Gene Therapy for the Treatment of Metastatic Breast Cancer by In Vivo Transduction with Breast-Targeted Retroviral Vector Expressing Antisense c-fos RNA. Vanderbilt University Medical School, Nashville, Tennessee

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Abstract
Although murine retroviral vectors can transduce diverse types of proliferating cells, inclusion of tissue-specific or inducible promoters within retroviral vectors should theoretically target expression to allow selective expression within tumor cells. The mouse mammary tumor virus (MMTV) long terminal repeat (LTR) is expressed at high levels in only certain tissues in vivo: breast, prostate, salivary gland. We have employed these vectors to transduce MCF-7 human breast cancer cells. Transduction of cultured cells by supernatants from cloned producer cells expressing either antisense c-fos RNA or antisense c-myc RNA (titer 9 × 105 virions/ml) produces a greater than 90% reduction in the tumor size when cells are injected into an estrogen-dependent nude mouse model (compared with control MMTV-based viral vectors). Based upon these findings, we have proposed a clinical trial to determine if infusion of antisense c-fos viral vectors will induce regression of metastatic breast cancer in the peritoneum (malignant ascites) or pleura (malignant pleuritis). The patient population will consist of women who have failed standard therapy and have extensive, biopsy or cytology-proven metastatic breast cancer involving the peritoneum or pleura which result in malignant effusions. In this protocol, patient effusions will be drained daily for 4 days and the fluid replaced with retroviral vector. These are patients who have failed standard therapy for their cancer and are expected to survive for a few months. We are studying the possibility of slowing the growth of metastatic breast cancer by inhibiting “oncogenes” (growth-promoting genes) within the cancer cells. The purpose is to introduce gene sequences which block the growth or spread of breast cancer cells by blocking the function of specific oncogenes by a genetic engineering technique called antisense. The oncogenes which we have selected for inhibition in these initial studies are named c-fos and c-myc. By transferring antisense sequences into breast cancer cells, using a disabled mouse virus called a “vector,” we change gene expression within the cancer cells so the cancer cells now grow more slowly and then-spread is diminished. Experiments in mice have shown that the transfer of antisense sequences into breast cancers using viral vectors, results in a marked decrease in the growth and spread of the breast cancer. We have found no evidence of spread of the virus to other tissues within the body, and no apparent ill effects of the viral vectors. Based upon these findings, we propose a human clinical trial for patients with widespread breast cancer which has spread to produce fluid-filled spaces (effusions) which surround the lungs and abdomen. In this study, patients will undergo injection of viral vector into the cancerous fluid in an attempt to induce regression of the cancer, and to stop the spread of the cancer cells. The patient population consists of women with breast cancer who have failed standard therapy and have metastatic breast cancer with an expected survival of a few months.