Increased awareness and systematic screening for breast cancer has resulted in early detection of this disease. However, 20-30% of node negative breast carcinoma patients will develop recurrent tumors, and given the highly metastatic nature of breast cancer, many of these patients progress to disseminated disease. Although developments in experimental therapies for the treatment of advanced breast cancer are promising, much of the existing treatment for advanced metastatic cancer is palliative. Among the numerous symptoms of advanced cancer, pain remains the most significant determinant of quality of life. Despite pain being the most feared symptom of advanced cancer, clinical management of cancer pain remains inadequate. Limitation in the clinical management of advanced cancer pain appears multifactorial ranging from the nature of pain itself to the irrational fear of prescribing large quantities of opiates among the treating physicians. A novel non-opioid approach to pain management that requires minimal high-technology resources will have wide spread applications in the management of terminal cancer pain and other intractable pain syndromes.

In this proposal, we describe a novel viral-vector mediated gene-therapeutic approach to pain management. This notion is based on well documented observations that all vertebrate nervous systems including humans' posses an endogenous analgesic system. Of the numerous neurotransmitter systems implicated in such an endogenous analgesic system, one of the best described descending analgesic mechanisms is the brain stem serotonergic input to the spinal cord. Stimulation of brain stem neurons results in release of serotonin, an amine neurotransmitter, at the spinal cord that modulates the transmission along the pain pathway. The goal of this project is to examine if enhancement of this endogenous serotonergic analgesic system can provide analgesia. We take advantage of the natural ability of virus to introduce foreign genes into non-dividing cells such as neurons. A recombinant adenovirus designed to express one subtype (5HT3) of the serotonin receptor thought to mediate part of the descending analgesic action of serotonin will be created and introduced into the subarachnoid space. The intrathecally administered recombinant adenovirus will transduce the 5HT3 receptor gene, overexpress this analgesic receptor, and thereby provide analgesia through enhancing this endogenous analgesic control.

The project utilizes molecular biological, immunohistochemical, and whole animal behavioral methods to evaluate this novel approach to pain management. The technical objectives are designed to (1) systematically evaluate the effectiveness of intrathecal recombinant adenovirus as a potential approach to providing analgesia and (2) design new viral vectors and protocols for virus co-administration with immune-modulators with the goal of overcoming the limited utility of the current generation adenovirus for actual human applications. The preliminary data accompanying this proposal indicate the high likelihood of virally mediated overexpression of spinal cord 5HT3 receptors providing analgesia. Should the proposed studies prove successful, in future studies, this adenovirus based pain management strategy will be tested in a more realistic animal model of cancer pain with the ultimate goal of bringing this approach to the clinical arena for human trials. The Principal Investigator's close affiliation with the Pain Treatment Center at the University of Rochester Medical Center, which is already actively involved in the management of intractable pain in terminal cancer patients, will facilitate the efficient translation of basic research to the clinics.