Abstract A74: Identification of novel targetable resistance mechanisms and candidate clinical response biomarkers in drug-resistant ovarian cancer, following single-agent and combination chemotherapy

Ovarian cancer is still the fourth cause of death by cancer among women and the most fatal among gynecological tumors. The purpose of this symposium is, year after year, to report and discuss the new developments in the treatment of patients with ovarian cancer, the majority of whom still present with advanced disease. It also tries to make it clear to the participants what is evidence-based and what is not. Mature data of both classic studies like GOG-111, OV-10, and more recent studies like GOG-158, AGO-OVAR-3, and the intergroup paclitaxel/epirubicin/carboplatin (TEC) versus paclitaxel/carboplatin (TC) study have been presented. Other current controversial issues included in this edition were sequential single-agent versus simultaneous administration of combination chemotherapy, the role of combination chemotherapy in second-line treatment, the role of consolidation therapy, the role of anthracyclines in the treatment, and cost-effectiviness studies in ovarian cancer. Although the main topic of the symposium is advanced disease, this edition included the results of two parallel randomized studies (ACTION and ICON1) on the treatment of early disease. In addition, new trends in early detection of ovarian cancer have been updated.The pace of new agent development has increased, and it would be helpful to have more efficient preclinical models and early phase-clinical trials to guide the selection of active agents for phase III evaluation. Reaching international consensus is a challenge but offers the opportunity to test multiple regimens more efficiently against a single-control population, rather than conducting multiple smaller studies with redundant internal controls. If indeed answers to the relevant questions are to be obtained more quickly, then, a network of current national or international groups could potentially facilitate this.

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The Significance of Combination Chemotherapy in Epithelial Ovarian Cancer

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000055 ◽

2014 ◽

Vol 24 (2) ◽

pp. 226-232 ◽

Cited By ~ 3

Author(s):

Janice S. Kwon ◽

Colleen McGahan ◽

Ulrike Dehaeck ◽

Jennifer Santos ◽

Kenneth Swenerton ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Combination Chemotherapy ◽

Practice Patterns ◽

Performance Status ◽

Single Agent ◽

Population Level ◽

Population Based ◽

First Line ◽

Line Chemotherapy

ObjectiveSince the publication of International Collaborative Ovarian Neoplasm 3, various practice patterns have evolved with respect to practice patterns and survival among women with epithelial ovarian cancer in British Columbia, Canada. The objectives of this study were to evaluate different strategies for first-line chemotherapy in ovarian cancer and to determine their effect on survival at a population level.Methods and MaterialsThis was a retrospective population-based cohort study of 854 women with epithelial ovarian cancer in British Columbia from 2005 to 2008. Details were ascertained on stage, grade, histotype, performance status, surgeon type, extent of debulking, first-line chemotherapy including type and number of cycles, and cause and date of death. A Cox regression model was used to evaluate the association of covariates on overall survival.ResultsOf the 817 women eligible for chemotherapy, 729 (89.2%) received treatment, including 106 (14.5%) women who received single-agent carboplatin and 623 (85.5%) women who received combination platinum-based chemotherapy. Chemotherapy was evaluated as a time-varying covariate. Median numbers of single-agent carboplatin and combination chemotherapy cycles were 5 (range, 1–11) and 6 (range, 1–12), respectively. After adjustment for demographic, disease, and treatment factors, the covariates significantly associated with survival were stage, performance status, extent of debulking, and chemotherapy type. Single-agent carboplatin had a mortality hazards ratio of 5.15 (95% confidence interval, 2.39–11.11) relative to combination chemotherapy.ConclusionsIn this population-based study, first-line platinum-based combination chemotherapy was associated with improved survival compared with single-agent carboplatin after adjustment for covariates in ovarian cancer. Higher rates of combination chemotherapy may improve outcomes at a population level.

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1542. The Evaluation of the In Vitro Synergy of Colistin in Combination with Meropenem and Tigecycline against 50 Multi-Drug-resistant Acinetobacter baumannii strains

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1406 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S562-S563

Author(s):

Jacinda Abdul-Mutakabbir ◽

Juwom Yim ◽

Logan Nguyen ◽

Razieh Kebriaei ◽

Kyle Stamper ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Bactericidal Activity ◽

Single Agent ◽

Resistance Mechanisms ◽

Drug Resistant ◽

Initial Inoculum ◽

Log Reduction ◽

Carbapenem Resistant ◽

Time Kill

Abstract Background Acinetobacter baumannii possess inherent and acquired antibiotic resistance mechanisms that have rendered most antibiotics, including carbapenems, inactive. Colistin (COL) has risen as salvage therapy against these organisms due to its retained activity against A. baumannii. However, COL monotherapy is often met with suboptimal outcomes. Recently, combination therapy with COL and meropenem (MEM) or tigecycline (TGC) has been shown to be effective in eradicating multi-drug-resistant A. baumannii infections. The objective of this study was to further evaluate the efficacy of COL in combination with MEM or TGC against 50 multi-drug-resistant A. baumannii strains. Methods Fifty carbapenem-resistant A. baumannii strains were evaluated using combination minimum inhibitory concentration (MIC) testing and time-kill analysis (TKA). Single-drug MIC testing was performed for each strain by broth microdilution. Combination MIC testing was performed for COL+MEM and COL+TGC. Each strain was evaluated via 24-hour TKA to assess the synergistic capabilities of COL+MEM, and COL+TGC. Synergy was defined as a ≥ 2-log reduction CFU/mL in either combination from the most active single agent, while bactericidal activity was defined as a ≥ 3-log reduction CFU/mL of either combination from the initial inoculum. Results All 50 strains were resistant to MEM and TGC with MICs ≥ 64 µg/mL and ≥ 4 µg/mL respectively; while 3 strains were resistant to COL, MICs ≥ 2 µg/mL. MEM and TGC MIC values were reduced as much as 128-fold (median 2-fold) and 32-fold (median 2-fold),, respectively, in the presence of subinhibitory COL. COL MIC values were reduced as much as 512-fold (median 4-fold) from baseline in the presence of subinhibitory MEM, and as high as 16-fold (median 2-fold) in the presence of TGC. In TKAs, COL+MEM was synergistic in 45/50 (90%) strains and bactericidal against 43/50 (86%) strains. COL+TGC TKAs revealed synergy in 32/50 (64%) strains, and bactericidal activity against 28/50 (56%) strains. Conclusion The combinations of COL+MEM and COL+TGC demonstrate promise in combating highly resistant A. baumannii. Further research is mandated to explore other combinations that are capable of eradicating multi-drug-resistant A. baumannii. Disclosures All authors: No reported disclosures.

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Taxane platinum combination chemotherapy versus single agent platinum for the first line treatment of epithelial ovarian cancer

Cochrane Database of Systematic Reviews ◽

10.1002/14651858.cd010194.pub2 ◽

2015 ◽

Author(s):

Nick Johnson ◽

Tracie Miles ◽

Paul Cornes ◽

Edward Gilby

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Combination Chemotherapy ◽

Single Agent ◽

Line Treatment ◽

First Line ◽

First Line Treatment

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Taxane-platinum combination chemotherapy versus single agent platinum for the first-line treatment of epithelial ovarian cancer

10.1002/14651858.cd010194 ◽

2012 ◽

Author(s):

Nick Johnson ◽

Tracie Miles ◽

Paul Cornes ◽

Edward Gilby

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Combination Chemotherapy ◽

Single Agent ◽

Line Treatment ◽

First Line ◽

First Line Treatment

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Influence of Asparaginase on a Combination Chemotherapy Protocol for Canine Multicentric Lymphoma

Journal of the American Animal Hospital Association ◽

10.5326/0410221 ◽

2005 ◽

Vol 41 (4) ◽

pp. 221-226 ◽

Cited By ~ 26

Author(s):

Antonella Borgatti Jeffreys ◽

Deborah W. Knapp ◽

William W. Carlton ◽

Rosanne M. Thomas ◽

Patty L. Bonney ◽

...

Keyword(s):

Clinical Response ◽

Combination Chemotherapy ◽

Clinical Remission ◽

Single Agent ◽

Induction Phase ◽

Canine Lymphoma ◽

Free Interval ◽

Chemotherapy Protocol ◽

Multicentric Lymphoma ◽

Single Agent Chemotherapy

Combination chemotherapy is superior to single-agent chemotherapy for treating canine lymphoma, but the effect of each drug on efficacy remains unknown. By comparing 34 dogs treated with a modified cyclophosphamide, vincristine, prednisone (COP) chemotherapy protocol and 42 dogs given asparaginase in the induction phase of the same protocol, the effect of asparaginase on the chemotherapeutic protocol was determined. Both groups were compared based on clinical response at 2 weeks and 6 weeks, and on the progression-free interval. Asparaginase did not significantly increase the likelihood of a clinical remission or prolong the initial progression-free interval in the dogs studied.

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OTX015 Epi-Drug Exerts Antitumor Effects in Ovarian Cancer Cells by Blocking GNL3-Mediated Radioresistance Mechanisms: Cellular, Molecular and Computational Evidence

Cancers ◽

10.3390/cancers13071519 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1519

Author(s):

Francesca Megiorni ◽

Simona Camero ◽

Paola Pontecorvi ◽

Lucrezia Camicia ◽

Francesco Marampon ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Single Agent ◽

Resistance Mechanisms ◽

Ovarian Cancer Cells ◽

Cancer Resistance ◽

Patient Death ◽

Antitumor Effects ◽

Cellular Models ◽

Migration Capacity

Ovarian cancer (OC) is the most aggressive gynecological tumor worldwide and, notwithstanding the increment in conventional treatments, many resistance mechanisms arise, this leading to cure failure and patient death. So, the use of novel adjuvant drugs able to counteract these pathways is urgently needed to improve patient overall survival. A growing interest is focused on epigenetic drugs for cancer therapy, such as Bromodomain and Extra-Terminal motif inhibitors (BETi). Here, we investigate the antitumor effects of OTX015, a novel BETi, as a single agent or in combination with ionizing radiation (IR) in OC cellular models. OTX015 treatment significantly reduced tumor cell proliferation by triggering cell cycle arrest and apoptosis that were linked to nucleolar stress and DNA damage. OTX015 impaired migration capacity and potentiated IR effects by reducing the expression of different drivers of cancer resistance mechanisms, including GNL3 gene, whose expression was found to be significantly higher in OC biopsies than in normal ovarian tissues. Gene specific knocking down and computational network analysis confirmed the centrality of GNL3 in OTX015-mediated OC antitumor effects. Altogether, our findings suggest OTX015 as an effective option to improve therapeutic strategies and overcome the development of resistant cancer cells in patients with OC.

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Evaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models

10.26434/chemrxiv.7877987.v1 ◽

2019 ◽

Author(s):

Daniel Sun ◽

Soumya Poddar ◽

Roy D. Pan ◽

Juno Van Valkenburgh ◽

Ethan Rosser ◽

...

Keyword(s):

Solid Tumor ◽

Small Cell Lung Carcinoma ◽

Single Agent ◽

Resistance Mechanisms ◽

Tumor Models ◽

Cell Lung Carcinoma ◽

Adaptive Resistance ◽

Cancer Models ◽

Nanomolar Range

The lead compound, an ⍺-N-heterocyclic carboxaldehyde thiosemicarbazone HCT-13, was highly potent against a panel of pancreatic, small cell lung carcinoma, and prostate cancer models, with IC90 values in the low-to-mid nanomolar range. We show that the cytotoxicity of HCT-13 is copper-dependent, that it acts as a copper ionophore, induces production of reactive oxygen species (ROS), and promotes mitochondrial dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (ATR), were identified as actionable adaptive resistance mechanisms following HCT-13 treatment. Taken together, HCT-13 is potent against solid tumor models and warrants in vivo evaluation against aggressive tumor models, either as a single agent or as part of a combination therapy.

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