Career Goals: During my Ph.D. training in the Department of Biochemistry at the University of Mississippi Medical Center (UMC), I had the opportunity to help develop a very promising new drug for breast cancer. My previous training included extensive work with cancer cells grown outside the body, and the drug we have developed works well in this type of testing. However, for further advancement of this new drug toward the clinical market, its effectiveness must be proven in animal testing. For the proposed postdoctoral fellowship, I will be trained by Dr. Hamed Benghuzzi in the Department of Diagnostic and Clinical Health Sciences at UMC, where I will learn detailed methodology for animal experimentation. By transferring my training to an animal expert at UMC, I have the unique opportunity to continue development of a promising new drug begun during my doctoral training, while simultaneously learning a new field of research methods. After completion of this fellowship, I will be well equipped to pursue further postdoctoral training outside of Mississippi and to eventually attain a tenure-track position focused on developmental therapeutics for breast cancer at a competitive research institution.

Objective and Rationale: Breast cancer is most often treated by surgically removing the cancerous tissue, then treating the patient with chemo- and/or radiation therapy. Currently, chemotherapy is limited by the extreme toxicity of chemotherapy drugs, leading to severe side effects. Our long-term goal is to overcome these limitations by developing a drug carrier that can be targeted to the site of the cancer, which would increase the specificity and effectiveness of the therapy while simultaneously reducing the side effects. c-Myc is a protein that plays a central role in the regulation of cell growth and proliferation and is often made in very high amounts in cancerous tissue. Consequently, the inhibition of c-Myc function is a powerful method of inhibiting proliferation of cancer cells. We have developed a thermally responsive protein that inhibits c-Myc function and cancer cell proliferation in cell culture. This inhibitory protein can be targeted to the site of a tumor by applying focused heat to that site. Focused heating has been applied in the clinical setting for years, and it may be achieved using focused radio waves or high intensity focused ultrasound. Our hypothesis is that after intravenous administration, this heat-targeted drug carrier will accumulate at the tumor site where focused heat will be applied. This will result in inhibition of tumor growth. Our preliminary experiments demonstrate very significant killing of cancer cells grown outside the body in a dish by the heat-responsive c-Myc inhibitor. However, to prove that this strategy is useful for cancer therapy, it must be evaluated in an animal model of cancer. In order to address the hypothesis that the c-Myc inhibitory protein can be targeted to tumor tissue by heat in the body, we will evaluate the effectiveness of the c-Myc inhibitory protein for the treatment of breast cancer tumors grown in mice with and without localized heating. Two breast tumors will be grown in each mouse. The c-Myc inhibitory protein will be injected into the mice intravenously, and one tumor will be heated while the second is left at normal body temperature. We will follow the distribution of the protein in order to determine if it in fact accumulates at a higher level in the heated tumor. In a separate set of experiments, we will also test whether the c-Myc inhibitory protein can shrink the size of these tumors and whether the tumor size reduction is enhanced by heating the tumor.

Applicability: These studies will provide the basis for a new technology for specific targeting of a c-Myc inhibitor to cancerous tissue by localized heating. The potential use of this new drug will be in treatment of breast cancer patients after the main tumor has been surgically removed. The heat-targeted inhibitor will have far fewer side effects than conventional chemotherapy. Postsurgical patients can be given this new drug intravenously, and any cancerous tissue that was left in the body because it was not accessible to the surgeon or any area of the body where suspected cancer metastasis may develop can be heated. This treatment may reduce cancer recurrence by killing off any remaining cancer cells invisible or inaccessible to the surgeon. This proposal describes the development of a c-Myc targeted drug, but this approach is not limited to the c-Myc inhibitor. If successful, this approach may be modified for tumor-specific delivery of any drug or therapeutic agent by attaching it to the heat-targeted carrier. Thus, development of the proposed drug delivery system would provide a means to increase the specificity and effectiveness of treatment and reduce the toxicity in normal tissues. The successful completion of the proposed research will provide the animal data necessary to move this technology to the next stage, human therapeutics.