protein that when turned on allows tumour cells to “hide” from the immune system allowing them to grow and proliferate. In this research project we will determine if blocking or loss of AHR, alone or in combination with current immunotherapy treatments, reduces breast cancer growth and progression. Our project has three work packages (WP). In WP1 we will determine how blocking or loss of AHR influences breast cancer cell growth. In WP2 we will study how blocking or loss of AHR signalling affects interactions between breast cancer cells and immune cells. Finally, in WP3, we will determine how blocking or loss of AHR alone or in combination with existing immunotherapy treatments reduces mammary tumour growth and formation rodent models of cancer. Overall, this application will establish the suitability of targeting AHR alone, or as part of combination therapy, to treat breast cancer, which could lead to new therapeutic options for patients that suffer from this disease.

Cancers, including triple negative breast cancer (TNBC), initiate and develop through a complex sequence of biological events, including DNA mutations and changes in the immune system. The immune system plays an important role in protecting us from cancer, but these protective mechanisms are lost or altered when tumors are formed. Targeting the immune system in an approach known as cancer immunotherapy, has led to unprecedented clinical benefit to many patients; but unfortunately, not all patients respond, and those that do, experience relapse. Therefore, there is urgent need to find new therapies to improve this treatment. The aryl hydrocarbon receptor (AHR) is a signaling protein that when turned on causes tumor cells to grow and proliferate, but also allows them to “hide” from immune system. In the current proposal we will test the hypothesis that inhibition or loss of AHR, alone or in combination with cancer immunotherapy, reduces TNBC growth and progression. We will test this hypothesis in three work packages (WP). In WP1 we will determine how loss or inhibition of AHR influences TNBC cell growth. In WP2 we will study how inhibition of AHR signaling affects interactions between TNBC cells and tumor associated immune cells. Finally, in WP3, we will determine how loss or inhibition of AHR alone or in combination with cancer immunotherapy reduces TNBC tumors in preclinical mouse models of cancer. Overall, this application will establish the suitability of targeting AHR alone, or as part of combination therapy, to treat TNBC; a disease with few current treatment options.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Funding Sources