Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy

Abstract

Based on clinical presentation, glioblastoma (GBM) is stratified into primary and secondary types. The protein 53 (p53) pathway is functionally incapacitated in most GBMs by distinctive type-specific mechanisms. To model human gliomagenesis, we used a GFAPHRas V12 mouse model crossed into the p53ER TAM background, such that either one or both copies of endogenous p53 is replaced by a conditional p53ER TAM allele. The p53ER TAM protein can be toggled reversibly in vivo between wild-type and inactive conformations by administration or withdrawal of 4-hydroxytamoxifen (4-OHT), respectively. Surprisingly, gliomas that develop in GFAP-HRas V12 ; p53 +/KI mice abrogate the p53 pathway by mutating p19 ARF / MDM2 while retaining wild-type p53 allele. Consequently, such tumors are unaffected by restoration of their p53ER TAM allele. By contrast, gliomas arising in GFAP-HRas V12 ;p53 KI/KI mice develop in the absence of functional p53. Such tumors retain a functional p19 ARF /MDM2-signaling pathway, and restoration of p53ER TAM allele triggers p53-tumor-suppressor activity. Congruently, growth inhibition upon normalization of mutant p53 by a small molecule, Prima-1, in human GBM cultures also requires p14 ARF /MDM2 functionality. Notably, the antitumoral efficacy of p53 restoration in tumor-bearing GFAP-HRas V12 ;p53 KI/KI animals depends on the duration and frequency of p53 restoration. Thus, intermittent exposure to p53ER TAM activity mitigated the selective pressure to inactivate the p19 ARF /MDM2/p53 pathway as a means of resistance, extending progression-free survival. Our results suggest that intermittent dosing regimes of drugs that restore wild-type tumorsuppressor function onto mutant, inactive p53 proteins will prove to be more efficacious than traditional chronic dosing by similarly reducing adaptive resistance.preclinical model | Nutlin 3 | intermittent treatment

APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma

“…Indeed, Tessoulin et al 12 showed that endogenous levels of glutathione correlated with APR-246 sensitivity in multiple myeloma cells, while in astrocytoma, the absence of p14 ARF expression, an endogenous MDM2 inhibitor, was associated with resistance to APR-246 32. Importantly, Aryee et al 33 proposed a panel of 42 apoptotic genes that may predict APR-246 response in sarcoma cells.…”

Individual roles of p53 and NF1 in OPC Competition and Gliomagenesis

“…The restoration of p53 has strong anti-tumor effects in Tu-OPCs and human glioma cells suggest that targeting p53 in glioma may prove useful in the clinic. Our findings are in line with recent work demonstrating that p53 restoration is efficacious for astrocytomas (Shchors et al, 2013). Furthermore, of the 20% of glioma patients harboring p53…”

“…OPCs at pre-malignant stages (Schwartzbaum et al, 2006;Shchors et al, 2013;Zhu and Parada, 2002). While NF1 controls the expansion, proliferation, and differentiation of OPCs early on, p53 clearly plays a later but vital role in preventing OPC transformation since NF1-null OPCs never transform despite their overwhelming expansion in the brain parenchyma.…”

CDH2 expression is of prognostic significance in glioma and predicts the efficacy of temozolomide therapy in patients with glioblasotma

“…However, although it has significant effect in prolonging the lifespan of some patients with glioma, the efficacy of TMZ for treating certain GBM patients is limited (14), and TMZ resistance may result in a poor prognostic outcome in patients with GBM. Several mechanisms, including DNA repair mechanisms (15), high expression of epidermal growth factor receptor (16), the mutation of p53 (17) and the deficiency of phosphatase and tensin homolog (18), are involved in TMZ resistance. However, in a previous study, one-third of patients exhibited hypermethylation of methylguanine-DNA methyltransferase promoter, signifying sensitivity toward alkylating agents (19).…”