Potentiation of Immune Checkpoint Blockade by Inhibition of Epoxyeicosatrienoic Acid-Driven Tumor Respiration
Abstract
This application addresses the following overarching challenge: “Identify what drives breast cancer growth; determine how to stop it.” The median overall survival (OS) for ER+HER2- metastatic breast cancer (MBC) is ~30 months and, to date, there is no survival advantage seen for cyclin dependent kinase inhibitors (CDKi’s). Dual mTOR inhibitors, such as TAK-228, aren’t far enough in clinical development to be tested for OS. There is an unmet need for strategies that unequivocally improve OS in ER+HER2- MBC. We have discovered that CYP3A4, an enzyme that metabolizes about half of all prescription drugs in the liver, is also expressed in breast cancer and is associated with estrogen receptor alpha (ER) expression. Silencing of CYP3A4 causes ER+HER2- tumors to lay dormant in mice. Furthermore, we localized CYP3A4 to the mitochondria, powerhouses of cells, which function at the endpoint of oxidative metabolism and provide energy for breast cancer cells. CYP3A4 turns on the burning of fuel by the mitochondrial “engine.” As such, the mitochondria of breast cancer cells consume vast quantities of oxygen (O2), making tumors very low in O2 or “hypoxic.” This consumption of O2 prevents T cells, which require O2, from conducting immune surveillance and killing breast cancer cells. The biguanide diabetes drug metformin is a weak mitochondrial poison, which decreases O2 consumption and restores normal O2 making tumors more “normoxic,” meaning having more normal O2 levels. It has been proposed that metformin can make T cells work better under conditions where there is relief of the immune checkpoint by PD-1 antibodies, which remove tumor blockade of T cell function. Nonetheless, the metformin strategy does not work with tumors more than a few millimeters in diameter. We propose that this lack of activity of metformin is because it only weakly inhibits O2 consumption by the tumor. To make progress, we need an entirely different type of drug to more potently shut off the O2 consumption by tumors. To this end, we have designed hexyl-benzyl-biguanide (HBB), entirely different from metformin, which is 250-fold more potent at inhibiting cancer cell O2 consumption and 100-fold more potent than metformin at inhibiting ER+HER2- mammary tumor growth. Furthermore, unlike metformin, HBB potently inhibits regulatory T cells (Tregs), which suppress effector CD4+ and CD8+ T cells tumor infiltrating lymphocytes (TIL) that fight cancer. Tregs are therefore an enemy to be defeated. There are few drugs that selectively inhibit Tregs in cancer. HBB can inhibit the tumor and Tregs at similar concentrations, making it useful as a dual approach to treat the cancer and activate anti-tumor immunity. There is a significant gap in knowledge in our understanding about how to activate the immune system in breast cancer. Without better understanding of how to activate the immune system in ER+HER2- breast cancer, we cannot make similar progress as seen in other solid tumors. To improve our understanding of how to restore oxygenation to tumors, we will test HBB for inhibition of oxygen consumption by the tumor and determine whether restoration of oxygen to tumors promotes the function of TIL. We will also learn how to suppress Tregs in breast cancer and promote CD4+ and CD8+ effector T cell function using HBB. We hypothesize that improved activation of cytotoxic T cells by HBB and similar highly active biguanides in the presence of PD-1 antibody will help eradicate breast cancer. As such, the aims are: Aim 1: Determine the extent to which biguanides affect T cell phenotypes in mouse mammary carcinoma. This aim will tell us which animal models will be best for our studies of HBB in breast cancer. Aim 2: Determine how HBB inhibits tumor O2 consumption and reduces TIL hypoxia, improving their function. This aim will tell us how to restore oxygen levels in breast tumors using HBB and how to improve function of tumor-infiltrating lymphocytes
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910099
Entities
People
- David Potter
Organizations
- United States Army
- University of Minnesota