SBIR-STTR Award

The aim of this proposal is to test the feasibility of the use of a p53 fusion protein as a cancer therapeutic. World wide 10 million people are diagnosed every year with cancer. 50% of human cancers involve a mutation in the p53 gene. In addition, these mutations are frequently found in solid tumors that are resistant to conventional therapies. These facts clearly demonstrate that p53 is an important target for anti-neoplastic therapies. Development of a novel p53- targeted anti-neoplastic therapeutic has the potential to save millions of lives worldwide each year, yet there are currently no FDA approved cancer therapies targeting this gene product. Using a patented refolding technology developed at ProteomTech, Inc., Pt-Fold, we have identified conditions that allow us to produce large amounts of stable tetrameric recombinant human p53 protein. To our knowledge, we are the only group that has been successful in accomplishing this. However, an efficient means of delivering this protein into cells is required for a successful protein therapeutic. We propose to achieve intracellular delivery by producing a form of p53 that is fused to a peptide that will mediate cell entry. Feasibility issues that will be addressed in phase 1 of this application include expression, refolding, purification and functional testing of the fusion proteins in p53-deficient cancer cell lines. Our goal of phase I of the proposal is to identify the best fusion protein for pre-clinical studies for a Phase II application. Development of a novel anti-neoplastic therapeutic for cancers that are characterized by a mutation if p53 and refractory to current therapies would represent a significant contribution to the oncology field and has the potential to benefit millions of people each year. According to the International Agency for Research on Cancer (IARC), world wide 10 million people will be diagnosed every year with cancer. Furthermore, the IARC estimated that up to half of all human cancers carry an inactivating mutation in the p53 gene. P53 mutations are frequently found in solid tumors that are resistant to conventional therapies. Despite the importance of this target, there are currently no FDA approved cancer therapies targeting p53. The aim of this proposal is to test the feasibility of the use of a p53 fusion protein as a novel cancer therapeutic

TP53 is a transcription factor that exerts tumor suppressor function by regulating the cell cycle, DNA repair and apoptosis. Its transcriptionally active form is a homotetramer consisting of four identical monomeric units. Somatic mutations in the p53 gene are found in over 50% of human cancers and germ line mutations in p53 are responsible for an inherited cancer predisposition, Li-Fraumeni syndrome. In addition, for those cancer cells that lack a p53 mutation, up to 80% exhibit a 5-10-fold reduction of p53 protein levels compared to corresponding normal tissues. It has been proven that by supplement p53 protein in these p53-difficient cancer cells to their normal level, the cells will undergo apoptosis and tumors can be controlled or eliminated. Our innovative approach involves the development of a p53 fusion protein therapeutic using our unique, patented refolding technology, Pt-Fold, in conjunction with an efficient, specific, peptide-based delivery technology. During the SBIR Phase I funding period, we have refolded the wild-type, full-length p53 as well as a fusion protein, gonadotropin-releasing hormone-p53 (GnRH-p53), in a stable tetrameric form, from E. coli inclusion bodies. In addition, we have demonstrated a proof of the concept that GnRH-p53 binds to GnRH receptors on the cell surface, enters the cell nuclear, and inhibits the growth of cancer cells in vitro. In preliminary animal studies using rodent tumor models, our university collaborator demonstrated that the GnRH-p53 tested was capable of dramatically slowing tumor growth when compared to controls. In the Phase II project, we will further develop the GnRH-p53 therapeutic into various preclinical dosage forms for therapeutic application. The long term objective of this study is to develop GnRH-p53 into an effective antineoplastic drug to treat patients with breast, ovarian, and prostate cancers.

Public Health Relevance:
This project is to develop new process for efficiently producing GnRH-p53 protein therapeutic for scale-up production and formulation development. The ultimate goal is to develop GnRH-p53 into an effective antineoplastic drug to treat patients with breast, ovarian, and prostate cancers.

Public Health Relevance:
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