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Wednesday, September 09, 2020 1:26:29 PM
https://www.cancernetwork.com/view/p53-tumor-suppressor-gene-therapy-cancer
https://www.nature.com/articles/nbt0104-3
A recent study of p53 gene therapy, with nice history of p53 gene therapy:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415316/
Various pharmaceutical approaches have been developed to restore the WT function of p53 mutants (using p53 reactivation and induction of massive apoptosis [PRIMA-1], SH group-targeting compound that induces massive apoptosis [STIMA-1], CP-31398, and other compounds) or to block interactions of WT p53 with MDM2/MDMX (using nutlin-3a, RG7112, CGM097, SAR405838, and other compounds).28, 29, 39, 40 Each of these approaches has its limitations. For example, it is unclear whether PRIMA-1 and similar compounds effectively target all mutant p53 variants and whether the tumor suppressor functions of p63 and p73 could be negatively affected by these drugs. Further, although MDM2/MDMX antagonists may be beneficial in cancers with WT p53 and high MDM2/MDMX expression, they are unlikely to be effective in tumors with a high prevalence of p53 mutations, where Hsp90 inhibits MDM2-mediated mutant p53 degradation.38 Moreover, because in the absence of this Hsp90 activity MDM2 is able to inactivate p53,38, 41, 42 the use of MDM2/MDMX antagonists in premalignant lesions may increase the number of p53 mutant forms and the risk of tumor progression. Indeed, long-term exposure to nutlin-3a promotes the emergence of p53 mutations.29, 30, 40, 43
Many of these challenges associated with p53 could be more effectively addressed through the development of approaches allowing successful delivery and expression of the WT p53 transgene in tumor cells. Unlike the pharmaceutical approaches described above, p53 gene therapy is expected to be effective independently of the p53 tumor status. The history of p53 as a cancer gene therapeutic has been reviewed.44 In brief, in the late 1980s and early 1990s it was known that treatment of cancer cells with WT p53 resulted in senescence45 or apoptosis46 depending on the cancer tested. Dr. Jack Roth (MD Anderson Cancer Center) was the first to successfully use p53 therapy in vivo in humans using replication-deficient retroviral vector-driven expression of human p53 against non-small cell lung carcinoma.47 The focus of the p53-based cancer gene therapy field then shifted to replication-deficient adenoviral vectors because of their low risk of integration into the host genome, the ability of the vectors to inhibit growth of many malignancies in vitro, and the ability to achieve cost-effective, large-scale good manufacturing practice (GMP) production.44 Since then, many clinical trials were conducted using different p53 expression replication-deficient viral vectors (discussed below), with thousands of patients receiving the therapies without significant adverse effects. This approach also had limited success.44 To date, no such therapeutic approach has been approved in the United States.
Inserting a new WT p53 gene into cancer cells, using transcriptional regulation to increase WT p53 in cancer cells (if not mutated), or using transcriptional regulation or RNAi to knockout or decrease transcription of mutant p53 all would be examples of gene therapy.
Kevetrin small molecule pharmaceutical approach used to modify the p53 protein or its metabolism is not gene therapy.
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