Karina Matissek

Graduate Student

Phillips Universität
University of Utah, Department of Pharmaceutics & Pharmaceutical Chemistry

30 S 2000 E
LS Skaggs Pharmacy Institute
Salt Lake City, Utah, 84112
USA
ph: 801.581.7120

Karina.Matissek@utah.edu

 

Research Project

Breast cancer is a well characterized disease with various therapy options. However, many patients with advanced breast cancer are resistant to standard chemotherapy or hormone therapy. Furthermore, chemotherapeutic agents such as anthracycline have serious side effects and anti-hormone therapy can lead to uterine cancer. Thus, there is a need for new therapeutic approaches that are effective in patients for whom standard therapies fail. Patients with p53 mutations or inactivation have a less than ideal response to current anti-cancer agents characterized by a poor prognosis.

Studies have demonstrated that the tumor suppressor p53 inhibits tumor development causing cell cycle arrest, DNA repair, senescence and apoptosis. Even though, most of these abilities can be linked to its role as transcriptional factor, recent work has clearly demonstrated that p53 can cause apoptosis through its transcriptional-independent mitochondrial arm. Extranuclear effects of p53 in the mitochondria are associated with mitochondrial outer membrane permeabilization (MOMP). The DNA binding domain of p53 interacts with multi-domain proteins from the Bcl-2 family, such as the anti-apoptotic Bcl-XL protein triggering rapid and complete release of potent apoptotic activators.

The goal of my project is to develop an optimal version of the tumor suppressor p53 engineered with mitochondrial targeting signal (MTS) to trigger rapid apoptosis via the intrinsic pathway. Increased mitochondrial localization will be achieved by selecting an optimal MTS and the removal of the strongest nuclear localization signal in p53. Additionally, the minimally active version of p53 will be chosen to minimize side effects and delivery issues. Constructs will be tested in breast cancer cells with mislocalized p53 (MCF-7), multidrug resistant MCF-7 cells and those with mutated p53 (T47D).

In summary, mitochondrial targeted p53 triggers a rapid apoptotic response and is an excellent target for inflammatory breast carcinoma, an aggressive and deadly form of breast cancer that has mutated and mislocalized p53. This gene therapy approach is also expected to be beneficial for other types of aggressive cancers that currently have no effective therapies.