Benjamin Garcia

 Introduction: Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide1. Colorectal cancer commonly arises from benign neoplasms, called tubular adenomas and serrated polyps, which slowly evolves into CRC over many years2. Over the last three decades, many factors have been identified in the progression of benign polyp to CRC, and CRC diagnosis and therapy has advanced significantly1,2. However, CRC prevalence continues to rise and the 5-year mortality remains high1. Mutations in TP53 has been identified in 40-50% of colorectal cancers, making these CRC strains resistant to many therapies1,3. The prevalence of TP53 mutations in CRC has made it an attractive target for small molecule compounds such as PRIMA-1 MET (p53 re-activation and induction of massive apoptosis, methylated derivative)3. PRIMA-1 MET has been reported to restore both wild type structure and function of mutant p53, suggesting a new potential therapy for CRC3. Methods: To gain a deeper understanding of the potential anti-cancer effects of PRIMA-1 MET in CRC, a panel of different CRC cell lines with different p53 status was utilized and treated with PRIMA-1 MET. A variety of assays, including a xenograft mouse model, were then conducted followed by statistical analysis by SPSS. Comparison between groups of data was conducted using ANOVA. Results: PRIMA-1 MET was found to inhibit growth of CRC lines independent of p53 status in a dose and time dependent manner3,4. PRIMA-1 MET induced massive apoptosis in mainly mutant p53 strains through upregulated expression of pro-apoptotic molecule Noxa3. PRIMA-1 MET was also found to inhibit p53-independent phosphorylation of MEK (mitogen-activated or extracellular signal-related protein kinase) through directing binding of MEK which impaired proliferation and anchorage-independent cell growth in vitro4. Xenograft mouse models demonstrate that PRIMA-1 MET effectively suppresses CRC tumor  growth3,4. Conclusions: These studies provide evidence in the CRC anti-tumor effects of PRIMA-1 MET. In vitro and in vivo results from these studies suggest that PRIMA-1 MET is a promising candidate for clinical  trials in patients with CRC. There are limited clinical trials to assess PRIMA-1 MET antitumor effects in CRC. However, there is one phase I clinical trial involving PRIMA-1 MET therapy in CRC which demonstrates that PRIMA-1 MET therapy is safe and has a favorable pharmacokinetic profile5.

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3. Li X-L, Zhou J, Chan Z-L, Chooi J-Y, Chen Z-R, Chng W-J. PRIMA-1met(APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct Oncotarget. 2015;6(34):36689-36699
4. Lu T, Zou Y, Xu G, et PRIMA-1Metsuppresses colorectal cancer independent of p53 by targeting MEK. Oncotarget. 2016;7(50):83017-83030
5. Lehmann S, Bykov V, Andersson P, et Targeting p53 in vivo: a first-in-human study with p53- targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. Journal of Clinical Oncology: Official Journal Of The American Society Of Clinical Oncology. October 10, 2012;30(29):3633-3639