Cisplatin Resistance in Ovarian Cancer: Classical Outlook and Newer Perspectives

Ovarian cancer is one of the most common gynecological cancers. Recently, there is increase in incidence of ovarian cancer not only India but also worldwide. Ovarian cancer patients exhibit nonspecific symptoms during early course of disease. As a consequence, 70% of these patients are diagnosed in advanced stages. Ovarian cancer treatment includes cytoreductive surgery followed by platinum-based chemotherapy. However, these patients develop fatal recurrence due to development of platinum resistance. Cisplatin, (platinum analog) resistance is multifactorial and complex. Earlier, resistance was mainly attributed to conventional molecular mechanisms like decreased intracellular accumulation of cisplatin, enhanced DNA repair and increased cisplatin detoxification. Nevertheless, emergence of knowledge of tumor biology have lead to discovery of other contributing mechanisms. These tumor microenvironment related factors include physical blockade, hypoxia, cancer stem cells, cancer associated fibroblasts and many others. Understanding these mechanisms of cisplatin resistance is crucial for development of novel strategy to combat the same. Hence, this review summarizes all the mechanisms of resistance of cisplatin in ovarian cancer.

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How to sequence treatment in relapsed ovarian cancer

Future Oncology ◽

10.2217/fon-2020-1122 ◽

2020 ◽

Author(s):

Sandro Pignata ◽

Sabrina Chiara Cecere

Keyword(s):

Ovarian Cancer ◽

Recurrent Disease ◽

Recurrent Ovarian Cancer ◽

Platinum Resistance ◽

Front Line ◽

Related Factors ◽

Drug Classes ◽

Stage Disease ◽

Platinum Based Chemotherapy ◽

Line Setting

Numerous disease- and patient-related factors must be considered when selecting systemic therapy for recurrent ovarian cancer. Anti-angiogenics (bevacizumab) and poly(ADP-ribose) polymerase inhibitors (olaparib, niraparib, rucaparib) have an important role as maintenance of platinum-based chemotherapy for recurrent disease and their use in the first-line setting of advanced-stage disease is becoming established. As previous exposure to none, one or both of these drug classes is integral to selecting next therapy, front-line use impacts on options available to treat recurrent disease. A key strategy to delay platinum resistance and improve prognosis of recurrent disease is to alternate treatments with different mechanisms of action. The multiple mechanisms of trabectedin and its complementarity with platinum allow intercalation between platinum regimens in potentially platinum-responsive patients with recurrent disease.

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Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer

Biomedicines ◽

10.3390/biomedicines9010070 ◽

2021 ◽

Vol 9 (1) ◽

pp. 70

Author(s):

David Schweer ◽

J. Robert McCorkle ◽

Jurgen Rohr ◽

Oleg V. Tsodikov ◽

Frederick Ueland ◽

...

Keyword(s):

Ovarian Cancer ◽

Transcription Factor ◽

Cisplatin Resistance ◽

Therapeutic Agents ◽

Therapeutic Window ◽

Platinum Resistance ◽

Narrow Therapeutic Window ◽

Platinum Based Chemotherapy ◽

Ovarian Tumorigenesis ◽

Novel Therapeutic

Ovarian cancer is a highly deadly malignancy in which recurrence is considered incurable. Resistance to platinum-based chemotherapy bodes a particularly abysmal prognosis, underscoring the need for novel therapeutic agents and strategies. The use of mithramycin, an antineoplastic antibiotic, has been previously limited by its narrow therapeutic window. Recent advances in semisynthetic methods have led to mithramycin analogs with improved pharmacological profiles. Mithramycin inhibits the activity of the transcription factor Sp1, which is closely linked with ovarian tumorigenesis and platinum-resistance. This article summarizes recent clinical developments related to mithramycin and postulates a role for the use of mithramycin, or its analog, in the treatment of platinum-resistant ovarian cancer.

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USP1 links platinum resistance to cancer cell dissemination by regulating Snail stability

Science Advances ◽

10.1126/sciadv.aav3235 ◽

2019 ◽

Vol 5 (5) ◽

pp. eaav3235 ◽

Cited By ~ 16

Author(s):

Maura Sonego ◽

Ilenia Pellarin ◽

Alice Costa ◽

Gian Luca Rampioni Vinciguerra ◽

Michela Coan ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cell ◽

Platinum Resistance ◽

Dependent Manner ◽

Tumor Dissemination ◽

Platinum Based Chemotherapy ◽

Specific Protease ◽

Novel Strategy ◽

The Stability ◽

Cell Dissemination

Resistance to platinum-based chemotherapy is a common event in patients with cancer, generally associated with tumor dissemination and metastasis. Whether platinum treatment per se activates molecular pathways linked to tumor spreading is not known. Here, we report that the ubiquitin-specific protease 1 (USP1) mediates ovarian cancer cell resistance to platinum, by regulating the stability of Snail, which, in turn, promotes tumor dissemination. At the molecular level, we observed that upon platinum treatment, USP1 is phosphorylated by ATM and ATR and binds to Snail. Then, USP1 de-ubiquitinates and stabilizes Snail expression, conferring resistance to platinum, increased stem cell–like features, and metastatic ability. Consistently, knockout or pharmacological inhibition of USP1 increased platinum sensitivity and decreased metastatic dissemination in a Snail-dependent manner. Our findings identify Snail as a USP1 target and open the way to a novel strategy to overcome platinum resistance and more successfully treat patients with ovarian cancer.

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Combination of Niraparib, Cisplatin and Twist Knockdown in Cisplatin-Resistant Ovarian Cancer Cells Potentially Enhances Synthetic Lethality through ER-Stress Mediated Mitochondrial Apoptosis Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22083916 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3916

Author(s):

Entaz Bahar ◽

Ji-Ye Kim ◽

Dong-Chul Kim ◽

Hyun-Soo Kim ◽

Hyonok Yoon

Keyword(s):

Ovarian Cancer ◽

Cell Culture ◽

Cell Death ◽

Er Stress ◽

Cisplatin Resistance ◽

Cross Resistance ◽

Ovarian Cancer Cells ◽

Apoptosis Pathway ◽

Platinum Based Chemotherapy

Poly (ADP-ribose) polymerase 1 inhibitors (PARPi) are used to treat recurrent ovarian cancer (OC) patients due to greater survival benefits and minimal side effects, especially in those patients with complete or partial response to platinum-based chemotherapy. However, acquired resistance of platinum-based chemotherapy leads to the limited efficacy of PARPi monotherapy in most patients. Twist is recognized as a possible oncogene and contributes to acquired cisplatin resistance in OC cells. In this study, we show how Twist knockdown cisplatin-resistant (CisR) OC cells blocked DNA damage response (DDR) to sensitize these cells to a concurrent treatment of cisplatin as a platinum-based chemotherapy agent and niraparib as a PARPi on in vitro two-dimensional (2D) and three-dimensional (3D) cell culture. To investigate the lethality of PARPi and cisplatin on Twist knockdown CisR OC cells, two CisR cell lines (OV90 and SKOV3) were established using step-wise dose escalation method. In addition, in vitro 3D spheroidal cell model was generated using modified hanging drop and hydrogel scaffolds techniques on poly-2-hydroxylethly methacrylate (poly-HEMA) coated plates. Twist expression was strongly correlated with the expression of DDR proteins, PARP1 and XRCC1 and overexpression of both proteins was associated with cisplatin resistance in OC cells. Moreover, combination of cisplatin (Cis) and niraparib (Nira) produced lethality on Twist-knockdown CisR OC cells, according to combination index (CI). We found that Cis alone, Nira alone, or a combination of Cis+Nira therapy increased cell death by suppressing DDR proteins in 2D monolayer cell culture. Notably, the combination of Nira and Cis was considerably effective against 3D-cultures of Twist knockdown CisR OC cells in which Endoplasmic reticulum (ER) stress is upregulated, leading to initiation of mitochondrial-mediated cell death. In addition, immunohistochemically, Cis alone, Nira alone or Cis+Nira showed lower ki-67 (cell proliferative marker) expression and higher cleaved caspase-3 (apoptotic marker) immuno-reactivity. Hence, lethality of PARPi with the combination of Cis on Twist knockdown CisR OC cells may provide an effective way to expand the therapeutic potential to overcome platinum-based chemotherapy resistance and PARPi cross resistance in OC.

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Long-Term Follow-Up of a Female Patient Treated with Olaparib—Hope for a Long Life without Relapse?

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18073430 ◽

2021 ◽

Vol 18 (7) ◽

pp. 3430

Author(s):

Mateusz Kozłowski ◽

Katarzyna Nowak ◽

Aneta Cymbaluk-Płoska

Keyword(s):

Ovarian Cancer ◽

Parp Inhibitor ◽

Brca1 Gene ◽

High Specificity ◽

Reproductive Organs ◽

Platinum Based Chemotherapy ◽

Long Term Follow Up ◽

History Of ◽

Advanced Stages

Ovarian cancer is one of the most common cancers of the reproductive organs. As there are no symptoms in the early stages, it is mainly detected in the advanced stages. Even then, the symptoms are non-specific and include, for example, abdominal pain, early satiety, or changes in bowel habits. Both biochemical marker levels and imaging studies are used in the initial diagnosis. However, it should be emphasized that they are not characterized by high specificity. Treatment is multistage, and usually first-line debulking surgery is used followed by platinum-based chemotherapy. Here we present a clinical case of a 56-year-old female, a carrier of a mutation in the BRCA1 gene, with a history of breast cancer and with recurrent epithelial ovarian cancer. The patient was qualified for treatment with a PARP inhibitor and is currently undergoing treatment with olaparib. In the patient’s follow up of 50 months to date, there has been no recurrence of cancer. Few side effects have been observed, and the most serious one that can be effectively treated is anemia. On the basis of the described case, the authors concluded that olaparib treatment is effective, relatively safe, and does not significantly affect daily functioning.

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MiR-149-3p promotes the cisplatin resistance and EMT in ovarian cancer through downregulating TIMP2 and CDKN1A

Journal of Ovarian Research ◽

10.1186/s13048-021-00919-5 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Jin Wang ◽

Lingxia Liu

Keyword(s):

Ovarian Cancer ◽

Molecular Mechanisms ◽

Cisplatin Resistance ◽

Epithelial Mesenchymal Transition ◽

Gynecological Cancer ◽

Gene Expression Omnibus ◽

Luciferase Assay ◽

Migration And Invasion ◽

Mesenchymal Transition

Abstract Background Ovarian cancer (OC), a kind of gynecological cancer, is characterized by high mortality rate, with microRNAs (miRNAs) playing essential roles in it. However, the clinical significance of miRNAs and their molecular mechanisms in OC are mostly unknown. Methods miR-149-3p expression was predicted through Gene Expression Omnibus (GEO) data in OC and confirmed by q-PCR in various OC cells and tissues from patients with different clinical characteristics. Moreover, its roles in terms of proliferation, migration and invasion were measured by CCK-8, colony formation, wound healing and transwell assays in OC cells including cisplatin-resistant and cisplatin-sensitive cells. And its effect on epithelial-mesenchymal transition was also assessed through detecting related protein expression. Additionally, its potential targets were verified by dual luciferase assay and Ago-RIP assay. Finally, its oncogenic functions were explored in vivo. Results In data from GSE79943, GSE131790, and TCGA, miR-149-3p was found to be highly expressed in OC tissues and associated with poor survival. In metastasis and chemoresistant tissues and cisplatin-resistant OC cells, its high expression was confirmed. In terms of tumorigenic effects, miR-149-3p knockdown in cisplatin-resistant OC cells inhibited its cisplatin resistance and other malignant phenotypes, while miR-149-3p overexpression in cisplatin-resistant OC cells led to contrary results. Mechanistically, miR-149-3p targeted 3’UTR of CDKN1A and TIMP2 to function as an oncogenic miRNA. Conclusion In brief, miR-149-3p promoted cisplatin resistance and EMT in OC by downregulating CDKN1A and TIMP2, which might provide a potential therapeutic target for OC treatment.

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Development of a Genomic Signatures-Based Predictor of Initial Platinum-Resistance in Advanced High-Grade Serous Ovarian Cancer Patients

Frontiers in Oncology ◽

10.3389/fonc.2020.625866 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yuan Li ◽

Xiaolan Zhang ◽

Yan Gao ◽

Chunliang Shang ◽

Bo Yu ◽

...

Keyword(s):

Ovarian Cancer ◽

Predictive Accuracy ◽

Predictive Performance ◽

Platinum Resistance ◽

High Grade ◽

Serous Ovarian Cancer ◽

Single Nucleotide Variants ◽

Tissue Samples ◽

Platinum Sensitive ◽

Platinum Based Chemotherapy

BackgroundHigh grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. Although platinum-based chemotherapy has been the cornerstone for HGSOC treatment, nearly 25% of patients would have less than 6 months of interval since the last platinum chemotherapy, referred to as platinum-resistance. Currently, no precise tools to predict platinum resistance have been developed yet.MethodsNinety-nine HGSOC patients, who have finished cytoreductive surgery and platinum-based chemotherapy in Peking University Third Hospital from 2018 to 2019, were enrolled. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on the collected tumor tissue samples to establish a platinum-resistance predictor in a discovery cohort of 57 patients, and further validated in another 42 HGSOC patients.ResultsA high prevalence of alterations in DNA damage repair (DDR) pathway, including BRCA1/2, was identified both in the platinum-sensitive and resistant HGSOC patients. Compared with the resistant subgroup, there was a trend of higher prevalence of homologous recombination deficiency (HRD) in the platinum-sensitive subgroup (78.95% vs. 47.37%, p=0.0646). Based on the HRD score, microhomology insertions and deletions (MHID), copy number changes load, duplication load of 1–100 kb, single nucleotide variants load, and eight other mutational signatures, a combined predictor of platinum-resistance, named as DRDscore, was established. DRDscore outperformed in predicting the platinum-sensitivity than the previously reported biomarkers with a predictive accuracy of 0.860 at a threshold of 0.7584. The predictive performance of DRDscore was validated in an independent cohort of 42 HGSOC patients with a sensitivity of 90.9%.ConclusionsA multi-genomic signature-based analysis enabled the prediction of initial platinum resistance in advanced HGSOC patients, which may serve as a novel assessment of platinum resistance, provide therapeutic guidance, and merit further validation.

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New biomarkers to predict platinum resistance in ovarian cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17085 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17085-e17085

Author(s):

Oana Trifanescu ◽

Laurentia Minea Gales ◽

Maria Iuliana Gruia ◽

Bianca Andreea Gusoiu ◽

Florina Torliceanu ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Roc Curve ◽

Advanced Ovarian Cancer ◽

Progression Free Survival ◽

Initial Response ◽

Platinum Resistance ◽

Platinum Sensitive ◽

Platinum Salts ◽

Platinum Based Chemotherapy

e17085 Background: Epithelial ovarian cancer is the second most common gynecologic malignancy and is characterized by the highest mortality of all gynecological cancers. Despite of initial response, platinum resistance develops and contributes to the poor outcome of advanced stage ovarian cancer patients. The aim of the study was to identify biomarkers helpful in predicting treatment response to platinum salts. Methods: Forty eight patients with advanced ovarian (stage II, III and IV) cancer were prospectively enrolled between 2014 and 2017. All patients underwent surgery followed by platinum-based chemotherapy. Serum reactive oxygen species parameters such as malondialdehyde, ceruloplasmine, and serum VEGF were measured before each cycle of chemotherapy. Results: Mean age at diagnostic was 51.3 +/- 8.1 years, (range 42 - 78). Median follow up was 39 months (range 12-56). Twenty tree percent were platinum resistance. Median progression free survival was 22 months and estimated median overall survival was 84 months, 77% of patients being alive at 3 years. VEGF levels were significantly higher in patients with platinum resistance disease (1210 pg/ml) compare to platinum sensitive (mean VEGF levels 945pg/ml, p = 0.0003). We used a ROC curve to estimate the sensitivity and specificity of VEGF as a predictor to platinum response and find out that the aria under the curve (AUC) was 0.874, p = 0.003, 95% CI 0.734-1 and cut-off value (80% sensibility, 80% specificity) was 1085pg/ml. Malondialdehyde levels were statistically significant higher in patients with platinum resistance disease (mean value 11.1 μmol/100 ml vs. 7.4 μmol/100 ml in platinum sensitive, p = 0.02. The ROC curve for malondialdehyde identify an aria under the curve of 0.818, p = 0.0001 and CI 95% (0.744-0.893) and a cut-off value of 7.74 μmol/100 ml to estimate with 81.3% sensitivity and 64% specificity platinum response validating this bio markers as predicting platinum response. For Ceruloplasmine AUC was 0.706, p = 0.0001, 95% CI (0.617,-0.796). Conclusions: Malondialdehyde, ceruloplasmine and VEGF can estimate with precision the resistance to platinum salts in advanced ovarian cancer patients.

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Roads to the strategic targeting of ovarian cancer treatment

Reproduction ◽

10.1530/rep-19-0593 ◽

2021 ◽

Vol 161 (1) ◽

pp. R1-R11

Author(s):

Griselda Irusta

Keyword(s):

Ovarian Cancer ◽

Ovarian Tumor ◽

Tumor Biology ◽

Therapeutic Strategies ◽

High Rate ◽

Ovarian Cancer Cells ◽

Antiangiogenic Agents ◽

Molecular Events ◽

Platinum Based Chemotherapy ◽

Canonical Wnt

Although ovarian cancer mortality rates have slightly declined in the last 40 years, ovarian cancer continues to be the eighth cause of cancer death in women. Ovarian cancer is characterized by its high response to treatments but also by its high rate of recurrence. Although treatments are limited to cytoreductive surgery and platinum-based chemotherapy, other therapies using antiangiogenic agents and poly (ADP-ribose) polymerase inhibitors are being tested. Nevertheless, these therapeutic strategies have had poor results and new potential targets and approaches are thus needed. The present review focuses on the recent evidence on antiangiogenic strategies in ovarian cancer cells and on the mechanisms governed by Notch and β-catenin proteins. It also describes the concept of ‘vascular normalization’ by using the platelet-derived growth factor, PDGFB, molecule as a tool to regulate ovarian tumor angiogenesis and thus improve ovarian tumor treatment. It has been reported that alterations in the Notch system components and changes in the canonical Wnt/β-catenin signaling, the other pathway of our interest, are relevant to molecular events that contribute to ovarian cancer development. Thus, in this review, we consider these aspects of the ovarian tumor biology as potential new therapeutic strategies for the treatment of this disease.

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Significance of Platinum Distribution to Predicts Platinum Resistance in Ovarian Cancer After Platinum Treatment in Neoadjuvant Chemotherapy

10.21203/rs.3.rs-882249/v1 ◽

2021 ◽

Author(s):

Kaname Uno ◽

Nobuhisa Yoshikawa ◽

Akira Tazaki ◽

Shoko Ohnuma ◽

Kazuhisa Kitami ◽

...

Keyword(s):

Ovarian Cancer ◽

Adjuvant Chemotherapy ◽

Neoadjuvant Chemotherapy ◽

Inductively Coupled Plasma ◽

Advanced Ovarian Cancer ◽

Type A ◽

Platinum Resistance ◽

Tumor Type ◽

Platinum Based Chemotherapy ◽

Platinum Accumulation

Abstract Most advanced ovarian cancer patients experience recurrence and develop resistance to platinum-based agents. However, the diagnosis of platinum resistance based on platinum-free interval is not always accurate and timely. In this study, we employed laser ablation inductively coupled plasma mass spectrometry to visualize platinum distribution in the tissues at the time of interval debulking surgery following neoadjuvant chemotherapy. Twenty seven patients with advanced high grade serous ovarian cancer were enrolled. Two distinct patterns of platinum distribution were observed. Type A (n = 16): platinum accumulation at the adjacent stroma but little in the tumor; type B (n = 11): even distribution of platinum through tumor and adjacent stroma. Type A was significantly correlated with worse prognosis (P = 0.031). Patients classified in type A and treated with platinum-based adjuvant chemotherapy after operation were significantly shorter period of recurrence after last platinum-based chemotherapy (P = 0.020) and diagnosed with “platinum-resistant recurrence”. Treatment with non-platinum-based chemotherapy after operation could be effective for the patients who were classified in type A. Our data indicate that the platinum resistance can be predicted prior to recurrence with platinum distribution. Thus, we will be able to select more appropriate adjuvant chemotherapy, which may possibly lead to improve patient’s prognosis.

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