Gemcitabine reverses platinum resistance in platinum-resistant ovarian and peritoneal carcinoma

2005 ◽  
Vol 15 (Suppl 1) ◽  
pp. 18-22 ◽  
Author(s):  
P. G. Rose
Keyword(s):  
Ovarian Cancer ◽  
Excision Repair ◽  
Ovarian Cancer Cell Line ◽  
Single Agent ◽  
Cancer Cell Line ◽  
Platinum Resistance ◽  
Synergistic Activity ◽  
Primary Therapy ◽  
Platinum Sensitive ◽  
Platinum Resistant

Platinum compounds are the key components of chemotherapy for ovarian cancer. Preclinical models in an ovarian cancer cell line (A2780) have demonstrated synergistic activity when gemcitabine is added to cisplatin compared with either single agent alone. Furthermore, the combination leads to increased platinum-adduct retention as a result of decreased DNA repair compared with cisplatin alone. Inhibition of specific exonucleases, such as excision repair cross-complementation group 1 (ERCC1), is integral to the platinum–gemcitabine synergy. In platinum-sensitive recurrent ovarian cancer patients (defined as those patients whose cancer recurs after >6 months following primary therapy), platinum and gemcitabine have demonstrated an improvement in progression-free survival compared with platinum alone. This is also true for the patients who are only moderately platinum sensitive (defined as those patients who have cancer recurring 6–12 months after primary therapy). Increasing numbers of phase II experiences have demonstrated the activity of the platinum–gemcitabine combination in patients defined as platinum resistant (those with disease progression on therapy or whose disease recurs within 6 months of a platinum-based regimen).

Extracellular vesicle-associated miRNAs in ovarian cancer – design of an integrated NGS-based workflow for the identification of blood-based biomarkers for platinum-resistance

2019 ◽  
Vol 57 (7) ◽  
pp. 1053-1062 ◽  
Author(s):  
Jan Dominik Kuhlmann ◽  
Issam Chebouti ◽  
Rainer Kimmig ◽  
Paul Buderath ◽  
Michael Reuter ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Independent Set ◽  
Extracellular Vesicle ◽  
Platinum Resistance ◽  
Diagnostic Purpose ◽  
Illumina Platform ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Next Generation Sequencing Ngs

AbstractBackgroundExtracellular vesicle (EV)-associated microRNAs (miRNAs) have been suggested as promising biomarkers for blood-based cancer diagnosis. However, one of the major limitations for the use of EVs with diagnostic purpose is the lack of standardized EV-profiling techniques. In this regard, the objective of our study was to design an integrated next-generation sequencing (NGS)-based workflow for analyzing the signature of EV-associated miRNA in the plasma of platinum-resistant ovarian cancer patients.MethodsFor EV-extraction, different enrichment methods were compared (ExoQuick vs. exoRNeasy). NGS was performed with the Illumina platform.ResultsWe established an integrated NGS-based workflow, including EV-enrichment with the ExoQuick system, which resulted in an optimal RNA-yield and consistent small RNA libraries. We applied this workflow in a pilot cohort of clinically documented platinum-sensitive (n=15) vs. platinum-resistant (n=15) ovarian cancer patients, resulting in a panel of mature EV-associated miRNAs (including ovarian cancer associated miR-181a, miR-1908, miR-21, miR-486 and miR-223), which were differentially abundant in the plasma of platinum-resistant patients.ConclusionsThis is the first study, analyzing the profile of EV-associated miRNAs in platinum-resistant ovarian cancer patients. We provide rationale to further validate these miRNA candidates in an independent set of patients, in order to characterize their biomarker potential as predictors for platinum-resistance.

scholarly journals Bevacizumab in the Management of Epithelial Ovarian Cancer

2013 ◽  
Vol 09 (02) ◽  
pp. 129
Author(s):  
Maurie Markman ◽  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cancer Progression ◽  
Single Agent ◽  
Strong Support ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Phase Iii ◽  
Platinum Sensitive ◽  
Platinum Resistant

Preclinical investigations have provided strong support for the hypothesis that angiogenesis is a potent driver of epithelial ovarian cancer progression. Phase II data have revealed the activity of single-agent bevacizumab in previously treated and clinically defined platinum-resistant ovarian cancer. Several reported phase III randomized trials, involving primary and both ‘platinum-sensitive’ recurrent and platinum-resistant disease, have demonstrated the addition of bevacizumab to a cytotoxic chemotherapy regimen improves progression-free survival compared with chemotherapy alone. While there continues to be considerable debate regarding the optimal dose, timing, and duration of bevacizumab administration in ovarian cancer, the existing data provide strong support for an important role for this agent in the overall management paradigm for this malignancy.

scholarly journals [18F]Fluciclatide PET as a biomarker of response to combination therapy of pazopanib and paclitaxel in platinum-resistant/refractory ovarian cancer

2019 ◽  
Vol 47 (5) ◽  
pp. 1239-1251 ◽  
Author(s):  
Rohini Sharma ◽  
Pablo Oriol Valls ◽  
Marianna Inglese ◽  
Suraiya Dubash ◽  
Michelle Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Combination Therapy ◽  
Single Agent ◽  
Progression Free Survival ◽  
Platinum Resistance ◽  
Open Label ◽  
Intention To Treat ◽  
Resistant Refractory ◽  
Platinum Resistant ◽  
Pet Tracer

Abstract Background Angiogenesis is a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum-resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both upregulated in tumor-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. Patients and methods We conducted an open-label, phase Ib study in patients with platinum-resistant/refractory ovarian cancer. Patients received 1 week of single-agent pazopanib (800 mg daily) followed by combination therapy with weekly paclitaxel (80 mg/m2). Following completion of 18 weeks of combination therapy, patients continued with single-agent pazopanib until disease progression. Dynamic [18F]fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities, and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. Results Fourteen patients were included in the intention-to-treat analysis. Complete and partial responses were seen in seven patients (54%). Median progression-free survival (PFS) was 10.63 months, and overall survival (OS) was 18.5 months. Baseline [18F]fluciclatide uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and fibroblast growth factor (FGF) were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modeling of PET data indicated a reduction in K1 and Ki following pazopanib indicating reduced radioligand delivery and retention. Conclusions Combination therapy followed by maintenance pazopanib is effective and tolerable in platinum-resistant/refractory ovarian cancer. [18F]Fluciclatide-PET uptake parameters predict clinical outcome with pazopanib therapy indicating an anti-angiogenic response.

The activity of the conjugated antimetabolite 5-FdU-ECyd against platinum-resistant ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17077-e17077
Author(s):  
Pauline Wimberger ◽  
Barbara Klink ◽  
Konrad Gruetzmann ◽  
Julian Puppe ◽  
Daniel Klotz ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Parp Cleavage ◽  
Strong Increase ◽  
Platinum Resistance ◽  
Secondary Resistance ◽  
Therapeutic Concept ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Platinum Based Chemotherapy

e17077 Background: Primary or secondary resistance to platinum-based chemotherapy is an important clinical challenge in the treatment of ovarian cancer (OC) and limits survival. Therefore, the development of innovative drugs against platinum resistance is urgently needed. Our therapeutic concept is based on the conjugation of two chemotherapeutic compounds to a monotherapeutic pro-drug, which is taken up by cancer cells and is subsequently cleaved into several active cytostatic metabolites. Our in vitro study evaluates the effects of the conjugated antimetabolite 5-FdU-ECyd, consisting of 2-deoxy-5-fluorouridine (5-FdU) and ethynylcytidine (ECyd), on platinum-resistant OC cells. Methods: In vitro assays and RNA-Seq (Illumina) were applied for characterization of 5-FdU-ECyd treated platinum-sensitive A2780 and isogenic platinum-resistant A2780cis as well as independent platinum-resistant Skov-3-IP OC cells. Results: Nano molar 5-FdU-ECyd concentrations induced a rapid dose-dependent decline of cell viability in platinum-sensitive and platinum-resistant OC cells. The cytotoxicity of 5-FdU-ECyd was accompanied by the formation of DNA double strand breaks and by the induction of apoptosis, indicated by a strong increase of pro-apoptotic molecular markers (caspase-3/7 activation, PARP-cleavage). Moreover, 5-FdU-ECyd efficiently decreased cell migration of platinum-resistant OC cells and inhibited other tumor-associated cellular functions, such as clonogenic or spheroidal growth. Transcriptome analysis indicated that, independently of platinum-resistance status, 5-FdU-ECyd influences distinct cellular pathways, involved in cell cycle regulation, apoptosis, DNA-damage response and RNA/pyrimidine metabolism. Combination treatment of 5-FdU-ECyd and platin did not show a synergistic cellular response, suggesting the potential use of 5-FdU-ECyd as a monotherapeutic agent. Conclusions: Our data provide a rationale to characterize the effect of 5-FdU-ECyd in a pre-clinical in vivo setting. We hypothesize that this conjugate is a promising therapeutic option for OC patients with resistance to conventional platinum-based chemotherapy.

Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): Activity and safety analyses in phase I pooled expansion cohorts.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5547-5547 ◽  
Author(s):  
Kathleen N. Moore ◽  
Ursula A. Matulonis ◽  
David M. O'Malley ◽  
Jason A. Konner ◽  
Lainie P. Martin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Folate Receptor ◽  
Single Agent ◽  
Phase Iii ◽  
Platinum Resistance ◽  
Low Grade ◽  
Antibody Drug Conjugate ◽  
Pivotal Phase ◽  
Platinum Resistant

5547 Background: The early clinical evaluation of mirvetuximab soravtansine (IMGN853), an ADC that comprises a FRα-binding antibody linked to the tubulin-disrupting maytansinoid DM4, has revealed encouraging signs of activity in pts with ovarian cancer. A pooled analysis of safety and efficacy was performed including individuals with platinum-resistant EOC, enrolled across three expansion cohorts of an ongoing phase I trial (NCT01609556), who met the eligibility criteria for the pivotal phase III study of IMGN853 (FORWARD I; NCT02631876). Methods: Pts were administered IMGN853 intravenously once every 3 weeks at 6 mg/kg using adjusted ideal body weight dosing. Responses were assessed according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.0. Results: A total of 37 EOC pts treated as part of the three phase I expansion cohorts (pooled population; n = 113) met the FORWARD I enrollment criteria of moderate to high tumor FRα levels (≥ 50% of cells with ≥ 2+ FRα expression) and 1-3 prior lines of therapy. In this group of pts with platinum-resistant disease, confirmed objective tumor responses were observed in 17 individuals (1 complete response [CR] and 16 partial responses [PR]) for an overall response rate (ORR) of 46% (95% CI, 29.5, 63.1) and a median PFS of 6.7 months (95% CI, 4.1, 9.0). The safety profile of the pooled population was consistent with that previously reported (ASCO Annual Meeting, 2016) with the most common AEs being diarrhea, fatigue, nausea, and blurred vision; these were low grade and readily managed. Conclusions: IMGN853 continues to be characterized by favorable tolerability and encouraging activity in pts with platinum-resistant EOC. In particular, both the ORR (46%) and PFS (6.7 months) achieved in this group of pts are superior to outcomes typically seen with established single-agent chemotherapy within the setting of primary platinum resistance. Overall, these analyses provide continued, robust support for the patient eligibility strategy employed in the phase III evaluation of IMGN853. Clinical trial information: NCT01609556.

[18F] Fluciclatide PET as a biomarker of clinical response to combination therapy of pazopanib and paclitaxel in patients with platinum-resistant or platinum-refractory advanced ovarian cancer: Results of a phase Ib study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3070-3070
Author(s):  
Rohini Sharma ◽  
Pablo Oriol Valls ◽  
Marianna Inglese ◽  
Suraiya Rahim Dubash ◽  
Michelle Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Combination Therapy ◽  
Kinetic Modelling ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Platinum Resistance ◽  
Phase Ib ◽  
Resistant Refractory ◽  
Platinum Resistant ◽  
Pet Tracer

3070 Background: Angiogenesis has been shown to be a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both up-regulated in tumour-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. Methods: We conducted an open-label, phase Ib study in patients with platinum resistant/refractory ovarian cancer. Patients received 1 week of single agent pazopanib (800mg daily) followed by combination therapy with weekly paclitaxel 80mg/m2. Following completion of 18 weeks of therapy, patients continued with single agent pazopanib until disease progression. Dynamic [18F]Fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. Results: Fourteen patients were included in the intention-to-treat analysis. Complete and partial response was seen in 7 patients (54%). Median progression free survival (PFS) was 7.97 months, and overall survival (OS) was 18.5 months. A reduction in [18F]fluciclatide uptake was observed following 1 week of pazopanib, and the reduction in uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and FGF were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modelling indicated a reduction in K1 and Ki following pazopanib indicating reduced radiotracer delivery and retention. Conclusions: Combination therapy followed by maintenance pazopanib is effective and tolerable in patients with platinum resistant/refractory ovarian cancer. We have shown that [18F]fluciclatide-PET uptake parameters alter with pazopanib therapy indicating an anti-angiogenic response. Clinical trial information: NCT01608009.

scholarly journals Immune-Checkpoint Inhibitors in Platinum-Resistant Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1663
Author(s):  
Alice Indini ◽  
Olga Nigro ◽  
Csongor György Lengyel ◽  
Michele Ghidini ◽  
Angelica Petrillo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Single Agent ◽  
Clinical Trial Data ◽  
Parp Inhibitors ◽  
Platinum Resistance ◽  
Combination Strategies ◽  
Platinum Resistant

Platinum-resistant ovarian cancer (OC) has limited treatment options and is associated with a poor prognosis. There appears to be an overlap between molecular mechanisms responsible for platinum resistance and immunogenicity in OC. Immunotherapy with single agent checkpoint inhibitors has been evaluated in a few clinical trials with disappointing results. This has prompted exploration of immunotherapy combination strategies with chemotherapy, anti-angiogenics, poly (ADP-ribose) polymerase (PARP) inhibitors and other targeted agents. The role of immunotherapy in the treatment of platinum-resistant OC remains undefined. The aim of this review is to describe the immunobiology of OC and likely benefit from immunotherapy, discuss clinical trial data and biomarkers that warrant further exploration, as well as provide an overview of future drug development strategies.

Bevacizumab-based therapy in patients with heavily pretreated ovarian and other Mullerian tract cancers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16533-e16533
Author(s):  
Jutta Anna Kurbacher ◽  
Jutta Lepique ◽  
Susanne Herz ◽  
Gabriele Wessling ◽  
Christian M. Kurbacher
Keyword(s):  
Single Agent ◽  
Controlled Clinical Trial ◽  
Platinum Resistance ◽  
Adequate Treatment ◽  
Loss To Follow Up ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Significant Difference ◽  
Heavily Pretreated ◽  
Group B

e16533 Background: Bevacizumab (Bev) is approved for the therapy (Tx) of primary and platinum-sensitive recurrent Mullerian tract cancers (MTC) such as ovarian (OC), fallopian tube (FTC), type II endometrial (EC-II), and peritoneal papillary-serous carcinomas (PPSC). However, the role of Bev in the ≥ 3rd line Tx of MTCs is still unclear.This retrospective study summarizes our long-term experiences with Bev in patients (pts) with heavily pretreated MTC who did not qualify for recruitment into a controlled clinical trial. Methods: A total of 74 intensively pretreated MTC pts (OC, n = 65; FTC, n = 2; EC-II, n = 4; PPSC, n = 3) were included in this study with 43 (58.1%) being platinum-resistant. Pts had failed a median of 4 (range 1-10) prior chemotherapies (CTx ). Tx included Bev monotherapy (group A, n = 17), Bev + metronomic CTx (group B, n = 37), and Bev + conventionally dosed CTx (Group C, n=20). Bev was administered at either 10 mg/kg BW q2w or 15 mg/kg BW q3w. Adverse effects were classified according to CTCAE Vs 4.03. TTP was calculated from the start of Bev until progression, OS was calculated from the start of Bev until death or loss to follow up. Results: Most common Tx related toxicities were hypertension, proteinuria, headache, inflammation/infection, epistaxis, and subileus. Hypertension which often required adequate treatment was limiting in only one case as also were renal toxicity and infection. Median TTP was 27.8 wks and median OS was 53.6 wks with no significant difference between platinum-resistant and –sensitive pts. In regard to both TTP and OS, there was a non-significant trend favoring groups A (33.4/63.0 wks) and B (29.9/61.6 wks) vs group C (19.2/35.4 wks). Conclusions: Bev based Tx was active and generally well tolerated in this hard-to-treat population of pts with recurrent MTC. Both TTP and OS were equal or even superior to any conventional CTx used in this setting. Moreover, clinical platinum-resistance did not predict a worse clinical outcome. Although this is not a randomized trial, our results argue in favor that Bev should be preferably given either as single agent or combined with metronomic CTx in pts with heavily pretreated MTCs. Further clinical trials of Bev in recurrent MTCs may prove useful.

Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel.

1998 ◽  
Vol 16 (10) ◽  
pp. 3345-3352 ◽  
Author(s):  
M A Bookman ◽  
H Malmström ◽  
G Bolis ◽  
A Gordon ◽  
A Lissoni ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Phase Ii ◽  
Group Performance ◽  
Phase Ii Study ◽  
Single Agent ◽  
Epithelial Ovarian Carcinoma ◽  
Response Analysis ◽  
Primary Therapy ◽  
Platinum Resistant

PURPOSE Topotecan, a topoisomerase I inhibitor, was evaluated in a multicenter, phase II study of women with epithelial ovarian carcinoma who relapsed after one or two prior regimens that included platinum and paclitaxel. PATIENTS AND METHODS Topotecan 1.5 mg/m2 daily was administered as a 30-minute infusion for 5 consecutive days on a 21-day cycle. Eligibility criteria included bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of 2 or less, and adequate bone marrow, liver, and renal function. Efficacy was assessed by independent radiologic review. RESULTS One hundred thirty-nine patients were treated; 81% were platinum resistant. Sixty-two patients had received one prior regimen and 77 patients had received two prior regimens. Nine patients were not assessable for response; however, all patients were included in the response analysis. The overall response rate was 13.7%; 12.4% in platinum-resistant and 19.2% in platinum-sensitive patients. Stable disease lasted at least 8 weeks in 27.3% of the patients. The median duration of response and time to progression were 18.1 and 12.1 weeks, respectively. The median survival was 47.0 weeks. Grade 4 neutropenia occurred in 82% of the patients (34% of the courses) and thrombocytopenia in 30% of the patients (9% of the courses). Infectious complications occurred in 6% of the courses. Nonhematologic toxicities were mild. There were no drug-related toxic deaths. CONCLUSION As a single agent, topotecan has modest activity in women with advanced epithelial ovarian carcinoma who have progressed or not responded after one or two prior regimens with platinum and paclitaxel. Further investigation of combination regimens is indicated in the primary therapy for ovarian cancer based on the mechanism of action and tolerability.

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