New Radiation Therapy for HER-2-overexpressing Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Radiation therapy is an important component in breast cancer management in most patients. Patients treated with breast conservation surgery routinely receive additional therapy with external beam radiation. After total mastectomy with dissection of the lymph nodes, radiation therapy is also recommended for women with large primary tumors, extension of tumor beyond the lymph nodes, or the occurrence of tumor in four or more lymph nodes. The other important role of radiation therapy is in the palliation of symptoms caused by either the primary tumor or metastatic spread of the tumor to distant sites, such as bone. Radiation therapy generally causes injury to the DNA of breast cancer cells. In most cases, this radiation-induced DNA damage is irreversible, and the irradiated cancer cells are killed. However, in other cases, the cancer cells manage to repair the radiation-induced damage to their DNA, and the malignant cells then continue to grow and spread. The latter condition leads to higher chances for relapse of the breast cancer in the affected patient. In fact, some recent clinical studies show that the risk for breast cancer recurrence after treatment with surgery and radiation is higher among breast cancer patients with tumors demonstrating an abundance of a particular marker protein, termed HER-2. This protein is present at the blood surface of the cancer cell and acts as an antenna to attract growth-promoting signals from outside the cell. Abnormally high levels of the HER-2 growth-promoting protein can be found in 25-30% of human breast cancers. A new FDA-approved treatment for the management of patients with metastatic breast cancer is an antibody directed against this HER-2 protein. This new biologic agent, called Herceptin, can be used alone or in combination with certain chemotherapy drugs. Recent studies from our laboratory suggest that therapy of HER-2-overexpressing breast cancers with Herceptin enhances tumor sensitivity to radiation. In addition, combined therapy with Herceptin and radiation causes tumor remissions in breast cancers that failed treatment with radiation alone. This benefit appears to be specific to cells with large amounts of HER-2 and does not occur in cells with normal amounts. A clinical advantage may be achieved in combined Herceptin-radiation therapy if Herceptin selectively radiosensitizes tumor cells or if the two agents act additively and selectively. The possibility that radiation and Herceptin could act selectively against certain breast tumor cells is the subject of the present proposal.
 
 
 
 
 
 
 
 We propose to further evaluate Herceptin-induced radiosensitivity and plan to conduct extensive preclinical studies to evaluate the safety and efficacy of this new therapy. In addition, we hope to learn more about molecular events associated with radiation-antibody treatment in order to further improve utilization of this innovative approach. Human cancer cells damaged by radiation may be especially vulnerable to injury if they are also deprived of essential growth-promoting signals provided by the HER-2 growth promoting protein. We plan to exploit this weakness in HER-2-overexpressing breast cancers in order to develop a new approach to radiation therapy with better clinical outcome and quality of life for affected breast cancer patients in California and elsewhere.
 
 
 
 
 
 
 
 This project proposes an innovative treatment modality that has not been used before. The research team is multidisciplinary, with primary contributions from clinical investigators in Intenal Medicine and Medical Oncology and Radiation Oncology. The impact of this preclinical trial is truly translational. The proposed research exploits a postulated DNA repair-regulatory circuit involving cell surface HER-2 proteins and is intended to lead directly to clinical trials of radiation therapy in combination with Herceptin in patients with HER-2-overexpressing breast cancers.