Precision Glycocalyx Editing of Metastatic Bone Microenvironment
Abstract
This proposal will address the following overarching challenges: (1) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival; (2) Eliminate the mortality associated with metastatic breast cancer; (3) Identify what drives breast cancer growth; determine how to stop it; and (4) Identify why some breast cancers become metastatic. Twenty to forty percent of breast cancer (BCa) survivors will eventually suffer metastases to distant organs, sometimes years after initial treatment. We will focus on metastatic breast cancers (mBCa) in bone, which are involved in about 70% of all metastatic diseases. In more than two-thirds of cases, metastases will not remain only in bones, but rather spread to other organs and ultimately result in the mortality of patients. Recent analyses elucidated that bone is not the final destination of dissemination but may serve as a launch pad of further metastasis. Thus, developing treatments that target bone minimal residue disease is key not only to the cure of metastasis therein, but also to the prevention of multi-organ secondary metastases. Recently, targeted antibody therapy and immunotherapy have emerged as new avenues for mBCa therapy, but their efficacies on bone metastases are disappointing. For example, trastuzumab (Herceptin) and pertuzumab (Perjeta), antibodies targeting human epidermal growth factor receptor 2 (HER2), have been used to treat patients under adjuvant and metastatic conditions. Although some mBCa patients benefit from these treatments, a high number of mBCa patients with bone metastasis progress within 1 year of starting treatment and few experience prolonged remission. Besides antibody-based therapy, chimeric antigen receptor (CAR)-engineered immune cell therapy that endows patient s immune cells with reactivity for tumor cell surface molecules is emerging as an effective and innovative treatment for BCa. However, homing of therapeutic T cells to the disease site also remains a key limiting factor, especially for tumor cells in their bone niche. Thus, therapies with improved outcomes for BCa patients with bone metastases are highly desired. Previous collaboration between the Zhang lab (Baylor College of Medicine) and the Xiao lab (Rice University) has effectively overcome the inaccessibility issue of bone metastasis. We invented a bone-targeting approach to enable enrichment and retention of antibodies and peptides in the bone microenvironment. In this project, we will apply this approach to a novel target as elaborated below. We will study how a glyco-immune checkpoint in the bone metastatic niche may drive bone metastasis progression, and therefore, provide a therapeutic target. This glyco-immune checkpoint is called Siglec-15. As PD1 and CTLA-4, Siglec-15 is expressed in cancer cells and some immune cells. When binding certain sugar molecules on cell surface, Siglec-15 suppresses antitumor immunity, hence the term glycol (Greek prefix of sugar)-immune checkpoint (GIC). Besides its immune functions, Siglec-15 is enriched in bone and also involves in resorption of bone, which is a hallmark of breast cancer bone metastasis. Thus, targeting Siglec-15 may inhibit bone metastasis with multiple mechanisms. Three aims are proposed in this collaborative project. In Aim 1, we will further evaluate the therapeutic efficacy of GIC inhibitors for the treatment of BCa bone metastasis. Aim 2 will focus on the molecular mechanisms underlying the regulatory roles of Siglec-15 in the metastatic bone microenvironment. In Aim 3, the combinations of the bone-targeting GIC inhibitors and other immunotherapies will be further evaluated for the treatment of BCa bone metastasis. The resulting regiments from this study will have an enhanced efficacy for preventing and curing bone mBCa and further multi-organ metastases seeded from bone lesions. Thus, the fulfillment of the proposed research will
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310494
Entities
People
- Han Xiao
Organizations
- Rice University
- United States Army