Targeting Breast Cancer Brain Metastases with an Anti-DNA Autoantibody
Abstract
Breast cancer is the second leading cause of cancer death in women, and triple-negative breast cancer (TNBC) is the most aggressive and difficult to treat form. Absence of estrogen, progesterone, and HER2 receptors makes TNBC resistant to targeted therapies such as tamoxifen and trastuzumab. Compared to other subtypes of breast cancer, TNBC is more likely to spread into the brain to develop tumors that are referred to as breast cancer brain metastases (BCBMs). BCBMs ultimately develop in almost half of patients with advanced TNBC, which is associated with a poor prognosis and significant neurologic dysfunction and impaired quality of life. When only one or a few BCBMs are present in the brain, surgical resection or radiosurgery is considered. However, when numerous lesions are present (which is commonly the case), the standard of care treatment is whole brain radiation (WBRT). WBRT carries significant risks for toxicity including acute effects of headache, nausea and vomiting, fatigue, and hair loss, and longer term effects on memory and cognitive function. In addition, because radiation dose to the whole brain is necessarily limited to minimize risks of toxicity, disease recurrence and progression after WBRT is common. Improved methods to target and treat BCBMs with reduced toxicity are needed. Although TNBC lacks the usual surface receptors that are targeted by conventional therapies, it does harbor an intrinsic deficiency in DNA repair that has the potential to be capitalized on to develop a new approach to BCBM therapy. However, DNA is sequestered inside the nucleus of cancer cells, which is a difficult region for drugs to access. In addition, a challenge to the discovery and development of new drugs to treat BCBMs is the body’s own defense system. The brain has a highly developed method of protecting itself from drugs and other environmental toxins that may enter the bloodstream called the blood-brain barrier (BBB). The BBB excludes most drugs from the brain and prevents most chemotherapies from exerting any significant effects on BCBMs. Methods to cross the BBB and target intranuclear processes are needed. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by production of autoantibodies reactive against host DNA, and a small percentage of these lupus anti-DNA autoantibodies have the ability to directly penetrate into cell nuclei. These unusual autoantibodies offer a previously unrecognized resource to help develop antibody-based approaches to targeting intranuclear processes such as DNA repair and can also be used as delivery ligands for targeting regions enriched in DNA. We found that a nuclear-penetrating lupus anti-DNA autoantibody, 3E10, has potential to be used against BCBMs. 3E10 binds DNA and inhibits DNA repair in a manner that is not toxic to normal cells, but sensitizes tumors to radiation therapy and kills cancer cells with defects in DNA repair, such as TNBC. We have now re-engineered the autoantibody to minimize risks of lupus-like side effects and maximize its impact on tumors, and this optimized version is called Deoxymab-1 (DX1). Remarkably, we have found that DX1 has the ability to cross the BBB to localize into brain tumors. The autoantibody utilizes a DNA salvage transporter to penetrate cells, and this transporter is active at the BBB and we believe is the method by which DX1 crosses the BBB. The ability of DX1 to cross the BBB and localize to tumors, sensitize tumors to DNA damage, selectively kill TNBC cells as a single agent, and deliver linked nanocarriers to tumors makes it a compelling candidate for use against BCBMs and address the overarching challenges of identifying more effective treatments and improving treatment strategies of metastatic breast cancer. The aims of this proposal are to (1) elucidate and enhance the mechanism of BBB penetration by DX1 in BCBMs, (2) use DX1 to exploit the vulnerability of BCBMs to DNA damage both as a sin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910649
Entities
People
- James Hansen
Organizations
- United States Army
- Yale University