An overview of early investigational therapies for chemoresistant ovarian cancer

Marchetti, Cláudia; Ledermann, Jonathan A.; Panici, Pierluigi Benedetti

doi:10.1517/13543784.2015.1072168

Cited by 14 publications

(14 citation statements)

References 122 publications

(47 reference statements)

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“…Previous studies have shown that Wnt signaling pathway deregulation correlates with ovarian cancer cell proliferation, survival, invasion and metastasis (25,26,28,30,31). Furthermore, cisplatin chemoresistance has been an obstacle in the successful treatment of ovarian cancer (8,32,33). Several studies have concluded that aberrant regulation of Wnt signaling induces tumor cell chemoresistance (16–18).…”

Section: Discussionmentioning

confidence: 99%

“…The issue of resistance to cisplatin remains a major obstacle in the successful treatment of ovarian cancer (8). Previous studies have indicated that inhibition of intrinsic cell death signaling pathways, activation of cell survival signaling pathways, and dysregulation of oncogenes, tumor suppressor genes and microRNAs contributes to cisplatin chemoresistance in ovarian cancer cells (9,10).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplatin-induced chemoresistance in ovarian cancer

Jin

Feng

Zou

et al. 2016

Experimental and Therapeutic Medicine

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The aim of the present study was to explore the expression of Wnt signaling proteins β-catenin, c-Jun N-terminal kinase (JNK) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in ovarian cancer cells, and assess the correlation between this expression and cisplatin-induced chemoresistance. SKOV3 ovarian carcinoma cells and SKOV3/DDP (cisplatin resistant) cells were treated with cisplatin in the absence or presence of a Wnt signaling activator (CHIR-99021, glycogen synthase kinase 3β inhibitor) or inhibitor (XAV-939, tankyrase inhibitor). Following incubation for 48 h, cell viability, proliferation and cytotoxicity were measured using a sensitive colorimetric cell counting kit. Expression levels of β-catenin, JNK and CaMKII were detected by western blot and immunofluorescence staining. The results of the current study identified that β-catenin and JNK expression levels were significantly higher (P<0.01 and P<0.05 respectively), while CaMKII expression was lower (P>0.05), in SKOV3/DDP cells compared with SKOV3 cells. Moreover, following treatment with 20 µM cisplatin, reduced expression of β-catenin and JNK (P<0.05 and P<0.01 respectively), and increased expression of CaMKII (P<0.01), was observed in SKOV3 and SKOV3/DPP cell lines. Furthermore, inhibition of β-catenin signaling by XAV-939 effectively reversed cisplatin chemoresistance in SKOV3/DDP cells. Similarly, XAV-939 downregulated JNK expression (P<0.001), but upregulated CaMKII expression (P<0.001), in SKOV3/DDP cells. In conclusion, abnormal activation of Wnt/β-catenin and Wnt/JNK signaling pathways in ovarian cancer cells promotes cisplatin resistance, while the Wnt/Ca2+ signaling pathway reduces cisplatin resistance. This indicates that β-catenin, JNK and CaMKII are potential therapeutic targets in chemoresistant ovarian cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplatin-induced chemoresistance in ovarian cancer

Jin

Feng

Zou

et al. 2016

Experimental and Therapeutic Medicine

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“…For platinum-resistant disease, various sequential mono-chemotherapies including weekly paclitaxel, liposomal doxorubicin and gemcitabine are used until subsequent progression or unacceptable toxicity. However, as the expected response rate in the platinum-resistant setting are low (~10-15%), several trials are investigating new agents to overcome resistance 101 . In the platinumresistant setting, a phase III trial (AURELIA) showed that adding bevacizumab to various chemotherapy regimens increased the PFS from 3.4 to 6.7 months (HR 0.48 95% CI, 0.38-0.60; unstratified log-rank p<0.001).…”

Section: Treatmentmentioning

confidence: 99%

Epithelial ovarian cancer

et al. 2019

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Epithelial ovarian cancer (EOC) generally presents at an advanced stage and is the most common cause of gynecologic cancer death. Treatment requires expert multidisciplinary care. Population based screening has been ineffective to date but new approaches for early diagnosis and prevention that leverage molecular genomics are in development. Initial therapy includes surgery and adjuvant therapy. EOC is composed of distinct histologic subtypes with unique genomic characteristics, which are improving the precision and effectiveness of therapy, allowing discovery of predictors of response such as BRCA1/2 mutations, homologous recombination (HR) deficiency for DNA damage response pathway inhibitors, or resistance (CCNE1). Rapidly evolving techniques to measure genomic changes in tumour and blood allow assessment of sensitivity and emergence of resistance to therapy, and may be accurate indicators of residual disease. Recurrence unfortunately remains usually incurable, and patient symptom control and quality of life are key considerations at that time. Treatments for recurrence have to be designed from a patient's perspective, and incorporate meaningful measures of benefit. Urgent progress is needed to develop evidence and consensus-based treatment guidelines for each subgroup, and requires close international cooperation in conducting clinical trials through academic research groups such as the Gynecologic Cancer Intergroup.

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“…In the last decade, ROC has become increasingly viewed as a chronic disease process, and in a well-selected population, the administration of multiple lines of chemotherapy seems to be beneficial [25] ; of course, the more lines of chemotherapy, the higher the risk of toxicity and quality of life decrease. Therefore, one of the greatest challenges for gynecological oncologists who cope with this disease is to find the best approach, in balance between clinical benefit and patient-reported outcome.…”

Section: Discussionmentioning

confidence: 99%

Short-Infusion Trabectedin in Heavily Pretreated Ovarian Cancer Patients: A Single-Institution Experience

Marchetti¹,

Musella²,

Romito³

et al. 2017

Oncology

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Objective: The aim of this study was to assess the efficacy and tolerability of trabectedin given every 10 days as a single agent in recurrent ovarian cancer after 3 prior regimens. Method: Trabectedin 0.6 mg/m² was administered as a 3-h infusion every 10 days on a 21-day cycle. The study population was compared to patients treated with weekly paclitaxel 80 mg/m² intravenously on days 1, 8, 15, and 22 every 4 weeks. Results: We identified 34 patients previously submitted to at least 3 lines of chemotherapy who received single-agent trabectedin between 2010 and 2015. They were matched with a historical series of 34 patients who received weekly paclitaxel. No significant differences in response rate were found. Median progression-free survival was 4 months; 5 months in the trabectedin group and 4 months in the paclitaxel group. Overall survival (OS) was 13 months for the trabectedin group and 7 months for the paclitaxel group (p = 0.015). Patients who received platinum after trabectedin had a significant OS increase compared to those who received platinum after paclitaxel (18 vs. 9 months, respectively; p = 0.009). The most frequent drug-related grade 3/4 toxicities were reversible hepatic toxicity, neutropenia, anemia, thrombocytopenia, and gastrointestinal toxicity. Conclusion: Single-agent trabectedin every 10 days is an active treatment with a manageable toxicity profile in heavily pretreated advanced relapsed ovarian cancer patients.

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An overview of early investigational therapies for chemoresistant ovarian cancer

Cited by 14 publications

References 122 publications

Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplatin-induced chemoresistance in ovarian cancer

Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplatin-induced chemoresistance in ovarian cancer

Epithelial ovarian cancer

Short-Infusion Trabectedin in Heavily Pretreated Ovarian Cancer Patients: A Single-Institution Experience

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