scholarly journals Pretreatment with LCK Inhibitors Chemosensitizes Cisplatin-Resistant Endometrioid Ovarian Tumors

2020 ◽  
Author(s):  
Katie K. Crean-Tate ◽  
Chad Braley ◽  
Goutam Dey ◽  
Emily Esakov ◽  
Caner Saygin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Viability ◽  
Ovarian Carcinoma ◽  
Survival Data ◽  
Ovarian Tumors ◽  
Platinum Resistant ◽  
Endometrioid Ovarian Carcinoma ◽  
Endometrioid Ovarian Cancer ◽  
Km Plotter

AbstractObjectiveTo evaluate LCK inhibitors (LCKi) as chemosensitizing agents for platinum-resistant endometrioid ovarian carcinoma.MethodsKM Plotter survival data was obtained for endometrioid ovarian cancer based on LCK mRNA expression. Cisplatin resistant endometrioid ovarian carcinoma cell lines were cultured and treated first with LCKi or vehicle, then combination LCKi-cisplatin. Cell viability was assessed via CellTiter-Glo, and apoptosis with Caspase 3/7 Assay. Protein lysates were isolated from treated cells, with γ-H2Ax, a DNA adduct marker, assessed. In vivo study compared mice treated with vehicle or LCK inhibitor followed by LCK inhibitor, cisplatin, or combination therapy. One-way ANOVA and two sample t-test were used to assess statistical significance with GraphPad Prism.ResultsKM plotter data indicated LCK expression is associated with significantly worse median progression-free survival (HR 3.19, p=0.02), and a trend toward decreased overall survival in endometrioid ovarian tumors with elevated LCK expression (HR 2.45, p=0.41). In vitro, cisplatin resistant ovarian endometrioid cells treated first with LCKi followed by combination LCKi-cisplatin treatment showed decreased cell viability and increased apoptosis. Immunoblot studies revealed inhibition of LCK led to increased expression of γ-H2AX. In vivo results demonstrate treatment with LCKi followed by LCKi-cisplatin leads to significantly slowed tumor growth.ConclusionsWe identified a targetable pathway for chemosensitization of platinum resistant endometrioid ovarian cancer with initial treatment of LCKi followed by co-treatment with LCKi-cisplatin.

scholarly journals Pretreatment with LCK inhibitors chemosensitizes cisplatin‐resistant endometrioid ovarian tumors

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Katie K. Crean-Tate ◽  
Chad Braley ◽  
Goutam Dey ◽  
Emily Esakov ◽  
Caner Saygin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Progression Free Survival ◽  
The United States ◽  
Specific Protein ◽  
Ovarian Tumors ◽  
Platinum Resistant

Abstract Background Ovarian cancer is the most fatal gynecologic malignancy in the United States. While chemotherapy is effective in the vast majority of ovarian cancer patients, recurrence and resistance to standard systemic therapy is nearly inevitable. We discovered that activation of the non-receptor tyrosine kinase Lymphocyte Cell-Specific Protein-Tyrosine Kinase (LCK) promoted cisplatin resistance. Here, we hypothesized that treating high grade, platinum resistant endometrioid cancer cells with an LCK inhibitor (LCKi) followed by co-treatment with cisplatin would lead to increased cisplatin efficacy. Our objective was to assess clinical outcomes associated with increased LCK expression, test our hypothesis of utilizing LCKi as pre-treatment followed by co-treatment with cisplatin in platinum resistant ovarian cancer in vitro, and evaluate our findings in vivo to assess LCKi applicability as a therapeutic agent. Results Kaplan-Meier (KM) plotter data indicated LCK expression is associated with significantly worse median progression-free survival (HR 3.19, p = 0.02), and a trend toward decreased overall survival in endometrioid ovarian tumors with elevated LCK expression (HR 2.45, p = 0.41). In vitro, cisplatin resistant ovarian endometrioid cells treated first with LCKi followed by combination LCKi-cisplatin treatment showed decreased cell viability and increased apoptosis. Immunoblot studies revealed LCKi led to increased expression of phosphorylated H2A histone family X ($$\gamma$$ γ -H2AX), a marker for DNA damage. In vivo results demonstrate treatment with LCKi followed by LCKi-cisplatin led to significantly slowed tumor growth. Conclusions We identified a strategy to therapeutically target cisplatin resistant endometrioid ovarian cancer leading to chemosensitization to platinum chemotherapy via treatment with LCKi followed by co-treatment with LCKi-cisplatin.

scholarly journals Pretreatment with LCK Inhibitors Chemosensitizes Cisplatin-Resistant Endometrioid Ovarian Tumors

2020 ◽  
Author(s):  
Katie Crean-Tate ◽  
Chad Braley ◽  
Goutam Dey ◽  
Emily Esakov ◽  
Caner Saygin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Progression Free Survival ◽  
The United States ◽  
Specific Protein ◽  
Ovarian Tumors ◽  
Platinum Resistant

Abstract Background: Ovarian cancer is the most fatal gynecologic malignancy in the United States. While chemotherapy is effective in the vast majority of ovarian cancer patients, recurrence and resistance to standard systemic therapy is nearly inevitable. We discovered that CD55 via activation of the non-receptor tyrosine kinase Lymphocyte Cell-Specific Protein-Tyrosine Kinase (LCK) promoted cisplatin resistance. Here, we hypothesized that treating high grade, platinum resistant endometrioid cancer cells with an LCK inhibitor (LCKi) followed by co-treatment with cisplatin would lead to increased cisplatin efficacy. Our objective was to assess clinical outcomes associated with increased LCK expression, test our hypothesis of utilizing LCKi as pre-treatment followed by co-treatment with cisplatin in platinum resistant ovarian cancer in vitro, and evaluate our findings in vivo to assess LCKi applicability as a therapeutic agent. Results: Kaplan-Meier (KM) plotter data indicated LCK expression is associated with significantly worse median progression-free survival (HR 3.19, p=0.02), and a trend toward decreased overall survival in endometrioid ovarian tumors with elevated LCK expression (HR 2.45, p=0.41). In vitro, cisplatin resistant ovarian endometrioid cells treated first with LCKi followed by combination LCKi-cisplatin treatment showed decreased cell viability and increased apoptosis. Immunoblot studies revealed LCKi led to increased expression of phosphorylated H2A histone family X (-H2AX), a marker for DNA damage. In vivo results demonstrate treatment with LCKi followed by LCKi-cisplatin leads to significantly slowed tumor growth.Conclusions: We identified a strategy to therapeutically target cisplatin resistant endometrioid ovarian cancer leading to chemosensitization to platinum chemotherapy via treatment with LCKi followed by co-treatment with LCKi-cisplatin.

scholarly journals Group III phospholipase A2 downregulation attenuated survival and metastasis in ovarian cancer and promotes chemo-sensitization

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Upasana Ray ◽  
Debarshi Roy ◽  
Ling Jin ◽  
Prabhu Thirusangu ◽  
Julie Staub ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Viability ◽  
Phospholipase A2 ◽  
Mtt Assay ◽  
Metabolic Inhibitor ◽  
Autophagic Flux ◽  
Ciliated Cells ◽  
Group Iii

Abstract Background Aberrant lipogenicity and deregulated autophagy are common in most advanced human cancer and therapeutic strategies to exploit these pathways are currently under consideration. Group III Phospholipase A2 (sPLA2-III/PLA2G3), an atypical secretory PLA2, is recognized as a regulator of lipid metabolism associated with oncogenesis. Though recent studies reveal that high PLA2G3 expression significantly correlates with poor prognosis in several cancers, however, role of PLA2G3 in ovarian cancer (OC) pathogenesis is still undetermined. Methods CRISPR-Cas9 and shRNA mediated knockout and knockdown of PLA2G3 in OC cells were used to evaluate lipid droplet (LD) biogenesis by confocal and Transmission electron microscopy analysis, and the cell viability and sensitization of the cells to platinum-mediated cytotoxicity by MTT assay. Regulation of primary ciliation by PLA2G3 downregulation both genetically and by metabolic inhibitor PFK-158 induced autophagy was assessed by immunofluorescence-based confocal analysis and immunoblot. Transient transfection with GFP-RFP-LC3B and confocal analysis was used to assess the autophagic flux in OC cells. PLA2G3 knockout OVCAR5 xenograft in combination with carboplatin on tumor growth and metastasis was assessed in vivo. Efficacy of PFK158 alone and with platinum drugs was determined in patient-derived primary ascites cultures expressing PLA2G3 by MTT assay and immunoblot analysis. Results Downregulation of PLA2G3 in OVCAR8 and 5 cells inhibited LD biogenesis, decreased growth and sensitized cells to platinum drug mediated cytotoxicity in vitro and in in vivo OVCAR5 xenograft. PLA2G3 knockdown in HeyA8MDR-resistant cells showed sensitivity to carboplatin treatment. We found that both PFK158 inhibitor-mediated and genetic downregulation of PLA2G3 resulted in increased number of percent ciliated cells and inhibited cancer progression. Mechanistically, we found that PFK158-induced autophagy targeted PLA2G3 to restore primary cilia in OC cells. Of clinical relevance, PFK158 also induces percent ciliated cells in human-derived primary ascites cells and reduces cell viability with sensitization to chemotherapy. Conclusions Taken together, our study for the first time emphasizes the role of PLA2G3 in regulating the OC metastasis. This study further suggests the therapeutic potential of targeting phospholipases and/or restoration of PC for future OC treatment and the critical role of PLA2G3 in regulating ciliary function by coordinating interface between lipogenesis and metastasis.

PLGA-nanoparticles loaded with a thiosemicarbazone derived palladium(ii) complex as a potential agent to new formulations for human ovarian carcinoma treatment

2020 ◽  
Vol 44 (35) ◽  
pp. 14928-14935
Author(s):  
Carolina G. Oliveira ◽  
Luciana F. Dalmolin ◽  
R. T. C. Silva ◽  
Renata F. V. Lopez ◽  
Pedro I. S. Maia ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Viability ◽  
Ovarian Carcinoma ◽  
Cancer Cells ◽  
Plga Nanoparticles ◽  
Cytotoxic Agent ◽  
Ovarian Cancer Cells ◽  
Ovarian Cell ◽  
Encapsulation Process ◽  
Human Ovarian Carcinoma

The encapsulation process of the PdII complex [PdCl(PPh3)(PrCh)], a promising cytotoxic agent on ovarian cancer cells, in PLGA polymer was studied. The cytotoxicity results showed that the formulation led to a significant reduction of the ovarian cell viability (80% at 1 μM).

Tumor responses and preliminary survival data in a phase II trial of ofranergene obadenovec (VB-111) combined with paclitaxel in patients with recurrent platinum resistant ovarian cancer.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 5551-5551
Author(s):  
Richard T. Penson ◽  
Suzanne T. Berlin ◽  
Ashley M Hanbury ◽  
Amalia N Gonzalez ◽  
Siobhan A Collins ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase Ii ◽  
Survival Data ◽  
Phase Ii Trial ◽  
Platinum Resistant

Effect of therapeutic GAS6/AXL inhibition of tumor and stromal cells on DNA damage and response to chemotherapy in ovarian cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14676-e14676 ◽  
Author(s):  
Mary M Mullen ◽  
Elena Lomonosova ◽  
Hollie M Noia ◽  
Lei Guo ◽  
Lindsay Midori Kuroki ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Neoadjuvant Chemotherapy ◽  
Cell Viability ◽  
Mouse Models ◽  
Stromal Cells ◽  
Predictive Biomarker ◽  
Response To Chemotherapy

e14676 Background: Ovarian cancer is the leading cause of death due to gynecologic malignancy. Biomarkers to predict chemoresponse and novel therapies to target these proteins would be practice changing. We aim to establish serum and tissue GAS6 as a predictive biomarker of chemoresponse and to determine if AXL inhibition through sequestration of its ligand, GAS6, with AVB-S6-500 (AVB) can improve chemoresponse. Methods: AVB was supplied by Aravive Biologics. High grade serous ovarian cancer (HGSOC) tumor samples were obtained pre- and post-neoadjuvant chemotherapy. AXL and GAS6 expression were evaluated by immunohistochemistry and serum concentration. In vitro viability and clonogenic assays were performed on chemoresistant tumor (OVCAR8, OVCAR5, COV62, and POV71-hTERT) and stromal cells (CAF86) treated with chemotherapy +/- AVB. Mouse models (OVCAR8, PDX, OVCAR5) were used to determine if the combination of chemotherapy + AVB reduced tumor burden. Immunofluorescent assays targeting ɣH2AX were used to evaluate DNA damage. Results: Patients with high pretreatment tumor GAS6 expression ( > 85%, n = 7) or serum GAS6 concentrations ( > 25ng/mL, n = 13) were more likely to be resistant to neoadjuvant chemotherapy than those with low tumor GAS6 expression ( < 45%, n = 4) (P = 0.010) or low serum GAS6 concentrations ( < 15ng/mL, n = 5) (P = 0.002). Carboplatin plus AVB (2µM, 5µM) and paclitaxel plus AVB (1µM) resulted in decreased cell viability and clonogenic growth compared to chemotherapy alone (p < 0.05) in all tumor and stromal cell lines. Synergism was seen between carboplatin+AVB and paclitaxel+AVB with a weighted combination index < 1. In vivo tumor mouse models treated with chemotherapy+AVB had significantly smaller subcutaneous and intraperitoneal (IP) tumors than those treated with chemotherapy alone (3.1mg vs 64mg, P = 0.003 OVCAR8; 62mg vs 157mg, P = 0.0108 PDX subcutaneous model; 0.05mg vs 0.3669mg, P < 0.001 OVCAR5 IP model). Increased DNA damage was noted in tumor and stromal cells treated with carboplatin+AVB compared to carboplatin alone (OVCAR8, COV362, CAF86 P < 0.001). Conclusions: High GAS6 is associated with lack of neoadjuvant chemoresponse in HGSOC patients. The combination of chemotherapy with AVB decreases tumor cell viability, tumor growth, and an increase in DNA damage response.

scholarly journals A Review of the Clinical Characteristics and Novel Molecular Subtypes of Endometrioid Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Shuangfeng Chen ◽  
Yuebo Li ◽  
Lili Qian ◽  
Sisi Deng ◽  
Luwen Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Reproductive Tract ◽  
Molecular Subtypes ◽  
Female Reproductive Tract ◽  
Molecular Characteristics ◽  
The Novel ◽  
Endometrioid Ovarian Carcinoma ◽  
Endometrioid Ovarian Cancer ◽  
Prediction Of Prognosis ◽  
Novel Therapeutic Strategies

Ovarian cancer is one of the most common gynecologic cancers that has the highest mortality rate. Endometrioid ovarian cancer, a distinct subtype of epithelial ovarian cancer, is associated with endometriosis and Lynch syndrome, and is often accompanied by synchronous endometrial carcinoma. In recent years, dysbiosis of the microbiota within the female reproductive tract has been suggested to be involved in the pathogenesis of endometrial cancer and ovarian cancer, with some specific pathogens exhibiting oncogenic having been found to contribute to cancer development. It has been shown that dysregulation of the microenvironment and accumulation of mutations are stimulatory factors in the progression of endometrioid ovarian carcinoma. This would be a potential therapeutic target in the future. Simultaneously, multiple studies have demonstrated the role of four molecular subtypes of endometrioid ovarian cancer, which are of particular importance in the prediction of prognosis. This literature review aims to compile the potential mechanisms of endometrioid ovarian cancer, molecular characteristics, and molecular pathological types that could potentially play a role in the prediction of prognosis, and the novel therapeutic strategies, providing some guidance for the stratified management of ovarian cancer.

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