Super p53 for Treatment of Ovarian Cancer
Abstract
Rationale and Objective: The rationale for this project stems from the malfunctioning of tumor suppressor proteins, the leading cause for cancer development. The tumor suppressor protein, p53, is known to be mutated in more than 50% of all cancers, and in over 96% of high-grade serous ovarian cancers (HGSCs). As a result, efforts to use wild-type (wt) p53 (non-mutated) for cancer gene therapy have ensued. These wt p53 gene therapies, however, have not been effective in patients due to the "dominant negative effect" where mutated p53 in cancer cells binds to any added p53 and inactivates the added p53. The objective of this project is to use a re-engineered p53 (called super p53, and referred to as p53-CCmut in the proposal) for gene therapy that is not subject to dominant negative inhibition by mutated p53 in cancer cells. This super p53 is modified to contain a segment called a coiled-coil domain that allows binding with itself only (resulting in auto-activation). Super p53 cannot bind to other proteins in cancer cells, including wt p53, and subsequently is not inactivated. Critically, super p53 is expected to show tumor suppressor/anti-cancer activity regardless of the p53 status or other genetic heterogeneity of a patient with ovarian cancer. Central Problem in Ovarian Cancer Addressed: There are no current effective therapies for all ovarian cancer patients. Newer drugs are being tested including targeted therapies, but their success depends on patient-specific heterogeneous genomic factors. A recent study of ovarian cancer strikingly found p53 gene mutations in >96% of 500 patients with HGSCs. Recurrent mutations in other genes were noted, but at low prevalence, highlighting p53 mutation as the major driver in most ovarian cancers, paving the way for p53 gene therapy. However, in the 1990s, clinical trials for wt p53 in combination with carboplatin and paclitaxel failed due to the dominant negative inactivating effect exerted by mutated p53 in cancer cells. This proposal addresses the failure of wt p53 gene therapy for ovarian cancer. Super p53 has been designed to overcome this and has proven ability to do so in breast cancer models and other cancer cell lines. Due to the unlimited potential of p53-CCmut, we believe that it will have a significant impact on the outcome of patients with ovarian cancer. Relevance to Vision and Mission of the Ovarian Cancer Research Program: The use of super p53 represents an innovative project that could change the way ovarian cancer is treated. Super p53 represents a major advancement for killing ovarian cancer cells using rational design and re-engineering of wt p53. Overcoming the dominant negative effect of mutant p53 in cancer cells is currently the rate-limiting step for using wt p53 for gene therapy; super p53 overcomes this barrier. Critically, since loss of p53 function is also linked with metastasis, super p53 has the potential of overcoming metastatic disease, present in most patients with advanced disease. This novel p53-CCmut concept, coupled with the latest polymeric delivery strategies in combination with standard chemotherapy, represents a major advancement and will significantly accelerate the progress of ovarian cancer treatment. Which Individuals Will Be Impacted and How Will It Help Them? While this proposal focuses on the HGSC subtype of ovarian cancer, patients with all types of ovarian cancer are expected to benefit from this therapy. Our super p53 has already shown cell killing ability in other types of cancer cells (lung, breast, cervical cancer cells) with the entire spectrum of p53 statuses (mutated, mislocalized, null, wt). As most ovarian cancer patients are not diagnosed until late stage, this proposal includes a late stage (> stage III) ovarian cancer animal model to move towards the real-life clinical situation. Potential Clinical Applications, Benefits, and Risks (Potential Long-Term Outcomes): We were encouraged that in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510036
Entities
People
- Carol Lim
Organizations
- United States Army
- University of Utah