A research team at the David Geffen School of Medicine at UCLA received a $1.8 million, five-year grant from the National Institutes of Health (NIH) to develop new therapeutic and preventive strategies for ovarian cancer based on the tumor suppressor p53.
The team, led by Alice Soragni, PhD, will focus on the role of p53 in cancer onset and progression. It will also investigate the preventive effects of ReACp53, a p53-reactivating molecule that has shown promise in fighting ovarian cancer in preclinical studies.
P53 is a natural tumor suppressor that cells use to prevent uncontrolled growth. It arrests cell growth and promotes either DNA repair or cell death in cells with DNA damage or in stressful environments such as low oxygen or low nutrients. It also plays an important role in regulating several aspects of anti-tumor immune responses.
Mutations in TP53, the gene that contains the instructions to produce the p53 protein, block p53 anti-tumor function, leaving cells more susceptible to uncontrolled growth. A fraction of these mutations results in a protein with an abnormal structure, which promotes the formation of p53 aggregates, resulting in p53 inactivation.
TP53 is the most frequently mutated gene in human cancers — estimated to occur in over 50% of all tumors — and mutations in this gene are usually associated with cancer resistance to therapy and poor clinical outcomes. Currently, there are no approved therapies to restore p53 function.
High-grade serous carcinoma (HGSC), the most common and most deadly form of ovarian cancer, has the highest mutation rate of the TP35 gene, with mutations in this gene reported in over 96% of cases. Ovarian cancer affects more than 22,000 women in the United States and is the fifth-most common cause of cancer-related death among American women.
A recent study reported that pre-cancerous ovarian lesions already show TP53 mutations — while in a reduced level compared with cancer cells — but not all of them will develop into cancer. Thus, it is important to develop better ways to identify ovarian cancer at its very early stages and improve preventative care.
“This project will determine whether p53 aggregation is a feature that can be used to discriminate [pre-cancerous] tissue from normal tissue, and can be targeted for early therapy and prevention of ovarian cancer,” Soragni said in a press release.
The team will also evaluate whether ReACp53, a suppressor of p53 aggregation developed by Soragni and other UCLA researchers, can prevent pre-cancerous lesions from becoming full-blown ovarian cancer.
ReACp53 was shown to block p53 aggregation and promote p53 reactivation in 3D tumor spheres derived from HGSC patients and in mouse models of the disease. Reactivated p53 reduced cell growth and increased cell death in HGSC cells with the aggregating, mutated form of p53, but not in cells with normal p53.
The results suggested that blocking the aggregation of p53 through ReACp53 may be a successful therapeutic strategy to reactivate p53 and suppress tumor growth in patients with HGSC and other tumors associated with p53 mutations.
ReACp53 was licensed to ADRx, which is testing its safety with the aim to proceed to clinical trials as an anti-cancer therapy.