Abstract 2413: TP53 gene mutations differently regulate ovarian cancer metabolism: Ex vivo and in vitro studies

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.

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Differential antiplatelet effects of angiotensin converting enzyme inhibitors: Ex vivo and in vitro studies using whole blood aggregometry

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(03)82279-9 ◽

2003 ◽

Vol 41 (6) ◽

pp. 272-273

Author(s):

Dirk Skowasch ◽

Melanie Schneider ◽

Stefanie Schrempf ◽

Stefan Krämer ◽

Mario maylahn ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Whole Blood ◽

Enzyme Inhibitors ◽

Ex Vivo ◽

Angiotensin Converting Enzyme Inhibitors ◽

In Vitro Studies ◽

Converting Enzyme ◽

Converting Enzyme Inhibitors ◽

Whole Blood Aggregometry

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CD133 Promotes Adhesion to the Ovarian Cancer Metastatic Niche

Cancer Growth and Metastasis ◽

10.1177/1179064418767882 ◽

2018 ◽

Vol 11 ◽

pp. 117906441876788 ◽

Cited By ~ 16

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.

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TP53 Gene Mutations in Tumor Cells of Patients with Aggressive B-Cell Lymphomas

Clinical oncohematology ◽

10.21320/2500-2139-2019-12-3-263-270 ◽

2019 ◽

Vol 12 (3) ◽

pp. 263-270

Author(s):

AE Misyurina ◽

◽

SK Kravchenko ◽

VA Misyurin ◽

AM Kovrigina ◽

...

Keyword(s):

B Cell ◽

Tumor Cells ◽

Gene Mutations ◽

Tp53 Gene ◽

B Cell Lymphomas ◽

Tp53 Gene Mutations

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Quantitative detections of TP53 gene mutations improve the diagnosis and prognostic prediction of biliary tract cancers using droplet digital PCR

Journal of Clinical Laboratory Analysis ◽

10.1002/jcla.24103 ◽

2021 ◽

Author(s):

Xiao Xiao ◽

Jun Zhou ◽

Meng Fang ◽

Jun Ji ◽

Chenjun Huang ◽

...

Keyword(s):

Biliary Tract ◽

Gene Mutations ◽

Tp53 Gene ◽

Digital Pcr ◽

Droplet Digital Pcr ◽

Biliary Tract Cancers ◽

Prognostic Prediction ◽

Tp53 Gene Mutations

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Newly developed dual topoisomerase inhibitor P8-D6 is highly active in ovarian cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/17588359211059896 ◽

2021 ◽

Vol 13 ◽

pp. 175883592110598

Author(s):

Inken Flörkemeier ◽

Tamara N. Steinhauer ◽

Nina Hedemann ◽

Magnus Ölander ◽

Per Artursson ◽

...

Keyword(s):

Ovarian Cancer ◽

Topoisomerase I ◽

Ex Vivo ◽

Chemotherapy Resistance ◽

Membrane Integrity ◽

Three Dimensional ◽

New Drugs ◽

Highly Active ◽

Gynaecologic Neoplasms

Background: Ovarian cancer (OvCa) constitutes a rare and highly aggressive malignancy and is one of the most lethal of all gynaecologic neoplasms. Due to chemotherapy resistance and treatment limitations because of side effects, OvCa is still not sufficiently treatable. Hence, new drugs for OvCa therapy such as P8-D6 with promising antitumour properties have a high clinical need. The benzo[ c]phenanthridine P8-D6 is an effective inductor of apoptosis by acting as a dual topoisomerase I/II inhibitor. Methods: In the present study, the effectiveness of P8-D6 on OvCa was investigated in vitro. In various OvCa cell lines and ex vivo primary cells, the apoptosis induction compared with standard therapeutic agents was determined in two-dimensional monolayers. Expanded by three-dimensional and co-culture, the P8-D6 treated cells were examined for changes in cytotoxicity, apoptosis rate and membrane integrity via scanning electron microscopy (SEM). Likewise, the effects of P8-D6 on non-cancer human ovarian surface epithelial cells and primary human hepatocytes were determined. Results: This study shows a significant P8-D6-induced increase in apoptosis and cytotoxicity in OvCa cells which surpasses the efficacy of well-established drugs like cisplatin or the topoisomerase inhibitors etoposide and topotecan. Non-cancer cells were affected only slightly by P8-D6. Moreover, no hepatotoxic effect in in vitro studies was detected. Conclusion: P8-D6 is a strong and rapid inductor of apoptosis and might be a novel treatment option for OvCa therapy.

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