Identify and Target Innate Immune Checkpoints to Treat Metastatic Breast Cancer
Abstract
The recent case of Jimmy Carter’s cancer that was cured by immunotherapy illustrates that the immune system can be harnessed to cure cancer. My lab seeks to amplify these advances to specially treat metastatic breast cancers. Our immune system is divided into two main branches: the innate immune system, which is encoded at conception and varies only slightly between individuals, and the adaptive immune system, which is shaped by the environment we experience. The innate immune system is our first line of defense against disease pathogens and foreign materials. Often, individual cancer cells are recognized as pathogens and cleared by immune surveillance, without developing into tumors. It is only when our immune system is dysfunctional or overwhelmed that cancer cells can take root and form tumors. Indeed, the number of tumor infiltrating lymphocytes (TIL), a type of immune cell that can directly kill cancer cells, is the single most powerful predictor of patient outcome in many types of cancer including triple-negative breast cancers. The therapy that cured Jimmy Carter works by manipulating the adaptive immune system to make the cancer killing TIL more effective. Our goal is to therapeutically supercharge the more universal innate immune system to increase TIL counts, shifting the paradigm of cancer therapy to treat, maintain, and even cure patients with metastatic disease. Most current modulators of innate immunity are broad, non-specific, and poorly characterized, due to our lack of understanding of innate immune mechanisms. My lab is taking a more targeted approach. We use chemical biology to unveil how innate immunity functions, and in parallel, develop therapeutic hypotheses and drug leads for cancer treatment. Excitingly, immune-modulating small molecules represent an incredibly important and exciting new area for therapeutic development. We previously identified the key anti-cancer role of the 2´3´-cGAMP-STING pathway. 2´3´-cGAMP is a newly discovered endogenous innate immune second messenger that activates STING (stimulator of interferon genes) to induce the production of interferon-ß, a potent anti-cancer cytokine. A stable analog of 2´3´-cGAMP that we helped to develop has entered a Phase I clinical trial for palpable, metastatic solid cancers regardless of origin. However, this analog must be directly injected into tumors to maximize its effect and avoid inflammation elsewhere. These exciting advances point to an urgent need for a more effective and safe systemic 2´3´-cGAMP therapy to tackle internal, metastatic breast cancers. Our strategy is inspired by the recent discovery that radiation therapy works by inducing 2´3´-cGAMP production in tumors. However, we also discovered that 2´3´-cGAMP is quickly cleared by export pumps and an extracellular degradation enzyme named ENPP1, which is highly expressed in breast cancers and is correlated with poor prognosis. Our innovation proposed here is to combine local radiation therapy, which produced local 2´3´-cGAMP, with systemic administration of drugs that inhibit the clearance mechanism of 2´3´-cGAMP and prolong its half-life and anti-cancer effects. This combination systemic treatment will specifically activate the STING pathway in the tumors, thus avoiding undesirable immune responses. To develop such a drug, we urgently need to understand the molecular mechanism of 2´3´-cGAMP clearance. First, we will use a whole-genome CRISPR screen to identify export and import pump(s) that regulate 2´3´-cGAMP function. Second, we will develop drug leads based on tool compounds we previously developed to increase the half-life and effects of 2´3´-cGAMP where it is produced. We will collaborate with Stanford experts including Dr. Mark Smith (medicinal chemistry) and Dr. Marc Deller (crystallography) to identify and ameliorate technical challenges. Finally, we will test our drug leads in combination with radiation therapy in the syngeneic mouse tumor m
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810041
Entities
People
- Lingyin Li
Organizations
- Stanford University
- United States Army