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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246
Tung Hoang1,2, Philip Sutera1, Triet Nguyen1,2,3
1Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Purpose:
Despite well-informed work in several malignancies, the phenotypic effects of TP53 mutations in metastatic castration-sensitive prostate cancer (mCSPC) progression and metastasis are not clear. We characterized the structure-function and clinical impact of TP53 mutations in mCSPC.
Patients And Methods:
We performed an international retrospective review of men with mCSPC who underwent next-generation sequencing and were stratified according to TP53 mutational status and metastatic burden. Clinical outcomes included radiographic progression-free survival (rPFS) and overall survival (OS) evaluated with Kaplan-Meier and multivariable Cox regression. We also utilized isogenic cancer cell lines to assess the effect of TP53 mutations and APR-246 treatment on migration, invasion, colony formation in vitro, and tumor growth in vivo. Preclinical experimental observations were compared using t-tests and ANOVA.
Results:
Dominant-negative (DN) TP53 mutations were enriched in patients with synchronous (vs. metachronous) (20.7% vs. 6.3%, p < 0.01) and polymetastatic (vs. oligometastatic) (14.4% vs. 7.9%, p < 0.01) disease. On multivariable analysis, DN mutations were associated with worse rPFS (hazards ratio [HR] = 1.97, 95% confidence interval [CI]: 1.31-2.98) and overall survival [OS] (HR = 2.05, 95% CI: 1.14-3.68) compared to TP53 wild type (WT). In vitro, 22Rv1 TP53 R175H cells possessed stronger migration, invasion, colony formation ability, and cellular movement pathway enrichment in RNA sequencing analysis compared to 22Rv1 TP53 WT cells. Treatment with APR-246 reversed the effects of TP53 mutations in vitro and inhibited 22Rv1 TP53 R175H tumor growth in vivo in a dosage-dependent manner.
Conclusions:
DN TP53 mutations correlated with worse prognosis in prostate cancer patients and higher metastatic potential, which could be counteracted by APR-246 treatment suggesting a potential future therapeutic avenue.
Insights
Dominant-negative TP53 mutations worsen outcomes in metastatic castration-sensitive prostate cancer (mCSPC). APR-246 treatment counteracted these effects, showing therapeutic potential for mCSPC patients with TP53 mutations.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- TP53 mutations are common in many cancers, but their specific impact on metastatic castration-sensitive prostate cancer (mCSPC) progression and metastasis remains unclear.
- Understanding the phenotypic effects of TP53 mutations is crucial for developing targeted therapies in mCSPC.
Purpose of the Study:
- To characterize the structure-function and clinical impact of TP53 mutations in mCSPC.
- To investigate the potential of APR-246 in counteracting the effects of TP53 mutations in prostate cancer.
Main Methods:
- International retrospective review of mCSPC patients undergoing next-generation sequencing, stratified by TP53 mutational status and metastatic burden.
- Assessment of radiographic progression-free survival (rPFS) and overall survival (OS) using Kaplan-Meier and multivariable Cox regression.
- In vitro and in vivo studies using isogenic cell lines to evaluate the effect of TP53 mutations and APR-246 on cancer cell migration, invasion, colony formation, and tumor growth.
Main Results:
- Dominant-negative (DN) TP53 mutations were significantly enriched in patients with synchronous and polymetastatic disease.
- DN TP53 mutations were associated with significantly worse rPFS and OS compared to TP53 wild type (WT).
- TP53 mutant cells exhibited increased migration, invasion, and colony formation in vitro; APR-246 reversed these effects and inhibited tumor growth in vivo.
Conclusions:
- DN TP53 mutations correlate with poorer prognosis and increased metastatic potential in prostate cancer.
- APR-246 demonstrates potential as a therapeutic agent to counteract the negative effects of TP53 mutations in mCSPC.
- Targeting TP53 mutations with agents like APR-246 represents a promising future therapeutic strategy for mCSPC.
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