Therapeutically Targeting Extracellular cGAMP Hydrolysis in Breast Cancer
Abstract
The heterogeneity that exists among cells in any given tumor constitutes one of the most conspicuous features of aggressive breast cancers. This diversity allows cancer cells to constantly change and adapt to the environment. This capability is central to two of the deadliest properties of breast cancer: drug resistance and distant metastasis. This heterogeneity derives from genomic instability, where cells can rapidly change their genome or DNA content each time they divide. As such, they constantly acquire new properties that enable them to resist therapies and spread outside of the breast to distant organs. One major form of genomic instability is called chromosomal instability, where cells make mistakes each time they divide their chromosomes and this leads to unequal distribution of chromosomes. Chromosomal instability exists in over 80% of human tumors, and it is a distinctive hallmark of triple-negative breast cancer as well as a considerable subset of estrogen receptor-positive and Her2-positive breast cancers. Breast tumors with chromosomal instability have a much higher chance to spread to distant organs and relapse after therapy. Our recent work, funded by the Breast Cancer Research Program Breakthrough Award Level 1, showed that chromosomal instability drives metastasis in breast cancer. This work was published in the scientific journal Nature on January 25, 2018. Each time cancer cells make errors during division; some chromosomes are expelled from the nucleus – where they normally reside – and end up in the cytoplasm of the cell where they do not belong. Interestingly, the presence of DNA from these chromosomes in the cytoplasm triggers an antiviral response; our human cells have adapted to detect DNA in the cytoplasm as a foreign object because this is where viral DNA is typically first encountered. In normal circumstances, an antiviral response should kill the infected cell and lead its elimination from the body through the immune system. It turns out that breast cancer cells with chromosomal instability can hijack this chronic inflammation not only to survive but also to spread to distant organs. We identified an enzymatic pathway called the cGAS-STING pathway that detects DNA in the cytoplasm and found that removing either cGAS or STING using genetic tools is sufficient to suppress metastasis in mouse models of metastatic breast cancer. In this proposal, we now aim to use the knowledge that aggressive breast cancer cells are addicted to chromosomal instability and the ensuing inflammation to develop therapeutic strategies that use this inflammation as a “lethal trap.” Under normal conditions, this type of inflammation is toxic to cells and draws the attention of the immune system to attack cancer cells. However, aggressive breast cancer cells have devised adaptive steps to co-exist with chronic inflammation and avoid immune system activation. One way they achieve this is by expressing a protein on their surface called ENPP1 that counteracts inflammation and prevents it from spreading and alerting the immune system. Indeed, human breast cancers with high levels of ENPP1 tend to exhibit lower infiltration of immune cells and spread more readily to distant organs. We will directly test whether pharmacologic inhibition of ENPP1 can be used as a strategy to unmask aggressive breast cancer cells to the immune system. This will be done through an academic-industrial partnership with Volastra Therapeutics, Inc., a biotech startup company co-founded by the Principal Investigator of this proposal. Specifically, we will test the role of inhibiting ENPP1 under the context of radiation and immunotherapy and whether the combination can enhance anti-cancer immune attack. This approach would be particularly useful in the advanced primary disease setting as well as patients with metastatic breast cancer whereby the synergistic combination of radiation and immunotherapy can lead to durable and systemic disease cont
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110608
Entities
People
- Samuel F Bakhoum
Organizations
- Sloan-Kettering Institute
- United States Army