Developing Combined Therapies with Hemichannel-Targeting Antibodies and FDA-Approved Therapies in Treating Breast Cancer Bone Metastasis
Abstract
Breast cancer is the second leading cause of cancer death for women in the U.S. Cancer that spreads 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 cures skeletal breast cancer metastasis. Patients’ responses to the treatments vary. Some patients have adverse effects or develop drug resistance. New PD-1 targeted immunotherapies (such as Keytruda, pembrolizumab), although showing efficacies in triple-negative breast cancer types, have limited success in treating breast cancer bone metastasis. Therefore, there is an urgent medical need for a new specific treatment option with improved therapeutic effectiveness to help patients with this deadly disease. 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. Development of drugs that can maximize this potential by activating hemichannels, represents a new therapy for treatment of breast cancer bone metastases. With the support from the parental Breast Cancer Research Program (BCRP) grant, we have developed an antibody drug that targets hemichannels and suppresses bone metastasis of various subtypes of breast cancer. Through the collaboration with our commercial partner, we obtained a regulatory approval for Investigational New Drug (IND) and a clinical trial was initiated and is currently ongoing, and the results generated thus far from the clinical trial show that this antibody drug candidate is safe for human testing. In the current proposed research, we plan to expand the drug efficacy with combined therapy approaches by using this antibody drug along with the other two U.S. Food and Drug Administration (FDA)-approved therapies for the treatment of bone metastasis of breast cancer. The major objective of this drug development proposal is to optimize the treatment regimens in treating breast cancer bone metastasis by assessing efficacies of the combined therapies. Two overarching challenges will be addressed: (1) Revolutionizing treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival; and (2) Elimination of the mortality associated with metastatic breast cancer. In this study, we propose two specific aims. First, we will determine the efficacy of combined treatment of this antibody drug with zoledronate in various breast cancer subtypes at various combined treatment regimens. Second, we will assess the efficacy of combined immunotherapy treatment regimens with this antibody and PD-1 antibody, and the drug responses of cancer immunity. Results from these two aims will provide guidance for clinical trials and treatment alternatives. The outcome from this drug-development proposal will generate an entirely new class of antibody therapies that target novel mechanisms with high efficacy and low toxicity. Approximately 170,000 women in the U.S. currently live with breast cancer metastasis and about 50,000 die from this disease each year, including active-duty U.S. 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
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310843
Entities
People
- Jean Jiang
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio