The majority of patients with advanced breast cancer develop bone metastases causing considerable morbidity and mortality. Thus, there is a tremendous need to develop novel approaches to treat breast cancer, and is one of the missions of National Cancer Institute. The goal of this proposal is to develop a therapeutic approach that will destroy the primary tumor, and simultaneously inhibit the breast cancer-associated bone metastasis. We will target the transforming growth factor-? (TGF?) pathway because high levels of TGF? protein are known to contribute to the tumor progression, and are associated with bone metastasis in breast cancer patients. We will test whether oncolytic adenoviral vectors (dl01/07 based) expressing the soluble form of TGF? receptor II fused with human Fc lgG1 (Fc) (sTGF?RIIFc) have anti- tumor effects. We constructed a dl01/07 based adenoviral vector expressing sTGF?RIIFc (Ad.sT?RFc). To further restrict viral replication in breast tumor cells, we have constructed mhTERTAd.sT?RFc, a modified 01/07 based adenoviral vector expressing sTGF?RIIFc gene, in which viral replication is under the control of a modified human telomerase reverse transcriptase (mhTERT) promoter. We will test the hypothesis that Ad.sT?RFc and mhTERTAd.sT?RFc will be oncolytic to the tumor cells, will produce sTGF?RIIFc, and will cause minimum or no toxicity to the normal cells. We will also test the hypothesis that adenoviral-mediated production of sTGF?RIIFc will abolish the effects of TGF? on tumor progression, osteoclastogenesis, and osteoblast differentiation together inhibiting the metastatic potential of the breast cancer cells. Following are the Specific Aims.
Aim 1. To evaluate Ad.sT?RFc and mhTERT Ad.sT?RFc in vitro: Viral replication and sTGF?RIIFc production.
Aim 2. To evaluate sTGF?RIIFc-mediated inhibition of TGF? functions in vitro: TGF? signaling, osteoclastogenesis, and osteoblast differentiation.
Aim 3. To evaluate Ad.sT?RFc and mhTERTAd.sT?RFc in vivo: Virus distribution, replication, gene expression, safety, and toxicity.
Aim 4. To evaluate Ad.sT?RFc and mhTERT Ad.sT?RFc in vivo: Tumor growth, metastasis, and osteolytic bone destruction. Nearly 200, 000 women are diagnosed with breast cancer each year in the United States. Most of the patients with advanced breast cancer develop bone metastases causing considerable morbidity and mortality. Thus, there is an urgent need to develop novel approaches to treat breast cancer. The goal of this project is to develop a new gene therapy method to treat breast cancer. The successful completion of the preclinical research proposed here is essential before clinical trials on breast cancer patients can be initiated.
