Eliminating Bone Micrometastases by Bone-Targeting Antibodies
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) determine how to prevent lethal recurrence. Metastasis to distant organs is associated with significant morbidity for breast cancer patients and results in reduced life quality. Bone is the most frequent destination of metastasis. Over 45% of first-site metastases occur to bone, as compared to 19% to lung, 5% to liver, and 2% to brain. Patients with bone-only metastasis usually have better prognosis than those with visceral organs involved, leading to skepticism on the urgency of bone metastasis research. In fact, bone is not the final destination of dissemination. Over two-thirds of bone-only metastases subsequently develop other organ metastases via frequent metastasis-to-metastasis seeding. Thus, developing treatments that both prevent and treat microscopic metastases in bones is a key focus for curing metastatic breast cancer. Recently, antibody therapy and immunotherapy have emerged as immensely powerful treatments for metastatic breast cancer, but their efficacies with patients experiencing bone metastases has been disappointing. For example, human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients at early stage or advanced/metastatic stage have benefited from the treatment of trastuzumab (Herceptin), an antibody heralded as a triumph of precision medicine. However, a high number of breast patients with bone metastasis progress within 1 year and few experience prolonged remission with this treatment. In another recent clinical trial testing T cell-checkpoint inhibitor for metastatic triple-negative breast cancer, no significant difference was observed in the risk of progression or death between treatment and placebo groups among breast cancer patients with bone metastases. It is perhaps understandable that drug delivery for bone tissue is difficult because of relatively low vascularization and the physical barriers of penetration. Attempts to ensure effective concentrations of a therapeutic in bone drive high concentrations in other tissues, resulting in adverse systematic effects or side effects that may limit or exclude the use of a therapeutic in the bone. Thus, novel strategies to prevent and treat breast cancer patients with bone metastases are highly desired. In this study, we will prepare the first bone-targeting antibodies and study their effects on the survival and progression of microscopic breast cancer bone micrometastases and secondary metastasis seeding from bone lesions through a close collaboration between the labs at Rice University and Baylor College of Medicine (BCM). Our preliminary data establish that well-defined bone-targeted antibodies prepared using a novel antibody conjugation technology, called pClick (Xiao lab, Rice), exhibit enhanced bone targeting and inhibition of bone metastases and further multi-organ metastases in the animal models (Zhang lab, BCM). The resulting regimens from this study will have an enhanced efficacy, but reduced toxicity for preventing and curing bone metastatic breast cancer as well as further multi-organ metastases seeding from bone lesions, which is likely to eliminate the mortality associated with metastatic breast cancer. Thus, this study is well aligned with the mission of the Breast Cancer Research Program to apply innovative, creative, collaborative, and high-impact approaches to end breast cancer. We chose to use trastuzumab, a standard-of-care for HER2+ patient, as a proof-of-principle. Our preliminary indicates that the bone-targeting trastuzumab exhibited enhanced bone metastatic niche-targeting in vivo superb anti-tumor activity in a breast cancer-induced bone metastasis mouse model. Furthermore, it should be noted that HER2- patients with bone metastasis can also
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110789
Entities
People
- Han Xiao
Organizations
- Rice University
- United States Army