The laboratory has extensive experience in mouse cancer models and development of novel therapeutics. Our research focuses on preclinical cancer models in relation to immunosuppression within the tumor microenvironment. The working model is that 'oncogenic addiction' may play a role in sustained tumor suppression and that inhibition of this cell intrinsic signals will facilitate tumor specific immunity. We work on Her-2/neu expressing cancer models. Overexpression of the receptor tyrosine kinase ERBB2 (her2/neu) occurs in various solid tumors but most prominently in 30% of breast cancer patients.
While both, therapeutic antibodies and ERBB targeted kinase inhibitors are in use, inconsistent response rates and disease reoccurrence remain a problem for a large percentage of patients. Thus, we are developing ERBB2 targeted therapies with small molecule drugs isolated from plant derived compounds. We discovered that Withaferin A (WA), a steroidal lactone isolated from an Indian medicinal plant was effective against Her-2/neu expressing cancer cells. We demonstrated that Her-2 overexpression in human breast cancer cells confers an elevated level of WA sensitivity and was dependent on synergistic signaling by Her-3 and Her-2, even when the sensitivity to Her-2 targeting kinase inhibitors like Lapatinib is reduced. Furthermore, downregulation of Her-2 from cell the surface caused apoptotic cell death by inducing stress related proteins which has implications in tumor specific immunity.
Currently we are developing combination strategies such as Herceptin and oncolytic herpesviruses (oHSVs) to enhance and improve therapeutic benefit of these novel drugs. We have reported that intratumoral administration of oHSVs expressing murine cytokines delayed tumor growth and extended survival of immunocompetent mice bearing mammary tumors. Surviving mice rejected tumor re-challenge ninety days later thereby demonstrating the presence of long-term immunity. This research was funded through American Cancer Society, National Institute of Alternative and Complementary Medicine and Women's Cancer Association.