Meta-Analysis of Adenoviral p53 Gene Therapy Clinical Trials in Recurrent Head and Neck Squamous Cell Carcinoma

Sobol, Robert E.; Menander, Kerstin B.; Chada, Sunil; Wiederhold, Dora; Sellman, Beatha; Talbott, Max W.; Nemunaitis, John

doi:10.1101/2021.01.06.20248743

Cited by 1 publication

(1 citation statement)

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“…On the other hand, however, many of those tumours accumulate excessive mutp53 protein, which may act in a dominant-negative manner to neutralize the reintroduced wtp53. Interestingly, a meta-analysis of patients with recurrent HNSCC treated with adenovirus–p53 gene therapy showed that all responders had only weak p53 staining by immunohistochemistry (IHC) and no TP53 missense mutations 178 . Hence, abundant mutp53 might indeed restrict the efficacy of wtp53 gene therapy, suggesting strong p53 IHC staining as an exclusion criterion for such treatments.…”

Section: P53-based Genetic Therapiesmentioning

confidence: 99%

Drugging p53 in cancer: one protein, many targets

Hassin

Oren

2022

Nat Rev Drug Discov

317

181

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Mutations in the TP53 tumour suppressor gene are very frequent in cancer, and attempts to restore the functionality of p53 in tumours as a therapeutic strategy began decades ago. However, very few of these drug development programmes have reached late-stage clinical trials, and no p53-based therapeutics have been approved in the USA or Europe so far. This is probably because, as a nuclear transcription factor, p53 does not possess typical drug target features and has therefore long been considered undruggable. Nevertheless, several promising approaches towards p53-based therapy have emerged in recent years, including improved versions of earlier strategies and novel approaches to make undruggable targets druggable. Small molecules that can either protect p53 from its negative regulators or restore the functionality of mutant p53 proteins are gaining interest, and drugs tailored to specific types of p53 mutants are emerging. In parallel, there is renewed interest in gene therapy strategies and p53-based immunotherapy approaches. However, major concerns still remain to be addressed. This Review re-evaluates the efforts made towards targeting p53-dysfunctional cancers, and discusses the challenges encountered during clinical development.

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Section: P53-based Genetic Therapiesmentioning

confidence: 99%