CNR2: A Novel Therapeutic Target Against Aggressive and Metastatic Breast Cancer
Abstract
The overarching challenge of this proposal is to (1) eliminate the death (mortality) associated with metastatic breast cancer and (2) identify what drives breast cancer growth; determine how to stop it. Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype, has been associated with poor prognosis due to early metastasis to the lungs or brain and a lack of effective, established targeted therapies. TNBC patients have a higher mortality rate compared to metastatic non-TNBC patients. Therefore, there is the utmost need to develop therapies against TNBC metastasis to other organs. In this proposal, we are developing novel therapies against TNBC, specifically targeting metastasis. The human body contains an endocannabinoid system that consists of the cannabinoids receptors, CNR1 and CNR2, endocannabinoids and enzymes including fatty acid amide hydrolase (FAAH) that inactivate endocannabinoids and inhibit their activity. We have observed that CNR2 is expressed on TNBC cell lines and breast cancer patient tissue samples. Using available patient datasets, we found that high CNR2 expression in TNBC subtypes and in ERalpha- breast cancer patients correlates with better recurrence-free survival. In addition, we have shown that breast cancer tumor growth and metastasis were inhibited in mouse models that were treated with the small molecules that activate CNR2. Furthermore, deletion of CNR2 from mice resulted in enhanced breast tumor growth. We found that tumors treated with CNR2 activator showed increased number of immune cells that have been shown to destroy tumor cells. We also found a reduced number of immune suppressive cells in these tumors. Furthermore, we found that the tumor cells derived from mice that lacked CNR2 showed a higher expression of the recently described immune molecule programmed death-ligand-1 (PD-L1) that blocks immune responses against tumors. Cancer immunotherapies based on blockade of this molecule have achieved significant success. For instance, anti-PD-L1 therapy has shown promising therapeutic effects to different cancer types. However, the majority of cancer types, especially breast cancer are not sensitive to anti-PD-L1 therapy, and for those that are responsive, the overall response rates remain low. Combining anti-PD-L1 with other inhibitors has led to increased response rates but often at the price of severe autoimmune cytotoxicity. Thus, additional approaches that can enhance cancer susceptibility to anti-PD-L1 therapy without causing significant autoimmune toxicity and other side effects are highly desired. However, not much is known about the mechanism by which PD-L1 expression is regulated. We hypothesize that CNR2-mediated signaling plays an important role in enhancing immune responses against breast tumor and thereby inhibiting TNBC growth and metastasis. We also hypothesize that CNR2 enhances immune responses by inhibiting CXCL12/CXCR4 signaling. In this proposal, we will first determine the role of CNR2 on growth and spontaneous metastasis by generating a genetic breast cancer mouse model that has morphological similarities to human TNBC and is deficient in the CNR2 receptor. Next, we will analyze the clinical efficacy of the small molecular weight CNR2 activator in combination with CXCR4 inhibitors against TNBC growth and metastasis using various preclinical mouse models. We will also determine how CNR2-mediated signaling activates the immune system and inhibits TNBC development, progression, and metastasis. We will especially determine the effect of CNR2 on the recruitment of immune cells that destroy tumors. In addition, we will determine whether CNR2 inhibits the expression of the PD-L1 ligand that has been shown to block activation of the immune system against cancer cells. We will also determine the expression of CNR2 and CXCR4 in a large cohort of TNBC, metastatic, and invasive breast cancer patients to identify CNR2/CXCR4 as a novel prognos
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1710026
Entities
People
- Xue-feng Bai
Organizations
- Ohio State University
- United States Army