Understanding p53 functions for its therapeutic targeting
Cancer genome sequencing efforts have led to the identification of all major alterations that occur in a wide variety of genes. Among these, p53 is the most mutated gene across all cancer types. Mutant p53 often acquires gain-of-novel functions (GOF) properties to drive cancer progression and metastasis, making it a potential target for therapeutic intervention. Yet, there are no effective strategies to target mutant p53.
Our laboratory, along with many others, have contributed to the analyses of the various types of p53 mutants, which has led to the conclusion that not all p53 mutants are equal, as they vary in their ability to drive cancer progression. P53 mutants vary in their transactivation potential, from having lost functions partially (PF) or with complete loss of function (LOF), to dominant-negative (DN) and GOF, as depicted below.
Thus, there is no “one-size fits all” approach that can be employed to target mutant p53, and a systematic approach is required to develop mutation-specific reagents. In this regard, we have spent the last few years on a program to generate novel molecules that would target mutant p53 expression without having an effect on the WT allele, using a multitude of strategies, such as mutation-specific siRNAs and mutation-specific monoclonal antibodies.
Our proprietary p53 mutation-specific siRNAs are capable of targeting and silencing the expression of specific p53 mutations, without affecting the expression of the WT protein (please see example figure below). These tools are now being developed further to be eventually used in the clinical setting, particularly for targeting hepatocellular carcinoma, which has a high prevalence of the R249S p53 mutation.
The other technology we have developed together with Sir David Lane’s laboratory is the p53 mutation-specific antibodies. Similar to the mutant-specific siRNAs, these antibodies are highly specific for the intended p53 mutants (please see figure below) and could be used in the clinical setting for diagnosis of patients with the specific mutations. We are developing these antibodies further to be used clinically for tumor monitoring and therapy, and are also utilising this antibody platform to generate mutation–specific antibodies for other common mutations found in cancers.
We are also harnessing p53’s tumor suppressor potential to prevent cancer development, and to delay the relapse of cancers. Using genetically modified mice to express p53 in a temporal manner, we are exploring if p53 expression can delay tumor development in a variety of cancer models. Small molecules and natural compounds capable of p53 activation are also being pursued to achieve these goals.
Various other projects aimed at deciphering p53 functions to modulate its activity are underway.