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TP53 is one of the most common mutant genes in human cancer. It is estimated that more than 50% of cancers in carry TP53 gene mutations. Since TP53 was first reported in 1979, scientists have conducted in-depth research on the p53 protein encoded by TP53. However, p53 is also one of the most difficult targets to develop in oncology research. At present, no effective means to target p53 have been approved by FDA.
As the research on p53 is further deepened, scientists are using different means to target this target, including innovative treatment models such as traditional small molecule drugs to bispecific antibody , protein degradation therapy, gene therapy and RNA therapy. Recently, a review on Nature Reviews Drug Discovery has taken an inventory of different means of targeting p53. The role of
p53 in inhibiting cancer occurrence and development
The main function of wild-type p53 is to act as the transcription factor , which limits the proliferation and survival of tumor cells by activating the expression of a series of genes . In addition, p53 also has a function other than transcription factors, and its interaction with BCL-2 family proteins can promote cell apoptosis triggered by mitochondrial . p53 is also an important regulator of autophagy and can affect the tumor microenvironment and make it unfavorable for tumor growth.
Due to the multiple roles of p53 in inhibiting tumor growth, the TP53 gene is also one of the most commonly mutated genes in tumors. Most TP53 gene mutation into missense mutation , causing the p53 protein to fail to perform the function of inhibiting tumor growth normally. However, some mutations can cause p53 mutants to develop functions that promote tumor growth, such as activating genes that promote cancer cell growth, reducing cell apoptosis caused by endoplasmic reticulum stress, changing the tumor microenvironment, etc. Therefore, p53 is an attractive and important target in cancer treatment.
▲The inhibitory and pro-cancer effects of wild-type p53 and p53 mutants (Image source: Reference [1])
small molecule drug targeting p53
small molecule drug development for p53 began more than 20 years ago. Since most TP53 gene mutations lead to instability and loss of function of p53, the main goal of small molecule drug development for targeting p53 is to restore the structure and expression level of p53 so that p53 can exercise its normal tumor suppressor function . The small molecule drugs currently under development can be divided into three categories: the first type of drugs target negative regulators of p53 expression (including MDM2, MDM4 and HPV E6) through to increase the expression level of p53 ; the second type of drugs target specific p53 mutants through , aiming to restore the structural stability and function of p53 mutants ; the third type of drugs target the truncated p53 protein generated due to the nonsense mutations in the TP53 gene.
▲ Small molecule drug development strategy for targeting p53 (Image source: Reference [1])
The advantage of targeting p53 negative regulator is that it can have an effect on wild-type p53 and has a broader spectrum effect. For example, APG-115, the MDM2 inhibitor of Yasheng Pharmaceutical, blocks the interaction between MDM2 and p53 and restores the tumor-suppressing activity of p53. It has obtained several FDA qualifications for orphan drugs, 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 the level of p53. For example, Kymera Therapeutics' protein degradation drug KT-253, which targets MDM2, has shown better activity than MDM2 small molecule inhibitors in preclinical experiments. The company is expected to submit an IND application to the FDA by the end of this year.
However, since p53 is present in all cells, the effects of these drugs on p53 in healthy cells may have potential toxic side effects.
small molecule drugs targeting p53 mutants are designed to restore the normal structure and function of p53 by binding to the mutant. For example, Professor Kevan M. Shokat, who has made outstanding contributions to targeting KRAS recently published a paper describing covalent compound , a covalent compound that binds to the p53 Y220C mutant, which can restore its thermal stability to a level comparable to wild-type p53.
These targeted therapies target mutants caused by mutations in specific TP53 gene, so they have less impact on wild-type p53 and have less toxicity. However, the TP53 gene has many different gene mutations, and strategies to target specific p53 mutants may not be used for other mutants.
Targeting truncated p53 proteins due to nonsense mutations, the current strategy is to use drugs that promote read through, or drugs that inhibit degradation of truncated p53 proteins to increase p53 levels. However, whether these drugs can effectively increase p53 levels still needs to be verified, and their potential toxicity is also a worrying issue.
Immunotherapy against p53
Since p53 mutants are mostly highly expressed in tumor cells, their polypeptide fragments are also more likely to be presented to the cell surface by tumor cells, and thus recognized by the human immune system. immunotherapy against p53 enhances the human immune system's ability to recognize p53 mutants and activates the immune response against p53 mutants, thereby eliminating tumor cells expressing p53 mutants.
This strategy includes cancer vaccines based on p53 mutant, monoclonal antibodies targeting p53 mutant and bispecific antibodies. For example, in a study published last year in the journal Science, a research team led by scholars from Johns Hopkins University successfully developed bispecific antibody therapies targeting p53 mutants. It can identify mutant p53 polypeptide fragments and human leukocyte antigen (HLA) proteins with extremely high specificity. At the same time, the other end of this bispecific antibody can bind to the CD3 receptor on the surface of in T cells, activate T cells to kill tumor cells expressing p53 mutants. This study provides the first evidence that bispecific antibodies targeting p53 mutants of can still activate T cells and eliminate tumor cells when the expression level of neoantigen on the cell surface is extremely low. The authors of
review pointed out that the key to this strategy is to stimulate a specific immune response against p53 mutants. Normal cells also express p53. Although most cells have low p53 levels and present less antigen on the cell surface, some frequently divided cells (including stem cells and progenitor cells) will have an elevated p53 expression level, and avoiding the immune system attacks healthy cells is a problem that researchers need to consider.
▲Mechanism of action of antibody therapy against p53 mutants (Image source: Reference [1])
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 functions is also an important research and development direction for restoring p53 function. Using viral vector or lipid nanoparticles, transgenes encoding wild-type p53 protein can be delivered to tumor cells, restore normal p53 expression and produce a tumor suppressor effect.
▲ Development strategies for p53 at the gene and RNA level (Image source: Reference [1])
With the success of mRNA vaccine, the use of nanoparticles to deliver mRNA encoding p53 has also become one of the directions of drug development. In February this year, a research team from Harvard Medical School and Massachusetts General Hospital published a paper on Nature Communications. successfully used nanoparticles targeting CXCR4 to deliver mRNA expressing p53 in an hepatocellular carcinoma animal model. This therapy is combined with anti-PD-1 antibodies and effectively changes the cellular and molecular components of the tumor microenvironment.
▲Pairing of p53-expressing mRNA with anti-PD-1 antibodies significantly changes the tumor microenvironment (Image source: Reference [2])
This strategy requires attention to is that many p53 mutants not only lack their own functions, but also may block normal p53 functions due to increased expression levels. In this case, the effect of expressing normal p53 protein may not be significant. In addition, some p53 mutants carry acquired mutations that promote cancer, and expressing normal p53 protein does not prevent the oncogenic effects of these mutants. In addition to
gene therapy and mRNA therapy, RNAi can inhibit the expression of the mutant TP53 gene, and the CRISPR gene editing system has the potential to repair mutations in TP53 gene.
Looking forward to the future
Review authors pointed out that since 2000, many therapies targeting p53 have entered the clinical trial stage. 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.
▲Statistics of clinical trials targeting p53 (Image source: Reference [1])
However, developing safe and effective p53 targeted therapies still face multiple challenges. Unsolved problems include the generation of potential drug resistance, and how to use them in combination with other therapies to achieve enhanced anti-cancer effects, etc. Overall, targeting p53 is a "high risk/high return" process. The scientific progress in recent years is gradually giving people the hope of targeting this "unprepared" target. If breakthroughs are achieved, there is potential for transforming cancer treatment.
Reference:
[1] Hassin and Oren, (2022). Drugging p53 in cancer: one protein, many targets. Nature Reviews Drug Discovery, https://doi.org/10.1038/s41573-022-00571-8
[2] Xiao et al., (2022). Combining p53 mRNA nanotherapy with immuno checkpoint blockade reprograms the immuno microenvironment for effective cancer therapy. Nature Communications, https://doi.org/10.1038/s41467-022-28279-8
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