scholarly journals New therapeutic strategies to treat human cancers expressing mutant p53 proteins

2018 ◽  
Vol 37 (1) ◽  
Author(s):  
Giovanni Blandino ◽  
Silvia Di Agostino
Keyword(s):  
Therapeutic Strategies ◽  
Mutant P53 ◽  
Human Cancers

scholarly journals Genetic Engineering of Zebrafish in Cancer Research

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2168
Author(s):  
Ludivine Raby ◽  
Pamela Völkel ◽  
Xuefen Le Bourhis ◽  
Pierre-Olivier Angrand
Keyword(s):  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
Molecular Signatures ◽  
Reverse Genetic ◽  
Human Cancers ◽  
Oncogenic Mutations ◽  
Cancer Models ◽  
Conditional Expression ◽  
Cancer Initiation

Zebrafish (Danio rerio) is an excellent model to study a wide diversity of human cancers. In this review, we provide an overview of the genetic and reverse genetic toolbox allowing the generation of zebrafish lines that develop tumors. The large spectrum of genetic tools enables the engineering of zebrafish lines harboring precise genetic alterations found in human patients, the generation of zebrafish carrying somatic or germline inheritable mutations or zebrafish showing conditional expression of the oncogenic mutations. Comparative transcriptomics demonstrate that many of the zebrafish tumors share molecular signatures similar to those found in human cancers. Thus, zebrafish cancer models provide a unique in vivo platform to investigate cancer initiation and progression at the molecular and cellular levels, to identify novel genes involved in tumorigenesis as well as to contemplate new therapeutic strategies.

scholarly journals Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Sarah K. Madden ◽  
Aline Dantas de Araujo ◽  
Mara Gerhardt ◽  
David P. Fairlie ◽  
Jody M. Mason
Keyword(s):  
Transcription Factor ◽  
Side Effects ◽  
Therapeutic Strategy ◽  
Tumor Regression ◽  
Therapeutic Strategies ◽  
Lessons Learned ◽  
Direct Inhibition ◽  
Human Cancers ◽  
E Box

Abstractc-Myc is a transcription factor that is constitutively and aberrantly expressed in over 70% of human cancers. Its direct inhibition has been shown to trigger rapid tumor regression in mice with only mild and fully reversible side effects, suggesting this to be a viable therapeutic strategy. Here we reassess the challenges of directly targeting c-Myc, evaluate lessons learned from current inhibitors, and explore how future strategies such as miniaturisation of Omomyc and targeting E-box binding could facilitate translation of c-Myc inhibitors into the clinic.

scholarly journals Modified Gold Nanoparticles to Overcome the Chemoresistance to Gemcitabine in Mutant p53 Cancer Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2067
Author(s):  
Eduardo García-Garrido ◽  
Marco Cordani ◽  
Álvaro Somoza
Keyword(s):  
Gold Nanoparticles ◽  
Cancer Cells ◽  
Electrostatic Interactions ◽  
Human Cancer ◽  
Tp53 Gene ◽  
Therapeutic Strategies ◽  
Mutant P53 ◽  
Layer By Layer ◽  
Missense Mutations ◽  
Efficient Delivery

Mutant p53 proteins result from missense mutations in the TP53 gene, the most mutated in human cancer, and have been described to contribute to cancer initiation and progression. Therapeutic strategies for targeting mutant p53 proteins in cancer cells are limited and have proved unsuitable for clinical application due to problems related to drug delivery and toxicity to healthy tissues. Therefore, the discovery of efficient and safe therapeutic strategies that specifically target mutant p53 remains challenging. In this study, we generated gold nanoparticles (AuNPs) chemically modified with low molecular branched polyethylenimine (bPEI) for the efficient delivery of gapmers targeting p53 mutant protein. The AuNPs formulation consists of a combination of polymeric mixed layer of polyethylene glycol (PEG) and PEI, and layer-by-layer assembly of bPEI through a sensitive linker. These nanoparticles can bind oligonucleotides through electrostatic interactions and release them in the presence of a reducing agent as glutathione. The nanostructures generated here provide a non-toxic and powerful system for the delivery of gapmers in cancer cells, which significantly downregulated mutant p53 proteins and altered molecular markers related to cell growth and apoptosis, thus overcoming chemoresistance to gemcitabine.

scholarly journals Esophageal Cancer: Insights from Mouse Models

2015 ◽  
Vol 8s1 ◽  
pp. CGM.S21218 ◽  
Author(s):  
Marie-Pier Tétreault
Keyword(s):  
Esophageal Cancer ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Human Subjects ◽  
Surgical Techniques ◽  
Therapeutic Strategies ◽  
Human Cancers ◽  
Genetic Modifications ◽  
Wide Range ◽  
Gestation Time

Esophageal cancer is the eighth leading cause of cancer and the sixth most common cause of cancer-related death worldwide. Despite recent advances in the development of surgical techniques in combination with the use of radiotherapy and chemotherapy, the prognosis for esophageal cancer remains poor. The cellular and molecular mechanisms that drive the pathogenesis of esophageal cancer are still poorly understood. Hence, understanding these mechanisms is crucial to improving outcomes for patients with esophageal cancer. Mouse models constitute valuable tools for modeling human cancers and for the preclinical testing of therapeutic strategies in a manner not possible in human subjects. Mice are excellent models for studying human cancers because they are similar to humans at the physiological and molecular levels and because they have a shorter gestation time and life cycle. Moreover, a wide range of well-developed technologies for introducing genetic modifications into mice are currently available. In this review, we describe how different mouse models are used to study esophageal cancer.

scholarly journals Gain-of-function mutant p53 in cancer progression and therapy

2020 ◽  
Vol 12 (9) ◽  
pp. 674-687 ◽  
Author(s):  
Cen Zhang ◽  
Juan Liu ◽  
Dandan Xu ◽  
Tianliang Zhang ◽  
Wenwei Hu ◽  
...  
Keyword(s):  
Cancer Progression ◽  
P53 Gene ◽  
Amino Acid Difference ◽  
Protein Accumulation ◽  
Mutant P53 ◽  
P53 Mutations ◽  
Wild Type ◽  
Gain Of Function ◽  
Human Cancers ◽  
Wild Type P53

Abstract p53 is a key tumor suppressor, and loss of p53 function is frequently a prerequisite for cancer development. The p53 gene is the most frequently mutated gene in human cancers; p53 mutations occur in >50% of all human cancers and in almost every type of human cancers. Most of p53 mutations in cancers are missense mutations, which produce the full-length mutant p53 (mutp53) protein with only one amino acid difference from wild-type p53 protein. In addition to loss of the tumor-suppressive function of wild-type p53, many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression, termed gain-of-function (GOF). Mutp53 protein often accumulates to very high levels in cancer cells, which is critical for its GOF. Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer, therapies targeting mutp53 have attracted great interest. Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53. In this review, we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers.

scholarly journals The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

2020 ◽  
Author(s):  
Joanna E Zawacka-Pankau
Keyword(s):  
Cancer Therapy ◽  
P53 Protein ◽  
Drug Repurposing ◽  
Protein Family ◽  
Mutant P53 ◽  
Li Fraumeni Syndrome ◽  
Inherited Cancer ◽  
Human Cancers ◽  
New Treatments ◽  
Cycle Regulation

p53 and p73 are critical tumor suppressors inactivated in human cancers through various mechanisms. Owing to high structural homology, the proteins share many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the ‘guardian of the genome’ and forms a critical barrier against cancer development and progression. It is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li-Fraumeni Syndrome (LFS), the inherited cancer predisposition. Despite the ongoing effort, the treatment of cancers harbouring mutant p53 still remains challenging due to late diagnoses and the treatment-related toxicity and marginal benefit upon approval of new therapies. Presently, the efforts focus on activating p53 exclusively, neglecting the potential of the restoration of the p73 protein in tumors. Taken that several small molecules activating wild-type p53 have failed in clinical trials, and mutant p53 reactivating drugs have not been approved yet, there is a pressing need to develop new treatments activating p53 proteins. This review outlines the still despised therapeutic avenue, drug repurposing, which brings hope for the efficient reinstatement of the p53 protein family for improved cancer therapy.

scholarly journals Human MUS81: A Fence-Sitter in Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Sisi Chen ◽  
Xinwei Geng ◽  
Madiha Zahra Syeda ◽  
Zhengming Huang ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Dna Repair ◽  
Embryonic Development ◽  
Cell Viability ◽  
Gene Mutations ◽  
Therapeutic Strategies ◽  
Endonuclease Activity ◽  
Dna Structures ◽  
Human Cancers

MUS81 complex, exhibiting endonuclease activity on specific DNA structures, plays an influential part in DNA repair. Research has proved that MUS81 is dispensable for embryonic development and cell viability in mammals. However, an intricate picture has emerged from studies in which discrepant gene mutations completely alter the role of MUS81 in human cancers. Here, we review the recent understanding of how MUS81 functions in tumors with distinct genetic backgrounds and discuss the potential therapeutic strategies targeting MUS81 in cancer.

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