This gene is mutated in more than 50% of cancers! One article to understand the different strategies to overcome it

TP53 is one of the most commonly mutated genes in human cancers, and it is estimated that more than 50% of cancers carry the TP53 gene mutation
.
Since TP53 was first reported in 1979, scientists have conducted in-depth studies of the p53 protein encoded by TP53, but p53 is also one of the most difficult targets to develop in oncology research, and no effective means of targeting p53 has been approved
by the FDA.

With further research on p53, scientists are targeting this target using different means, from traditional small molecule drugs to innovative treatment models
such as bispecific antibodies, protein degradation therapy, gene therapy and RNA therapy.
A review in Nature Reviews Drug Discovery took stock of different approaches to targeting p53
.

The role of p53 in inhibiting the initiation and progression of cancer

The main role of wild-type p53 is to act as a transcription factor that limits the proliferation and survival of tumor cells by activating the expression of a range of genes.

In addition, p53 has functions beyond transcription factors, and its interaction with BCL-2 family proteins can promote mitochondria-excited apoptosis
.
p53 is also an important regulator of autophagy and can affect the tumor microenvironment, making it detrimental to tumor growth
.

Due to the multiple effects of p53 in inhibiting tumor growth, the TP53 gene is also one of
the most commonly mutated genes in tumors.
Most TP53 gene mutations are missense mutations, resulting in p53 protein not performing its function
of inhibiting tumor growth normally.
However, there are also some mutations that allow p53 mutants to produce functions that promote tumor growth, such as activating genes that promote the growth of cancer cells, reducing apoptosis caused by endoplasmic reticulum stress, and changing the tumor microenvironment
.
Therefore, p53 is an attractive and important target for cancer treatment
.

Small molecule drugs that target p53

The development of small molecule drugs against p53 began more than 20 years ago
.
Since most TP53 gene mutations lead to the instability of p53 structure and loss of function, the main goal of small molecule drug development targeting p53 is to restore the structure and expression level of p53, so that p53 can exercise its normal tumor suppression function
。 Small molecule drugs currently under development can be divided into three main categories: the first class of drugs increases p53 expression levels by targeting negative regulators of p53 expression, including MDM2, MDM4, and HPV E6; The second class of drugs aims to restore the structural stability and function of p53 mutants by targeting specific p53 mutants; The third class of drugs targets the truncated p53 protein
produced as a result of nonsense mutations in the TP53 gene.

The advantage of targeting p53 negative regulators is that it can have an effect on wild-type p53 and has a broader spectrum of potency
.
For example, Ascentage Pharma's MDM2 inhibitor APG-115 restores the tumor suppressive activity
of p53 by binding to MDM2 to block the interaction between MDM2 and p53.
It has obtained multiple orphan drug designations from the FDA for indications including acute myeloid leukemia, soft tissue sarcoma (STS), retinoblastoma (RB), stage IIB-IV melanoma, etc
.

In addition, protein degradation therapy can also be used to degrade regulators that inhibit p53, thereby increasing p53 levels
.
For example, KT-253, Kymera Therapeutics' MDM2-targeting protein-degrading drug, has demonstrated superior activity
to MDM2 small molecule inhibitors in preclinical experiments.
The company expects to file an IND application
with the FDA by the end of the year.

Small molecule drugs that target p53 mutants are designed to restore the normal structure and function
of p53 by binding to the mutants.
For example, the laboratory of Professor Kevan M.
Shokat, who has made outstanding contributions to targeting KRAS, has published a paper describing a covalent compound bound to the p53 Y220C mutant, which can restore its thermal stability to a degree
comparable to wild-type p53.

These targeted therapies have less impact on wild-type p53 and are less toxic because they target mutants caused by mutations in the specific TP53 gene, although the TP53 gene has a variety of different genetic mutations, and strategies to target specific p53 mutants may not be applicable to other mutants
.

For truncated p53 proteins produced due to nonsense mutations, current strategies are to raise levels
of p53 with drugs that promote ribosome-read-through or drugs that inhibit the degradation of truncated p53 proteins.
However, whether these drugs can effectively increase p53 levels still needs to be verified, and their potential toxicity is also a concern
.

Immunotherapy for p53

Since p53 mutants are mostly highly expressed in tumor cells, their peptide fragments are also more likely to be presented to the cell surface by tumor cells and thus recognized by the body's immune system
.
Immunotherapy against p53 enhances the body's immune system's ability to recognize p53 mutants and activates an immune response against p53 mutants, thereby eliminating tumor cells
expressing p53 mutants.

This strategy includes cancer vaccines based on p53 mutants, monoclonal antibodies and bispecific antibodies
targeting p53 mutants.
For example, in a study published last year in the journal Science, a team led by academics at Johns Hopkins University successfully developed a bispecific antibody therapy
that targets the p53 mutant.
It recognizes mutant p53 polypeptide fragments
and human leukocyte antigen (HLA) proteins with great specificity.
At the same time, the other end of this bispecific antibody can bind to CD3 receptors on the surface of T cells, activating T cells to kill tumor cells
expressing p53 mutants.
This study provides the first evidence that bispecific antibodies targeting p53 mutants can still activate T cells and destroy tumor cells
even at extremely low levels of neoantigen expression on the cell surface.

The review authors note that the key to this strategy is to stimulate a specific immune response
against the p53 mutant.
Normal cells also express p53, and while most cells have low levels of p53 and present fewer antigens on the cell surface, some cells that divide frequently, including stem and progenitor cells, have elevated p53 expression levels, making it a concern
for researchers to avoid the immune system attacking healthy cells.

Gene therapy and RNA therapy for p53

Since most TP53 gene mutations cause p53 inactivation, the use of gene therapy to express p53 with normal function is also an important research and development direction
to restore p53 function.
Using viral vectors or lipid nanoparticles, transgenes encoding wild-type p53 protein can be delivered to tumor cells to restore normal p53 expression and produce tumor suppression
.

With the success of mRNA vaccines, the use of nanoparticles to deliver mRNA encoding p53 has also become one of the directions of
drug development.
In February, a team of researchers from Harvard Medical School and Massachusetts General Hospital published a paper in Nature Communications that successfully used CXCR4-targeting nanoparticles to deliver p53-expressing mRNA
in an animal model of hepatocellular carcinoma.
This therapy is combined with anti-PD-1 antibodies to effectively change the cellular and molecular composition of
the tumor microenvironment.

One problem to note with this strategy is that many p53 mutants not only lose their own function, but may also block normal p53 function due to elevated expression levels
.
In this case, the effect of expressing normal p53 protein may not be significant
.
In addition, some p53 mutants carry cancer-promoting functionally acquired mutations, and expressing normal p53 proteins does not prevent the carcinogenic effects
of these mutants.

In addition to gene therapy and mRNA therapy, RNAi can inhibit the expression of the mutated TP53 gene, and the CRISPR gene editing system has the potential to
repair the TP53 gene mutation.

Looking to the future

The review authors noted that since 2000, a number of therapies targeting p53 have entered clinical trials, and with the further understanding of p53 mutants and the advancement of screening methods, the proportion of small molecule drugs targeting p53 in clinical trials has increased
significantly in the past 10 years.