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p53 Family in Cancer: How Close Are We to the Clinic?

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (25 March 2023) | Viewed by 17297

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Special Issue Editors

Prof. Dr. Marco M. Candeias

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Guest Editor

1. Molecular and RNA Cancer Unit, Kyoto University Graduate School of Medicine, Building E Rm 115, Yoshida Konoemachi, Sakyo-ku, Kyoto 606-8501, Japan
2. Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal
3. BioISI — BioSystems & Integrative Sciences, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
Interests: p53, p53 mRNA, p53 isoforms, mRNA translation; mRNA functions; cancer genetics
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Lucília Saraiva

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Guest Editor

LAQV/REQUIMTE, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 228, 4050-313 Porto, Portugal
Interests: cancer pharmacology; targeted therapy; drug discovery; p53 family proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Many years of research have uncovered impressive knowledge about p53 family proteins and their critical roles in cancer. The p53 protein has been one of the most studied tumor suppressors in human cancer owing to its multifaceted functions in cellular homoeostasis and tumorigenesis. The p53 relatives, p63 and p73, are entangled in the same regulatory network, actively contributing to the cellular outcome. The emerging picture is that of an interconnected pathway, in which all the p53 family proteins are involved in the response to oncogenic stress and physiological inputs. Dysregulations in the p53 family pathways are common events in human cancers and considerably affect the response to therapy. Notably, numerous studies relating to the (re)activation of p53/p63/p73 function have shown encouraging therapeutic benefits. Nonetheless, much knowledge still needs to be acquired concerning the multiple contributions of this intriguing family of proteins in cancer development and anticancer therapies.

With this Special Issue, we are pleased to invite you to submit your work describing recent advances in this field, which may pave the way for more effective therapeutic strategies against cancer. In this Issue, original research articles and reviews are welcome. The research areas may include (but not limited to) basic and more (pre)clinical aspects of the function, biology, and pharmacology of the p53 family.

We look forward to receiving your contributions.

Prof. Dr. Marco M. Candeias
Prof. Dr. Lucília Saraiva
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

p53
p63
p73
proteins
protein-coding and non-coding genes
genetics
drug discovery
cancer
targeted anticancer therapy

Published Papers (6 papers)

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Research

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14 pages, 17835 KiB

Open AccessArticle

P53 in Penile Squamous Cell Carcinoma: A Pattern-Based Immunohistochemical Framework with Molecular Correlation

by Isabel Trias, Adela Saco, Lorena Marimon, Ricardo López del Campo, Carolina Manzotti, Oriol Ordi, Marta del Pino, Francisco M. Pérez, Naiara Vega, Silvia Alós, Antonio Martínez, Leonardo Rodriguez-Carunchio, Oscar Reig, Pedro Jares, Cristina Teixido, Tarek Ajami, Juan Manuel Corral-Molina, Ferran Algaba, María J. Ribal, Inmaculada Ribera-Cortada and Natalia Rakislova Show full author list Hide full author list

Cancers 2023, 15(10), 2719; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15102719 - 11 May 2023

Viewed by 1827

Abstract

p53 immunohistochemistry (IHC) has been proposed as a surrogate for TP53 mutations in penile squamous cell carcinomas (PSCC). We aimed to evaluate the performance of a pattern-based evaluation of p53 IHC in PSCC. Human papilloma virus (HPV) DNA testing, p16 and p53 IHC, and whole exome sequencing were performed in a series of 40 PSCC. p53 IHC was evaluated following a pattern-based framework and conventional p53 IHC evaluation. Out of 40 PSCC, 12 (30.0%) were HPV-associated, and 28 (70.0%) were HPV-independent. The agreement between the p53 IHC pattern-based evaluation and TP53 mutational status was almost perfect (k = 0.85). The sensitivity and accuracy of the pattern-based framework for identifying TP53 mutations were 95.5% and 92.5%, respectively, which were higher than the values of conventional p53 IHC interpretation (54.5% and 70.0%, respectively), whereas the specificity was the same (88.9%). In conclusions, the pattern-based framework improves the accuracy of detecting TP53 mutations in PSCC compared to the classical p53 IHC evaluation. Full article

(This article belongs to the Special Issue p53 Family in Cancer: How Close Are We to the Clinic?)

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Review

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22 pages, 1224 KiB

Open AccessReview

State of the Art of Pharmacological Activators of p53 in Ocular Malignancies

by Fabio Casciano, Enrico Zauli, Massimo Busin, Lorenzo Caruso, Saleh AlMesfer, Samar Al-Swailem, Giorgio Zauli and Angeli Christy Yu

Cancers 2023, 15(14), 3593; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15143593 - 12 Jul 2023

Cited by 4 | Viewed by 1642

Abstract

The pivotal role of p53 in the regulation of a vast array of cellular functions has been the subject of extensive research. The biological activity of p53 is not strictly limited to cell cycle arrest but also includes the regulation of homeostasis, DNA repair, apoptosis, and senescence. Thus, mutations in the p53 gene with loss of function represent one of the major mechanisms for cancer development. As expected, due to its key role, p53 is expressed throughout the human body including the eye. Specifically, altered p53 signaling pathways have been implicated in the development of conjunctival and corneal tumors, retinoblastoma, uveal melanoma, and intraocular melanoma. As non-selective cancer chemotherapies as well as ionizing radiation can be associated with either poor efficacy or dose-limiting toxicities in the eye, reconstitution of the p53 signaling pathway currently represents an attractive target for cancer therapy. The present review discusses the role of p53 in the pathogenesis of these ocular tumors and outlines the various pharmacological activators of p53 that are currently under investigation for the treatment of ocular malignancies. Full article

(This article belongs to the Special Issue p53 Family in Cancer: How Close Are We to the Clinic?)

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34 pages, 9346 KiB

Open AccessReview

Metal-Based Anticancer Complexes and p53: How Much Do We Know?

by Samah Mutasim Alfadul, Egor M. Matnurov, Alexander E. Varakutin and Maria V. Babak

Cancers 2023, 15(10), 2834; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15102834 - 19 May 2023

Viewed by 1945

Abstract

P53 plays a key role in protecting the human genome from DNA-related mutations; however, it is one of the most frequently mutated genes in cancer. The P53 family members p63 and p73 were also shown to play important roles in cancer development and progression. Currently, there are various organic molecules from different structural classes of compounds that could reactivate the function of wild-type p53, degrade or inhibit mutant p53, etc. It was shown that: (1) the function of the wild-type p53 protein was dependent on the presence of Zn atoms, and (2) Zn supplementation restored the altered conformation of the mutant p53 protein. This prompted us to question whether the dependence of p53 on Zn and other metals might be used as a cancer vulnerability. This review article focuses on the role of different metals in the structure and function of p53, as well as discusses the effects of metal complexes based on Zn, Cu, Fe, Ru, Au, Ag, Pd, Pt, Ir, V, Mo, Bi and Sn on the p53 protein and p53-associated signaling. Full article

(This article belongs to the Special Issue p53 Family in Cancer: How Close Are We to the Clinic?)

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21 pages, 2255 KiB

Open AccessReview

Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials

by Shigeto Nishikawa and Tomoo Iwakuma

Cancers 2023, 15(2), 429; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15020429 - 09 Jan 2023

Cited by 22 | Viewed by 5381

Abstract

Mutations in the tumor suppressor p53 (p53) promote cancer progression. This is mainly due to loss of function (LOS) as a tumor suppressor, dominant-negative (DN) activities of missense mutant p53 (mutp53) over wild-type p53 (wtp53), and wtp53-independent oncogenic activities of missense mutp53 by interacting with other tumor suppressors or oncogenes (gain of function: GOF). Since p53 mutations occur in ~50% of human cancers and rarely occur in normal tissues, p53 mutations are cancer-specific and ideal therapeutic targets. Approaches to target p53 mutations include (1) restoration or stabilization of wtp53 conformation from missense mutp53, (2) rescue of p53 nonsense mutations, (3) depletion or degradation of mutp53 proteins, and (4) induction of p53 synthetic lethality or targeting of vulnerabilities imposed by p53 mutations (enhanced YAP/TAZ activities) or deletions (hyperactivated retrotransposons). This review article focuses on clinically available FDA-approved drugs and drugs in clinical trials that target p53 mutations and summarizes their mechanisms of action and activities to suppress cancer progression. Full article

(This article belongs to the Special Issue p53 Family in Cancer: How Close Are We to the Clinic?)

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23 pages, 1535 KiB

Open AccessReview

Deciphering the Role of p53 and TAp73 in Neuroblastoma: From Pathogenesis to Treatment

by Joana Almeida, Inês Mota, Jan Skoda, Emília Sousa, Honorina Cidade and Lucília Saraiva

Cancers 2022, 14(24), 6212; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14246212 - 16 Dec 2022

Cited by 1 | Viewed by 2493

Abstract

Neuroblastoma (NB) is an embryonic cancer that develops from neural crest stem cells, being one of the most common malignancies in children. The clinical manifestation of this disease is highly variable, ranging from spontaneous regression to increased aggressiveness, which makes it a major therapeutic challenge in pediatric oncology. The p53 family proteins p53 and TAp73 play a key role in protecting cells against genomic instability and malignant transformation. However, in NB, their activities are commonly inhibited by interacting proteins such as murine double minute (MDM)2 and MDMX, mutant p53, ΔNp73, Itch, and Aurora kinase A. The interplay between the p53/TAp73 pathway and N-MYC, a known biomarker of poor prognosis and drug resistance in NB, also proves to be decisive in the pathogenesis of this tumor. More recently, a strong crosstalk between microRNAs (miRNAs) and p53/TAp73 has been established, which has been the focused of great attention because of its potential for developing new therapeutic strategies. Collectively, this review provides an updated overview about the critical role of the p53/TAp73 pathway in the pathogenesis of NB, highlighting encouraging clues for the advance of alternative NB targeted therapies. Full article

(This article belongs to the Special Issue p53 Family in Cancer: How Close Are We to the Clinic?)

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15 pages, 619 KiB

Open AccessReview

Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use?

by Michael J. Duffy, Minhong Tang, Subhasree Rajaram, Shane O’Grady and John Crown

Cancers 2022, 14(18), 4499; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14184499 - 16 Sep 2022

Cited by 16 | Viewed by 3119

Abstract

Mutant p53 is one of the most attractive targets for new anti-cancer drugs. Although traditionally regarded as difficult to drug, several new strategies have recently become available for targeting the mutant protein. One of the most promising of these involves the use of low molecular weight compounds that promote refolding and reactivation of mutant p53 to its wild-type form. Several such reactivating drugs are currently undergoing evaluation in clinical trials, including eprenetapopt (APR-246), COTI-2, arsenic trioxide and PC14586. Of these, the most clinically advanced for targeting mutant p53 is eprenetapopt which has completed phase I, II and III clinical trials, the latter in patients with mutant TP53 myelodysplastic syndrome. Although no data on clinical efficacy are currently available for eprenetapopt, preliminary results suggest that the drug is relatively well tolerated. Other strategies for targeting mutant p53 that have progressed to clinical trials involve the use of drugs promoting degradation of the mutant protein and exploiting the mutant protein for the development of anti-cancer vaccines. With all of these ongoing trials, we should soon know if targeting mutant p53 can be used for cancer treatment. If any of these trials show clinical efficacy, it may be a transformative development for the treatment of patients with cancer since mutant p53 is so prevalent in this disease. Full article

(This article belongs to the Special Issue p53 Family in Cancer: How Close Are We to the Clinic?)

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