scholarly journals Evaluating Targeted Therapies in Ovarian Cancer Metabolism: Novel Role for PCSK9 and Second Generation mTOR Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3727
Author(s):  
Dafne Jacome Sanz ◽  
Juuli Raivola ◽  
Hanna Karvonen ◽  
Mariliina Arjama ◽  
Harlan Barker ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Lipid Metabolism ◽  
Cell Survival ◽  
Drug Testing ◽  
Cancer Metabolism ◽  
Ex Vivo ◽  
Specific Inhibitor ◽  
Low Grade ◽  
Serous Ovarian Cancer

Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied the role of PCSK9, a cholesterol-regulating enzyme, in OC cell survival and its downstream signaling. We also investigated the cytotoxic efficacy of a small library of metabolic (n = 11) and mTOR (n = 10) inhibitors using OC cell lines (n = 8) and ex vivo patient-derived cell cultures (PDCs, n = 5) to identify clinically suitable drug vulnerabilities. Targeting PCSK9 expression with siRNA or PCSK9 specific inhibitor (PF-06446846) impaired OC cell survival. In addition, overexpression of PCSK9 induced robust AKT phosphorylation along with increased expression of ERK1/2 and MEK1/2, suggesting a pro-survival role of PCSK9 in OC cells. Moreover, our drug testing revealed marked differences in cytotoxic responses to drugs targeting metabolic pathways of high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC) PDCs. Our results show that targeting PCSK9 expression could impair OC cell survival, which warrants further investigation to address the dependency of this cancer on lipogenesis and omental metastasis. Moreover, the differences in metabolic gene expression and drug responses of OC PDCs indicate the existence of a metabolic heterogeneity within OC subtypes, which should be further explored for therapeutic improvements.

scholarly journals The role of secondary cytoreduction in low-grade serous ovarian cancer or peritoneal cancer

2015 ◽  
Vol 136 (1) ◽  
pp. 25-29 ◽  
Author(s):  
Erin K. Crane ◽  
Charlotte C. Sun ◽  
Pedro T. Ramirez ◽  
Kathleen M. Schmeler ◽  
Anais Malpica ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Low Grade ◽  
Serous Ovarian Cancer ◽  
Peritoneal Cancer

Cost-effectiveness of maintenance hormonal therapy in patients with advanced low grade serous ovarian cancer

2021 ◽  
Vol 160 (1) ◽  
pp. 206-213
Author(s):  
Andra Nica ◽  
Ji Young Jennifer Lee ◽  
Nicole Look Hong ◽  
Taymaa May
Keyword(s):  
Ovarian Cancer ◽  
Cost Effectiveness ◽  
Hormonal Therapy ◽  
Low Grade ◽  
Serous Ovarian Cancer

scholarly journals CD133 Promotes Adhesion to the Ovarian Cancer Metastatic Niche

2018 ◽  
Vol 11 ◽  
pp. 117906441876788 ◽  
Author(s):  
Lynn Roy ◽  
Alexander Bobbs ◽  
Rachel Sattler ◽  
Jeffrey L Kurkewich ◽  
Paige B Dausinas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Metastasis ◽  
Ex Vivo ◽  
Surface Protein ◽  
Ovarian Cancer Cells ◽  
Metastatic Niche ◽  
Attractive Therapeutic Target ◽  
Peritoneal Mesothelium

Cancer stem cells (CSCs) are an attractive therapeutic target due to their predicted role in both metastasis and chemoresistance. One of the most commonly agreed on markers for ovarian CSCs is the cell surface protein CD133. CD133+ ovarian CSCs have increased tumorigenicity, resistance to chemotherapy, and increased metastasis. Therefore, we were interested in defining how CD133 is regulated and whether it has a role in tumor metastasis. Previously we found that overexpression of the transcription factor, ARID3B, increased the expression of PROM1 (CD133 gene) in ovarian cancer cells in vitro and in xenograft tumors. We report that ARID3B directly regulates PROM1 expression. Importantly, in a xenograft mouse model of ovarian cancer, knockdown of PROM1 in cells expressing exogenous ARID3B resulted in increased survival time compared with cells expressing ARID3B and a control short hairpin RNA. This indicated that ARID3B regulation of PROM1 is critical for tumor growth. Moreover, we hypothesized that CD133 may affect metastatic spread. Given that the peritoneal mesothelium is a major site of ovarian cancer metastasis, we explored the role of PROM1 in mesothelial attachment. PROM1 expression increased adhesion to mesothelium in vitro and ex vivo. Collectively, our work demonstrates that ARID3B regulates PROM1 adhesion to the ovarian cancer metastatic niche.

scholarly journals Increase in post-therapy tumor calcification on CT scan is not an indicator of response to therapy in low-grade serous ovarian cancer

2016 ◽  
Vol 41 (8) ◽  
pp. 1589-1595 ◽  
Author(s):  
Dhakshinamoorthy Ganeshan ◽  
Priya Bhosale ◽  
Wei Wei ◽  
Preetha Ramalingam ◽  
Eniola Mudasiru-Dawodu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ct Scan ◽  
Response To Therapy ◽  
Low Grade ◽  
Serous Ovarian Cancer ◽  
Post Therapy

scholarly journals BRAF Mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer

Cancer ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 548-554 ◽  
Author(s):  
Rachel N. Grisham ◽  
Gopa Iyer ◽  
Karuna Garg ◽  
Deborah DeLair ◽  
David M. Hyman ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Braf Mutation ◽  
Early Stage ◽  
Low Grade ◽  
Serous Ovarian Cancer ◽  
Early Stage Disease ◽  
Stage Disease ◽  
Improved Outcome

Low-grade serous ovarian cancer: State of the science

2020 ◽  
Vol 156 (3) ◽  
pp. 715-725 ◽  
Author(s):  
Brian Slomovitz ◽  
Charlie Gourley ◽  
Mark S. Carey ◽  
Anais Malpica ◽  
Ie-Ming Shih ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Low Grade ◽  
Serous Ovarian Cancer ◽  
State Of The Science

scholarly journals Heterotypic CAF-tumor spheroids promote early peritoneal metastasis of ovarian cancer

2019 ◽  
Vol 216 (3) ◽  
pp. 688-703 ◽  
Author(s):  
Qinglei Gao ◽  
Zongyuan Yang ◽  
Sen Xu ◽  
Xiaoting Li ◽  
Xin Yang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Peritoneal Dissemination ◽  
Tumor Stroma ◽  
Stromal Fibroblast ◽  
Low Grade ◽  
Cancer Associated Fibroblasts ◽  
Serous Ovarian Cancer ◽  
Active Involvement ◽  
Essential Components ◽  
Metastatic Capacity

High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5high (ITGA5high) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination. Intriguingly, fibroblasts inside MUs support ATC survival and guide their peritoneal invasion before becoming essential components of the tumor stroma in newly formed metastases. Cancer-associated fibroblasts (CAFs) recruit ITGA5high ATCs to form MUs, which further sustain ATC ITGA5 expression by EGF secretion. Notably, LGSOC is largely devoid of CAFs and the resultant MUs, which might explain its metastatic delay. These findings identify a specialized MU architecture that amplifies the tumor–stroma interaction and promotes transcoelomic metastasis in HGSOC, providing the basis for stromal fibroblast-oriented interventions in hampering OC peritoneal propagation.

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