Overcoming platinum resistance in ovarian cancer by targeting pregnancy-associated plasma protein-A

English version

Autoři: Diogo Torres ^aff001; Xiaonan Hou ^aff002; Laurie Bale ^aff003; Ethan P. Heinzen ^aff004; Matthew J. Maurer ^aff004; Valentina Zanfagnin ^aff002; Ann L. Oberg ^aff004; Cheryl Conover ^aff003; S. John Weroha ^aff002
Působiště autorů: Department of Obstetrics and Gynecology, Division of Gynecologic Surgery, Mayo Clinic, Rochester, MN, United States ^aff001; Department of Oncology, Division of Medical Oncology, Mayo Clinic, Rochester, MN, United States ^aff002; Division of Endocrinology, Mayo Clinic, Rochester, MN, United States ^aff003; Department of Health Science Research, Division of Biomedical Statistics and Informatics, Rochester, MN, United States ^aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0224564

Souhrn

Objectives

Inhibition of pregnancy-associated plasma protein-A (PAPP-A), an upstream activator of the insulin-like growth factor (IGF) pathway, is known to augment sensitivity to platinum-based chemotherapy. This study further tests the efficacy of PAPP-A inhibition with a monoclonal antibody inhibitor (mAb-PA) in ovarian cancer (OC) platinum-resistant patient-derived xenograft (PDX) models.

Methods

PAPP-A expression was quantitated in platinum-resistant PDX models by ELISA. A subset with High (n = 5) and Low (n = 2) expression were revived in female SCID/beige mice for studies with either saline, carboplatin/paclitaxel (CP) + mAb-PA, or CP + IgG2a. The primary endpoint was tumor area by ultrasound on day 28 relative to baseline. Conversion to platinum-sensitive was defined by average tumor regression below baseline. Statistical analyses included linear mixed effects modeling and Kaplan Meier curves. Response to therapy was correlated with changes in the ratio of phosphorylated/total AKT and ERK 1/2 using Wes analysis.

Results

The addition of mAb-PA to CP induced tumor regression below baseline in one High PAPP-A PDX model; another three models exhibited notable growth inhibition relative to CP + IgG2a. None of the Low PAPP-A PDX models regressed below baseline. The PDX model with the greatest magnitude of tumor regression from baseline after combination therapy was maintained on single agent mAb-PA or IgG2a, but no benefit was observed. Decreased phosphorylation of ERK1/2 correlated with conversion to platinum-sensitive.

Conclusions

The addition of mAb-PA to CP overcame platinum-resistance in one of five High PAPP-A PDX models; three other models demonstrated improved platinum-response. This supports further clinical development of this novel therapeutic.

Klíčová slova:

Cancer treatment – Enzyme-linked immunoassays – Biomarkers – Cancer chemotherapy – Ovarian cancer – Platinum – Monoclonal antibodies – Combination chemotherapy

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