Targeting Breast Cancer Metastasis through Selective Inhibition of RNA Polymerase I
Abstract
Overarching Challenges: Eliminate the mortality associated with metastatic breast cancer. Revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. We have discovered that a particular enzyme, RNA Polymerase I (Pol I), is required for the survival of cancer cells. While Pol I plays an important role in normal (healthy) cells as well, these cells can tolerate short-term inhibition of Pol I, whereas cancer cells cannot. Following this discovery, we initiated a program to develop the first selective inhibitor of Pol I activity, CX-5461. This compound was shown to have a good risk-to-benefit profile in animals and is now being tested in a human clinical trial involving patients with hematologic malignancies (blood cancers). Pol I inhibitors do not damage DNA and therefore should produce fewer side effects than many currently used anticancer agents. At the same time, we continued to study the role of Pol I in tumor development. A major advance was our demonstration that, for breast cancer, Pol I is required not only for primary tumor growth, but it is also crucial for the spread of the tumor to distant sites. This process is called metastasis and is the leading cause of death from breast cancer. One of the principal sites of breast cancer metastasis, which represents a particular challenge for treatment, is the brain. The brain is separated from the rest of the body by a blood-brain barrier that is designed to protect the brain from harmful foreign substances, but at the same time this barrier prevents many cancer drugs from reaching brain tumors. As a result, the prognosis for patients with breast cancer that has metastasized to the brain is very poor, with median survival being 6 months. Consequently, new medicines that can reach and treat breast cancer metastases in the brain are urgently needed. In this project we will discover and develop novel selective inhibitors of Pol I that can penetrate the blood-brain barrier and be used to prevent and treat breast cancer metastasis, including brain metastasis. Our compounds have the potential to benefit patients with late-stage tumors at highest risk for brain metastasis and with a very poor prognosis. These patients include those whose tumors possess high levels of a protein called HER-2, as well as those whose tumors lack this protein and two key hormone receptors (those binding estrogen and progesterone). The recent development of an antibody that blocks HER-2 protein function (trastuzumab) has improved the overall survival of patients with late-stage breast cancer having high levels of HER-2, from 20.3 to 25.1 months. Unfortunately, this increase in patient survival time is accompanied by an increase in brain metastasis, as the patients live longer. In clinical trials of trastuzumab, which does not penetrate the blood-brain barrier, patients developed brain metastases with an incidence of 25%-50% while tumors in other sites responded to the drug over a period of 4 to 24 months. Thus, an agent specifically designed to prevent and treat brain metastasis could significantly improve clinical outcome and could be used effectively in combination with others drugs such as trastuzumab. As we have extensive experience in drug discovery and development and have already identified novel compounds that are potent Pol I inhibitors with strong potential to penetrate the blood-brain barrier, we should be able to advance a drug into preclinical development within 2 years following funding approval. Very recently, we have shown that at least one of these compounds can block epithelial-mesenchymal transition and breast cancer cell migration in cell culture, a laboratory model for two aspects of the metastatic process. If this compound has an acceptable preclinical safety profile, it could be advanced into clinical testing within 3.5 to 4 years after the start of our proposed research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510224
Entities
People
- Denis Drygin
Organizations
- United States Army