Development of Hemichannel-Targeting Antibody Therapies for Breast Cancer Bone Metastasis
Abstract
Breast cancer is the second leading cause of cancer death for women in the United States. Cancers that spread to bones, bone metastases, are the most frequent complications, occurring in up to 80% of patients with advanced breast cancers. Bone metastases, like other metastatic diseases, typically make the disease incurable. Almost all patients with bone metastases suffer from various complications varying from severe bone pain and pathological fractures to general physical disability, which rapidly deteriorate the quality of life. Treatment options are very limited. These include chemotherapy combined with the administration of bisphosphonates (zoledronate (Zometa®) and pamidronate (Aredia®)) and an anti-RANKL antibody (Denosumab®). These therapies reduce bone metastasis-associated symptoms. However, none of the current therapies cure skeletal breast cancer metastasis. Patients responses to the treatments vary. Some patients have adverse effects or develop drug resistance. Therefore, there is an urgent medical need for a new, specific treatment option with improved therapeutic effectiveness to help patients with this deadly disease. Recent studies in our research team show that opening of a type of membrane channels, called connexin hemichannels, in bone cells can effectively defend bone tissues against breast cancer cell invasion. This research reveals intrinsic defensive potential in bone tissues that protects them against breast cancer invasion. Development of drugs that can maximize this potential by activating hemichannels represents a novel therapy for treatment of breast cancer bone metastases. We recently developed an antibody that specifically opens the connexin hemichannels. Our studies showed that mice treated with this antibody had suppressed breast cancer bone metastasis as compared to untreated animals. This treatment is very effective even with less frequent treatment. The major objective of this drug development proposal is to conduct preclinical studies by assessing the therapeutic value of this antibody and determining critical parameters required for clinical drug testing, such as effectiveness and toxicity. Two Overarching Challenges will be addressed: (1) Revolutionizing treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective; and (2) Elimination of the mortality associated with metastatic breast cancer. In this study, we propose three specific aims. First, we will investigate in what subtypes of breast cancer bone metastasis, dosage, and duration this drug will be most effective. Results from this aim will establish the treatment guideline for patients. Second, we will develop a process to produce this antibody drug in a large quantity. Finally, we will test this drug for its pharmaceutical properties and possible toxic side effects using animal models. Results from the last two aims will establish the necessary data package for filing and approval by the U.S. Food and Drug Administration (FDA) for human testing of the antibody drug. The outcome from this drug development proposal will generate an entirely new class of antibody therapy that targets a novel mechanism with high efficacy and low toxicity. Over 155,000 women in the US currently live with breast cancer metastasis and over 50,000 die from this disease each year, including active duty US military personnel, retirees, Veterans, and their family members. The drug developed in this proposal will offer enormous benefits to these patients with the reduction of breast cancer bone metastasis-associated symptoms and improvement of survival rate. The estimated time for the proposed project is 4 years. In Years 1-2, we will determine the antibody drug efficacy in various subtypes of breast cancer and animal models. In parallel, we will work out a production process and generate a large quantify of the antibody drug. Starting in Year 2 and ending in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710560
Entities
People
- Jean Jiang
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio