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A Recurrent Platinum Refractory Ovarian Cancer Patient With a Partial Response After RRx-001 Resensitization to Platinum Doublet.

ABSTRACT: This case report describes the clinical course of a heavily pretreated patient enrolled on the Phase II QUADRUPLE THREAT clinical trial (NCT02489903) with recurrent metastatic epithelial ovarian cancer that was previously treated with a platinum doublet and that benefited from another reintroduction of a platinum doublet after a brief priming period with RRx-001. Platinum-taxane combination is the initial treatment of choice in ovarian cancer and the "go-to regimen" for patients with recurrent, platinum-sensitive disease. However, platinum resistance is an inevitable and uniformly fatal development. One of the "Holy Grails" in ovarian cancer, besides early detection, is to reverse this resistance and retreat with a platinum doublet regimen. Because of the correlation between therapeutic resistance and poor clinical outcomes, this case, which potentially demonstrates a new avenue of anticancer development in epithelial ovarian cancer provided it is repeatable with other ovarian patients, was felt to merit a report.

SUBMITTER: Cottrill H

PROVIDER: S-EPMC5846910 | biostudies-literature | 2018 Jan-Dec

REPOSITORIES: biostudies-literature

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A Recurrent Platinum Refractory Ovarian Cancer Patient With a Partial Response After RRx-001 Resensitization to Platinum Doublet.

Cottrill Hope H Cason Stephanie S Caroen Scott S Oronsky Bryan B Donaldson Elvis E

Journal of investigative medicine high impact case reports 20180101

This case report describes the clinical course of a heavily pretreated patient enrolled on the Phase II QUADRUPLE THREAT clinical trial (NCT02489903) with recurrent metastatic epithelial ovarian cancer that was previously treated with a platinum doublet and that benefited from another reintroduction of a platinum doublet after a brief priming period with RRx-001. Platinum-taxane combination is the initial treatment of choice in ovarian cancer and the "go-to regimen" for patients with recurrent, ...[more]

PMID: 29552569

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Project description:DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize ovarian cancer cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of ovarian cancer patients.Significance: Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses. Cancer Res; 78(3); 631-44. ©2017 AACR.

Dataset Information

A Recurrent Platinum Refractory Ovarian Cancer Patient With a Partial Response After RRx-001 Resensitization to Platinum Doublet.

Publications

A Recurrent Platinum Refractory Ovarian Cancer Patient With a Partial Response After RRx-001 Resensitization to Platinum Doublet.

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