Read More. Meet Our Veterans Dept. About Us. Who Am I Calling? Call Now Healthy cells can become cancerous when carcinogens, such as asbestos, damage their DNA and cause them to start dividing and reproducing uncontrollably. The p53 gene prevents this by activating proteins that arrest cell division and repair corrupted DNA.
In cases where the DNA damage is irreparable, the p53 gene initiates a process called apoptosis that destroys the cancer cell before it reproduces itself. The p53 gene can also limit blood flow to tumors, which prevents growth and alerts nearby immune cells to attack cancer cells.
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Did this article help you? Full Name. Chat Now Call Now Related Topics. Address 1 S. Orange Ave. Monthly Newsletter Stay up-to-date on treatment, research, clinical trials, doctors and survivors Sign Up Now. Phone Number. Street Address. Zip Code. All rights reserved. Detailed Description:. This is a Phase 2 study of the combination of Ad-p53 administered intra-tumorally in combination with physician's choice of FDA approved immune checkpoint inhibitor therapy in patients with recurrent or metastatic cancers.
This is a safety and efficacy study with a single cohort, consisting of the combination of Ad-p53 and infusions of immune checkpoint inhibitors. Immune checkpoint inhibitor treatments will be administered in accordance with FDA package inserts. Biomarker testing of archival or fresh tissue is performed during the study. Enrollment will be up to 40 patients. Resource links provided by the National Library of Medicine MedlinePlus Genetics related topics: Head and neck squamous cell carcinoma.
MedlinePlus related topics: Genes and Gene Therapy. FDA Resources. Arms and Interventions. Outcome Measures. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision.
Inclusion Criteria Signed informed consent. Male or female greater than or equal to 18 years of age females of childbearing potential must be non-pregnant with a negative pregnancy test and non-lactating. Males and females must use contraception for the duration of the study. Primary diagnosis must be histologically confirmed. As far as possible, all target lesions utilized for RECIST response determination should be suitable for ultra-sound, CT or endoscopic guided intra-tumoral injection.
If all target lesions cannot be treated with Ad-p53, but the patient is otherwise suitable for the study, this should be reviewed with the Sponsor. No brain metastases or treated and stable brain metastases ECOG Performance Status Life expectancy greater than or equal to 6 months. Mutant p53 gene profiles should be reviewed with the Sponsor to confirm eligibility.
Normal troponin blood levels. Echo with normal ejection fractions. QTcb less than or equal to ms Normal lung oxygen saturation by pulse oximeter. Coagulation status should be suitable for intra-tumoral injections.
Prothrombin Time PT less than or equal to 1. Exclusion Criteria History of allergic reactions to any components of the treatments Ad-p53 or immune checkpoint inhibitors.
Except for ongoing treatment with anti-PD-1 or anti-PD-L1 which is permitted see Inclusion Criterion 4 above , there should be no other antibody-based therapy, targeted small-molecule therapy, hormonal therapy, chemotherapy, radiation, biological or investigational therapy within 14 days of first administration of Study Treatment C1D1.
MDSCs strongly expand in pathological conditions such as chronic infections and cancer, as a result of an altered hematopoiesis [ ].
Lymphocytic penetration, particularly cytotoxic T cells, is hindered when the wild-type p53 pathways are disturbed in ER-negative breast cancer and basal-like breast tumors. Both loss of heterozygosity and p53 mutations are linked to lower incidence of T cell infiltration and a worse prognosis [ ].
Multiple genetically altered mouse breast cancer models with p53 loss increased inflammatory Wnt signaling in tumor-associated macrophages, resulting in systemic neutrophilia and finally metastasis [ ]. Recent data have indicated that Immunological checkpoints and wild-type p53 are linked. The connection between PD-L1 on tissue and PD-1 on T cells decreases activation signals produced by T cells after antigen recognition, and this immune checkpoint controls inflammation.
Tumor amplification of PD-L1, on the other hand, takes advantage of this immune checkpoint mechanism to reduce tumor surveillance and build immunological tolerance [ ]. As a result, in some context, mutant p53 might be a useful biomarker for immunotherapy response and might associate with a better prognosis due to distinct immunogenic signals [ ].
Wild-type p53 controls Toll-like receptor TLR gene expression in T-lymphocytes and to a lesser extent in macrophages in a way that is dependent on genetic stress and the host genetic background [ ]. Polymorphisms in the p53 response areas of TLR gene promoters, in particular, confer different levels of susceptibility to genetic stress and infection Different levels of vulnerability to genetic stress and infection are conferred by polymorphisms in the p53 response regions of TLR gene promoters, in particular.
The anti-tumor effects of TLR induction become obvious when considering the importance of APC reactivation in the cancer microenvironment, where activated TLR pathways increase immune recognition and action against tumor-antigen carrying cells. On the other hand, TLR expression in tumor cells and surrounding cells is pro-tumorigenic [ ]. MAPK and NF-kB activation are common threads in TLRexpressing colorectal tumors, and it is associated with increasing proliferative capacity, apoptotic resistance, and metastatic potential [ ].
In breast cancer, TLR-4 expression has been associated with poor survival and invasiveness [ ]. Humans and apes are the only species that have a pTLR regulatory axis [ ]. This evolutionary gap is significant for considering TLR-mediated cancer treatment since mouse models do not mimic the regulatory axis that is present in humans [ ].
TLR3 sensitivity and reactivity to known ligands are affected by these alterations, which modulate type I interferon response and downstream genotoxic-stress-induced apoptosis. This control of TLR3 responsiveness is directly linked to the expression of transcriptionally active or TLR3-enhancing p53 mutants like PH and RH, while other mutations might instead inhibit the TLR3-mediated immune response [ ].
Macrophages are one of the most prevalent immune cell types in the TME [ ]. According to most research, both M1-like and M2-like polarization are often linked to increased levels of p53 expression. Exosomal-mediated microRNA transfer is crucial in many cancers, and another mutant-specific GOF of p53 might be relevant as well [ ]. Exosomes from RW and RH mutant pexpressing colon cancer cells had a high concentration of miR, a microRNA related to invasiveness and stemness [ ].
Mutant pexpressing tumors can cause comparable non-cell-intrinsic reprogramming of macrophages into TAM-like M2 phenotypes via exosomal microRNA transfer Fig. These reprogrammed macrophages additionally presented enhanced degradation of the extra cellular matrix and became more invasive when compared with macrophages that were introduced to tumor cells that did not carry any p53 mutation [ ].
In the elderly, cellular senescence and the accompanying secretory phenotype SASP induce illness. Targeting senescent cells through SASP regulation, or cellular reprogramming could be a new therapeutic path for cancer and age-related illnesses like neurodegeneration, pulmonary fibrosis, and renal failure.
The TP53 gene, encodes 12 or more p53 protein isoforms, regulates cellular senescence. The various p53 isoforms are generated by the use of different transcriptional and translational start sites, as well as alternative mRNA splicing. These shortened p53 isoform proteins play significant roles in cellular senescence, apoptosis, and DNA repair, as well as modulation of full-length pmediated cellular senescence, apoptosis, and DNA repair [ ]. In the context of senescence, p53 plays a critical role in deciding the fate of cells, and its activation can be DDR-dependent or DDR-independent [ ].
In the first example, replicative stress activates the DNA damage repair cascade by causing telomere erosion, DNA damage, hyperactivation of oncogenes, and inactivation of onco-suppressors oncogene induced senescence, OIS [ ]. The role of DDR activation as a necessary and causal element in p53 activation and senescence induction has lately been questioned. These findings, as well as the mechanisms they describe, highlight the critical role of p53 and ptriggered senescence in the inhibition of carcinogenesis following the occurrence of a first mutation [ ].
Because wild-type p53 is an efficient promoter of apoptosis and senescence [ ] in tumor cells, reactivating wild-type characteristics of p53 mutants, which are commonly overexpressed in cancer, is a viable therapeutic strategy.
Several clinical research investigations using viral and non-viral vectors delivering p53 genes, alone or combined with other therapeutic agents, have been completed to far [ ].
Some tumor-derived mutations that cause wild-type p53 loss-of-function can be restored by other point mutations that help stabilize the p53 protein, indicating that the structural change is reversible [ ].
PhiKan and PK are small chemicals that bind p53 and generate the YC mutant, stabilizing it and boosting the amount of wild-type p53 [ ]. The — Zinc binding domain is required for the proper folding of wild-type p53, whereas zinc binding is absent in the RH p53 mutant [ , ].
When zinc is added to the structural mutants GC and GD, the wild-type structure is for the most part restored [ ] As a consequence, the discovery of the ability of zinc to restore wild-type folding suggest that this technique might be able to restore anticancer drug chemosensitivity in cells harboring mutant p53 proteins [ ].
NSC, a thiourea metal chelator, is able to restore wild-type p53 function in p53 mutant cell lines, most likely via boosting zinc bioavailability to p53 mutants [ ]. Although certain components are designed to selectively inhibit mutant p53, many of them can also interact with and inhibit other members of the p53 family, including p63 and p A small compound called RETRA, which was identified in a screening of a drug used to identify stable wt p53, disrupts the interaction between mutant p73 and p RETRA increased the release of p53, which inhibited tumor cell survival and xenograft tumor development by activating the p73 gene.
However,mutant p53 can work as a biomarker in breast cancer, is not clearly defined [ ]. Critical Outcome Techonologies Inc. These drugs have been demonstrated to have anticancer action in preclinical models expressing mutant p53, which is consistent with the reactivation of mutant p However, whether any mutant p53 reactivating chemical is effective in the therapy of human cancer remains to be seen [ ].
Gendicine is a biological therapy that can be administered via intratumoral injection, intracavity infusion, or intravascular infusion. Based on more than 30 published clinical trials and 12 years of commercial use in over 30, patients, Gendicine has a proven track record of safety, and when combined with chemotherapy and radiotherapy, it has shown to produce much higher response rates than traditional therapies alone.
In addition to head and neck cancer, Gendicine has been used to successfully treat a variety of other cancer kinds and stages. Thirteen published trials with long-term survival data found that Gendicine combination regimens result in considerably longer progression-free survival periods than standard treatments alone. Despite the fact that the p53 gene is mutated in more than half of all human malignancies, the presence of a p53 mutation had no effect on efficacy or long-term survival in Ad-ptreated patients [ ].
The growing understanding of mutant p53 actions has contributed to the identification of a number of compounds with promising therapeutic potential. However, further experiments are required to fully characterize mutant p53 function in cancer. The fact that mutant p53 might play a role in promoting metastasis — the primary cause of cancer-related mortality — is particularly attractive in terms of possible therapeutic applications. Although many tumors express mutant p53, it is unclear if the many mutations present on this protein have similar activity, and we might have to personalize therapy depending on the presence of a particular mutation rather than only consider whether a cancer express a wild-type vs a mutant p53 mutant.
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Author information Article notes Copyright and License information Disclaimer. Marei, Email: ge. Corresponding author. Received Oct 16; Accepted Dec 6. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Abstract The p53 protein is a transcription factor known as the "guardian of the genome" because of its critical function in preserving genomic integrity. Keywords: p53 signaling, Tumor suppressor gene, Gain of function mutation, Cancer progression, Cancer therapy.
Introduction Tumor suppression is the main function of p53 protein, which is encoded by the TP53 gene on human chromosome Open in a separate window.
Mechanism of action of mutant p53 Mutant p53 and modulation of wild-type p53 function In contrast to wild-type p53 anti-tumor protective activity, mutant p53 proteins have oncogenic action in culture cells [ 18 ], and promote metastasis and genomic instability in mice models [ 19 , 20 ].
Mutant p53 and other regulatory mechanisms Mutant p53 also targets other regulatory molecules including microRNAs such as miRb, miR and miR Posttranscriptional modifications of mutant p53 p53 protein has a rapid turnover due to ubiquitination mediated by the E3 ubiquitin ligase MDM2 and subsequent proteasomal degradation [ 52 , 53 ]. Phosphorylation of p53 and its role in cancer progression and apoptosis regulation Different serine S and threonine T phosphorylation sites have been identified on p53 proteins particularly in the C- and N-terminal domains [ 56 ].
Acetylation of p53 and its effects on p53 transactivation and stability Acetylation of p53 is another post-translational reversible enzymatic process by which p53 action is fine-tuned in response to different cellular toxic signals including genotoxic stress and damage of DNA [ 68 ] and many studies have looked at the role that acetylation plays in regulating p53 action as a tumor suppressor Fig.
The tumor suppressor action of p53 is modulated by methylation P53 lysine K and arginine R residues can be methylated, and a growing number of studies have shown that p53 methylation occurs during the DNA damage response [ 73 ]. SUMOylation of p53 controls its localization The tumor suppressor p53 has dynamic nuclear output because its tetramer domain contains a leucine-rich nuclear export signal NES region [ 81 ].
Ubiquitination and ubiquitin-like proteins that impact on the p53 pathway Ubiquitination plays an important role in regulating protein function as in fact it modulates proteins trafficking, localization, stability and activity. Mutant p53 and other cancer related signaling pathways 0. Mutant p53 and tumor microenvironment TME CAFs cancer-associated fibroblasts are an essential part of the TME and modulate inflammatory and leukocyte recruitment signals [ ].
Mutant p53 and cancer immunology Despite the fact that p53 mutations are uncommon in immune cells, p53 can impair cell-mediated immunity by creating specific molecular fingerprints in tumor or stromal cells that affect immune cell recruitment and activation [ ]. P53 and cellular senescence In the elderly, cellular senescence and the accompanying secretory phenotype SASP induce illness.
Potential of p53 signaling targeting for cancer therapy Because wild-type p53 is an efficient promoter of apoptosis and senescence [ ] in tumor cells, reactivating wild-type characteristics of p53 mutants, which are commonly overexpressed in cancer, is a viable therapeutic strategy. Conclusions The growing understanding of mutant p53 actions has contributed to the identification of a number of compounds with promising therapeutic potential. Funding Not applicable. Availability of data and materials All data are included in the manuscript.
Declarations Ethics approval and consent to participate Not applicable. Competing interests The authors declare that there is no conflict of interest regarding the publication of this article.
Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. The multiple mechanisms that regulate p53 activity and cell fate. Nat Rev Mol Cell Biol. Timofeev O. Mutant p53 in cancer progression and personalized therapeutic treatments.
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