Understanding the impact of chemotherapy on the immune landscape of high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases. Mechanisms for this difference in response remain unknown. Therefore, the present study investigated the impact of platinum resistance on steroid metabolism in six established HGSOC cell lines sensitive and resistant against carboplatin using a high-resolution mass spectrometry assay to simultaneously quantify the ten main steroids of the estrogenic metabolic pathway. An up to 60-fold higher formation of steroid hormones and their sulfated or glucuronidated metabolites was observed in carboplatin-sensitive cells, which was reversible by treatment with interleukin-6 (IL-6). Conversely, treatment of carboplatin-resistant cells expressing high levels of endogenous IL-6 with the monoclonal anti-IL-6R antibody tocilizumab changed their status to “platinum-sensitive”, exhibiting a decreased IC50 value for carboplatin, decreased growth, and significantly higher estrogen metabolism. Analysis of these metabolic differences could help to detect platinum resistance in HGSOC patients earlier, thereby allowing more efficient interventions.

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Understanding the impact of chemotherapy on the immune landscape of high-grade serous ovarian cancer (HGSOC)

Gynecologic Oncology ◽

10.1016/j.ygyno.2019.04.179 ◽

2019 ◽

Vol 154 ◽

pp. 76

Author(s):

K. LaVigne ◽

J. Benhamida ◽

J. Young ◽

O. Zivanovic ◽

D.S. Chi ◽

...

Keyword(s):

Ovarian Cancer ◽

High Grade ◽

Serous Ovarian Cancer ◽

The Impact

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Reduced SKP1 and CUL1 expression underlies increases in Cyclin E1 and chromosome instability in cellular precursors of high-grade serous ovarian cancer

British Journal of Cancer ◽

10.1038/s41416-021-01317-w ◽

2021 ◽

Author(s):

Chloe Camille Lepage ◽

Michaela Cora Lynn Palmer ◽

Ally Catherina Farrell ◽

Nicole Marie Neudorf ◽

Zelda Lichtensztejn ◽

...

Keyword(s):

Ovarian Cancer ◽

Quantitative Imaging ◽

Chromosome Instability ◽

Dependent Manner ◽

High Grade ◽

Serous Ovarian Cancer ◽

Genomic Amplification ◽

Cyclin E1 ◽

Cycle Dependent ◽

The Impact

Abstract Background High-grade serous ovarian cancer (HGSOC) is the most common and lethal ovarian cancer histotype. Chromosome instability (CIN, an increased rate of chromosome gains and losses) is believed to play a fundamental role in the development and evolution of HGSOC. Importantly, overexpression of Cyclin E1 protein induces CIN, and genomic amplification of CCNE1 contributes to HGSOC pathogenesis in ~20% of patients. Cyclin E1 levels are normally regulated in a cell cycle-dependent manner by the SCF (SKP1–CUL1–FBOX) complex, an E3 ubiquitin ligase that includes the proteins SKP1 and CUL1. Conceptually, diminished SKP1 or CUL1 expression is predicted to underlie increases in Cyclin E1 levels and induce CIN. Methods This study employs fallopian tube secretory epithelial cell models to evaluate the impact diminished SKP1 or CUL1 expression has on Cyclin E1 and CIN in both short-term (siRNA) and long-term (CRISPR/Cas9) studies. Results Single-cell quantitative imaging microscopy approaches revealed changes in CIN-associated phenotypes and chromosome numbers and increased Cyclin E1 in response to diminished SKP1 or CUL1 expression. Conclusions These data identify SKP1 and CUL1 as novel CIN genes in HGSOC precursor cells that may drive early aetiological events contributing to HGSOC development.

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Investigating the impact of interval from primary debulking surgery to initiation of adjuvant chemotherapy in advanced high-grade serous ovarian cancer

Gynecologic Oncology ◽

10.1016/j.ygyno.2017.03.421 ◽

2017 ◽

Vol 145 ◽

pp. 185

Author(s):

Y. Lee ◽

L. Lu ◽

W. Xu ◽

T. Brown ◽

T. May

Keyword(s):

Ovarian Cancer ◽

Adjuvant Chemotherapy ◽

High Grade ◽

Serous Ovarian Cancer ◽

Debulking Surgery ◽

Primary Debulking Surgery ◽

The Impact

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Correction to: The effect of the peritoneal tumor microenvironment on invasion of peritoneal metastases of high-grade serous ovarian cancer and the impact of neoadjuvant chemotherapy

Virchows Archiv ◽

10.1007/s00428-020-02974-7 ◽

2020 ◽

Author(s):

J. O. A. M. van Baal ◽

C. A. R. Lok ◽

E. S. Jordanova ◽

H. Horlings ◽

W. J. van Driel ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Neoadjuvant Chemotherapy ◽

Peritoneal Metastases ◽

High Grade ◽

Serous Ovarian Cancer ◽

Peritoneal Tumor ◽

The Impact

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TP53 mutations in high grade serous ovarian cancer and impact on clinical outcomes: a comparison of next generation sequencing and bioinformatics analyses

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2018-000087 ◽

2019 ◽

Vol 29 (2) ◽

pp. 346-352 ◽

Cited By ~ 6

Author(s):

Victoria Mandilaras ◽

Swati Garg ◽

Michael Cabanero ◽

Qian Tan ◽

Chiara Pastrello ◽

...

Keyword(s):

Ovarian Cancer ◽

Next Generation Sequencing ◽

Rank Test ◽

High Grade ◽

Serous Ovarian Cancer ◽

Next Generation ◽

Gain Of Function ◽

The Impact ◽

Generation Sequencing ◽

Worse Prognosis

ObjectiveMutations in TP53 are found in the majority of high grade serous ovarian cancers, leading to gain of function or loss of function of its protein product, p53, involved in oncogenesis. There have been conflicting reports as to the impact of the type of these on prognosis. We aim to further elucidate this relationship in our cohort of patients.Methods229 patients with high grade serous ovarian cancer underwent tumor profiling through an institutional molecular screening program with targeted next generation sequencing. TP53 mutations were classified using methods previously described in the literature. Immunohistochemistry on formalin-fixed paraffin embedded tissue was used to assess for TP53 mutation. Using divisive hierarchal clustering, we generated patient clusters with similar clinicopathologic characteristics to investigate differences in outcomes.ResultsSix different classification schemes of TP53 mutations were studied. These did not show an association with first platinum-free interval or overall survival. Next generation sequencing reliably predicted mutation in 80% of cases, similar to the proportion detected by immunohistochemistry. Divisive hierarchical clustering generated four main clusters, with cluster 3 having a significantly worse prognosis (p<0.0001; log-rank test). This cluster had a higher concentration of gain of function mutations and these patients were less likely to have undergone optimal debulking surgery.ConclusionsDifferent classifications of TP53 mutations did not show an impact on outcomes in this study. Immunohistochemistry was a good predictor for TP53 mutation. Cluster analysis showed that a subgroup of patients with gain of function mutations (cluster 3) had a worse prognosis.

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