scholarly journals A highly annotated database of genes associated with platinum resistance in cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Dongqing Huang ◽  
Sara R. Savage ◽  
Anna P. Calinawan ◽  
Chenwei Lin ◽  
Bing Zhang ◽  
...  
Keyword(s):  
Cancer Research ◽  
Research Community ◽  
Platinum Resistance ◽  
Biological Processes ◽  
Mechanisms Of Resistance ◽  
Comprehensive Overview ◽  
Survival Pathways ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Drug Entry

AbstractPlatinum-based chemotherapy, including cisplatin, carboplatin, and oxaliplatin, is prescribed to 10-20% of all cancer patients. Unfortunately, platinum resistance develops in a significant number of patients and is a determinant of clinical outcome. Extensive research has been conducted to understand and overcome platinum resistance, and mechanisms of resistance can be categorized into several broad biological processes, including (1) regulation of drug entry, exit, accumulation, sequestration, and detoxification, (2) enhanced repair and tolerance of platinum-induced DNA damage, (3) alterations in cell survival pathways, (4) alterations in pleiotropic processes and pathways, and (5) changes in the tumor microenvironment. As a resource to the cancer research community, we provide a comprehensive overview accompanied by a manually curated database of the >900 genes/proteins that have been associated with platinum resistance over the last 30 years of literature. The database is annotated with possible pathways through which the curated genes are related to platinum resistance, types of evidence, and hyperlinks to literature sources. The searchable, downloadable database is available online at http://ptrc-ddr.cptac-data-view.org.

The successful phase 3 niraparib ENGOT-OV16/NOVA trial included a substantial number of patients with platinum resistant ovarian cancer (OC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5560-5560 ◽  
Author(s):  
Jose Maria Del Campo ◽  
Mansoor Raza Mirza ◽  
Jonathan S. Berek ◽  
Diane M. Provencher ◽  
Guenter Emons ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Complete Response ◽  
Resistance Rate ◽  
Parp Inhibition ◽  
Platinum Resistance ◽  
Phase 3 ◽  
Double Blind ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Duration Of Response

5560 Background: Niraparib is a highly selective poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor (PARPi); in preclinical studies, it concentrates in the tumor relative to plasma to deliver durable, near complete PARP inhibition and persistent antitumor effects.Niraparib demonstrated significantly longer progression free survival (PFS) vs placebo in patients (pts) with recurrent OC who were randomized following a complete response (CR) or partial response (PR) to platinum based chemotherapy in the controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. To more fully characterize the NOVA trial population, we assessed platinum resistance status, defined as a duration of response to platinum < 6 months to the most recent (ultimate) platinum regimen. Analysis was limited to pts in the placebo arm, as inclusion of pts receiving active treatment (niraparib) would have confounded the ability to determine duration of response to platinum alone. Methods: Pts with recurrent OC, no prior PARPi use, ≥2 prior courses of platinum based chemotherapy, and CR or PR to the most recent platinum based chemotherapy were eligible. Pts were assigned to one of two cohorts based on g BRCA testing (g BRCAmut or non-g BRCAmut) and randomized 2:1 within each cohort to niraparib 300 mg or placebo qd until progressive disease (PD). Randomization occurred up to 8 weeks following the last dose of the most recent platinum based chemotherapy. PFS was measured from time of randomization to death or earliest PD as assessed by independent review committee. Estimated probability of pts having disease progression in each cohort and pooled across cohorts 6 months after the last dose of their most recent platinum therapy was calculated using the Kaplan-Meier methodology. Results: 181 pts were randomized to placebo (65 g BRCAmut and 116 non-g BRCAmut). Platinum resistance rate estimates for the g BRCAmut, non-g BRCAmut, and pooled cohorts were 42%, 53%, and 49%, respectively. Conclusions: Approximately half of the pts in the NOVA study, where niraparib treatment met its primary endpoint of prolonging PFS following a response to platinum, had developed platinum resistance to their last line of chemotherapy. Clinical trial information: NCT01847274.

Safety of Vinflunine in Patients with Advanced Urothelial Carcinoma Refractory to Platinum-based Chemotherapy: A Prospective Pilot Study

2019 ◽  
Vol 14 (1) ◽  
pp. 31-36
Author(s):  
Raafat Abdel-Malek ◽  
Kyrillus S. Shohdy ◽  
Noha Abbas ◽  
Mohamed Ismail ◽  
Emad Hamada ◽  
...  
Keyword(s):  
Pilot Study ◽  
Adverse Events ◽  
Urothelial Carcinoma ◽  
Transitional Cell ◽  
Chemotherapeutic Agents ◽  
Serious Adverse Events ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Advanced Urothelial Carcinoma ◽  
Grade 3

Background: Several single chemotherapeutic agents have been evaluated as the second-line treatment of advanced urothelial carcinoma. Despite encouraging efficacy outcomes, toxicity has often led to dose modifications or discontinuation. We aimed to assess the safety of vinflunine in a particular population of advanced transitional cell carcinoma of urothelium (TCCU), that were exposed to the previous toxicity of chemotherapy. Methods: This is an open-label, prospective, single-center pilot study to evaluate the response rate and safety profile of vinflunine in patients with advanced TCCU. It was planned to enroll 25 evaluable patients. Eligible patients are those with progressive disease after first-line platinum-based regimen for advanced or metastatic disease. Results: The study was prematurely closed due to two sudden deaths that were judged by the review board as treatment-related. Only ten patients were evaluated and received at least one cycle of vinflunine. All but one were male and seven underwent radical surgery. Eight had a distant metastasis (mainly lung and/or liver). Disease control rate was 40%, four patients had a partial response with median duration of response of 3.5 months. The median overall survival was 3.2 months (95% CI:1.67- 4.73). There were three serious adverse events namely two sudden deaths and one grade 4 thrombocytopenia. Nine grade 3/4 adverse events occurred. The most common all-grade adverse events were fatigue (50%), constipation (40%) and vomiting (40%). Moreover, grade 3 fatigue occurred in 30% of patients. Only one patient, who achieved PR for 5 months, was fit to receive further cytotoxic chemotherapy. Conclusion: The activity of vinflunine in advanced urothelial carcinoma came at the expense of its safety. The use of vinflunine has to be limited to the selected group of patients. However, this is a single institute experience in a limited number of patients.

scholarly journals 363 Vactosertib and durvalumab as second or later line treatment for PD-L1 positive non-small cell lung cancer: interim result

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A388-A388
Author(s):  
Byoung Chul Cho ◽  
Ki Hyeong Lee ◽  
Ji-Youn Han ◽  
Byoung Yong Shim ◽  
Hye Ryun Kim ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Objective Response Rate ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Anti Tumor Activity

BackgroundTargeting transforming growth factor-β (TGF-β) is reported to augment the efficacy of immune checkpoint inhibitors (ICIs) through either enhanced anti-tumor immunity or the correction of tumor microenvironment (TME). Therefore, the combination of vactosertib, a highly selective TGF-β RI kinase inhibitor, and durvalumab is anticipated to improve anti-tumor activity of the ICI. A phase 1b/2a study was conducted to evaluate the combination of vactosertib and durvalumab in patients with advanced NSCLC who progressed after platinum-based chemotherapy.MethodsPatients were treated with vactosertib at a dose of 200 mg twice daily (five days on and two days off) and durvalumab at a dose of 1500 mg every four weeks. Eligible patients were ≥19 years old with good performance status (ECOG 0–1) and have no prior exposure to immune checkpoint inhibitors or other TGF- β R1 kinase inhibitors. The objectives of this analysis were to evaluate the safety, antitumor activity including objective response rate (ORR), duration of response (DOR), and time to response (TTR) as well as circulating pharmacodynamic biomarkers related to TGF-β signaling. Response was assessed per RECIST (v1.1).ResultsBy August 4 2020, twenty-six PD-L1 positive (SP263 assay) patients were analyzed. Median age was 61.5 years (range 48–83), 69.2% were male, median number of previous lines of chemotherapy was 1 (range 1–4), and all patients were PD-L1 positive (15 patients with PD-L1≥25% and 11 patients with PD-L1 1–24%). The most frequently reported treatment-related adverse events (TRAE) were itching (38.5%) and skin rash (34.6%), but no Gr≥3 itching and rash were observed. Each case of the following was reported as Grade 3 TRAEs: adrenal insufficiency, anemia, and pneumonitis; Grade 4 TRAE, CPK increase, was observed in one patient. Objective response rate was 30.8% and 40.0% in patients with PD-L1≥1% and ≥25% respectively. Circulating PAI-1 and CTGF evaluated in 15 patients decreased significantly on Cycle 1 day 5. Ongoing biomarker results will be presented.ConclusionsThe combination of vactosertib and durvalumab has demonstrated a manageable safety profile and encouraging anti-tumor activity as a potential therapeutic strategy in patients with advanced NSCLC. The efficacy outcomes of this combination in a larger number of patients with advanced NSCLC will be followed.Trial RegistrationNCT03732274Ethics ApprovalThe study was approved by Ethics Board of Severance Hospital (4-2018-0892), National Cancer Center (NCC2019-0057), St. Vincent’s Hospital (VC19MDDF0205), and Chungbuk National University Hospital (2019-08-015).

Neutrophil-lymphocyte radio (NLR) as a possible predictive factor in patients with advanced NSCLC WHO received immunotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21042-e21042
Author(s):  
Eduardo Richardet ◽  
Luciana Paola Acosta ◽  
Maria gimena Ferreira ◽  
Ignacio Magi ◽  
Rocio tello Alfonso ◽  
...  
Keyword(s):  
General Population ◽  
Predictive Factor ◽  
Statistical Power ◽  
Advanced Nsclc ◽  
Combined Treatment ◽  
Objective Response ◽  
Strong Relationship ◽  
Neutrophil Lymphocyte Ratio ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients

e21042 Background: There exists a strong relationship between cancer and inflammation. For this reason, attempts have been made to identify different biomarkers of inflammation in recent years. The neutrophil - lymphocyte ratio (NLR) a marker of systemic inflammation, and the infiltranting lymphocytes of the tumor stroma (TILs) have been studied by our research team in different tumors, such as melanoma, breast cancer, colon cancer and NSCLC in patient who had recieved tratment with chemotherapy. We could observe that there was a significant relationship beteween DFS and a high NLR on the one hand, and DSF an intense TILs on the other. Our main objective is to evaluate the relationship between the objective response rate (ORR) and the pretreatment NLR in patients with advanced NSCLC who recieved immunotherapy. Our secondary objective is to analyzed the associated between PFS and RNL in patients with advanced NSCLC undergoing immunotherapy. Methods: Patients with diagnosis of advanced-stage NSCLC who recieved only immunotherapy, immunotherapy with another immunomodulator or in combination with platinum-based chemotherapy werw included. All patients had a follow-up of at least 6 months. The cutoff value > or < 3 for the NLR was use to reference. The laboratory control prior to the beginning of treatment was taken, and the ORR was determined using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Statistical analysis was performed using dispersion and position measurements, T-Test and Chi Square test. For PFS analysis Kaplan-Meyer was used. The level of significance for the variables was p < 0.05. Results: 41 patients with advanced NSCLC were analyzed. 43.9% (18 pts) recieved immunotherapy alone with nivolumab. 34.14% (14 pts) received a combined treatment (nivo / ipi) and 21.95% (9 pts.), immuno / QT combination (based on platinum). Regarding the histological presentation, 80.48% were adenocarcinoma. 54% (22 pts) had an NLR > 3 and 46% (19 pts) an NLR < 3. The ORR in the general population was 24%. in pts with an NLR < 3, the ORR that was observed was 42% vs. ORR of 9% in pts with NLR > 3 (p: 0.02). These differences were statistically significant. The median PFS was 11.27 months in the general population. As regards RNL, the median PFS were 20.74 vs 5.52 months in favor of pts with an NLR < 3 (p: 0.04). Conclusions: We could conclude that patients with NSCLC and pretreatment NLR < 3, who undergo immunotherapy, had better ORR compared to those with NLR > 3. These differences was statistically significant. Also, we could observe better PFS in patient with NLR < 3. These difference was estatically significant. We will keep working to obtain a greater number of patients. Then we could have a better analysis and statistical power. It is possible that NLR will be a highly useful and easy-to-acces predictive factor, and it could be used in patients with immunotherapy in our daily practice.

scholarly journals Combining radiomics and mathematical modeling to elucidate mechanisms of resistance to immune checkpoint blockade in non-small cell lung cancer

2017 ◽  
Author(s):  
Daryoush Saeed-Vafa ◽  
Rafael Bravo ◽  
Jamie A. Dean ◽  
Asmaa El-Kenawi ◽  
Nathaniel Mon Père ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Checkpoint Inhibitor ◽  
Cancer Recurrence ◽  
Initial Response ◽  
Resistance Mechanisms ◽  
Ct Images ◽  
Immune Checkpoint Blockade ◽  
Imaging Features ◽  
Mechanisms Of Resistance ◽  
Number Of Patients

AbstractImmune therapies have shown promise in a number of cancers, and clinical trials using the anti-PD-L1/PD-1 checkpoint inhibitor in lung cancer have been successful for a number of patients. However, some patients either do not respond to the treatment or have cancer recurrence after an initial response. It is not clear which patients might fall into these categories or what mechanisms are responsible for treatment failure. To explore the different underlying biological mechanisms of resistance, we created a spatially explicit mathematical model with a modular framework. This construction enables different potential mechanisms to be turned on and off in order to adjust specific tumor and tissue interactions to match a specific patient's disease. In parallel, we developed a software suite to identify significant computed tomography (CT) imaging features correlated with outcome using data from an anti-PDL-1 checkpoint inhibitor clinical trial for lung cancer and a tool that extracts these features from both patient CT images and “virtual CT” images created from the cellular density profile of the model. The combination of our two toolkits provides a framework that feeds patient data through an iterative pipeline to identify predictive imaging features associated with outcome, whilst at the same time proposing hypotheses about the underlying resistance mechanisms.

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

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.

scholarly journals Cisplatin-mediated activation of glucocorticoid receptor induces platinum resistance via MAST1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chaoyun Pan ◽  
JiHoon Kang ◽  
Jung Seok Hwang ◽  
Jie Li ◽  
Austin C. Boese ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Glucocorticoid Receptor ◽  
Tumor Growth ◽  
Nuclear Translocation ◽  
Mapk Pathway ◽  
Underlying Mechanism ◽  
Patient Treatment ◽  
Platinum Resistance ◽  
Platinum Based Chemotherapy

AbstractAgonists of glucocorticoid receptor (GR) are frequently given to cancer patients with platinum-containing chemotherapy to reduce inflammation, but how GR influences tumor growth in response to platinum-based chemotherapy such as cisplatin through inflammation-independent signaling remains largely unclear. Combined genomics and transcription factor profiling reveal that MAST1, a critical platinum resistance factor that reprograms the MAPK pathway, is upregulated upon cisplatin exposure through activated transcription factor GR. Mechanistically, cisplatin binds to C622 in GR and recruits GR to the nucleus for its activation, which induces MAST1 expression and consequently reactivates MEK signaling. GR nuclear translocation and MAST1 upregulation coordinately occur in patient tumors collected after platinum treatment, and align with patient treatment resistance. Co-treatment with dexamethasone and cisplatin restores cisplatin-resistant tumor growth, whereas addition of the MAST1 inhibitor lestaurtinib abrogates tumor growth while preserving the inhibitory effect of dexamethasone on inflammation in vivo. These findings not only provide insights into the underlying mechanism of GR in cisplatin resistance but also offer an effective alternative therapeutic strategy to improve the clinical outcome of patients receiving platinum-based chemotherapy with GR agonists.

scholarly journals Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

2020 ◽  
Vol 21 (9) ◽  
pp. 3100 ◽  
Author(s):  
Alia Ghoneum ◽  
Ammar Yasser Abdulfattah ◽  
Bailey Olivia Warren ◽  
Junjun Shu ◽  
Neveen Said
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Metabolic Pathways ◽  
Redox Homeostasis ◽  
Ros Production ◽  
Biological Processes ◽  
Survival Pathways ◽  
Oncogenic Mutations ◽  
And Oxidative Stress ◽  
Shed Light

Reactive Oxygen Species or “ROS” encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.

scholarly journals First-Line Therapies for Metastatic Lung Adenocarcinoma Without a Driver Mutation

2018 ◽  
Vol 14 (9) ◽  
pp. 529-535 ◽  
Author(s):  
J. Nicholas Bodor ◽  
Vineela Kasireddy ◽  
Hossein Borghaei
Keyword(s):  
Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Driver Mutation ◽  
Driver Mutations ◽  
First Line ◽  
Histologic Subtype ◽  
First Line Therapy ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Common Histologic Subtype

Lung cancer is the leading cause of cancer-related death worldwide. The majority of these cancers are non–small-cell lung cancer, of which adenocarcinoma is the most common histologic subtype. Most patients are diagnosed at advanced stages when systemic treatment is needed. Whereas prognosis has improved for patients with targetable driver mutations, the majority of patients do not possess tumors with such molecular mutations. Platinum-based chemotherapy has traditionally been the mainstay of treatment, although in recent years immunotherapy has emerged as a treatment option and can result in robust and durable treatment responses in a subset of patients. Recent clinical trials on novel immunotherapy combinations and immunochemotherapy combinations may broaden the number of patients that may benefit from checkpoint inhibitors and elicit responses in those who otherwise may not have experienced a response to monotherapy with an immunotherapy drug. This review will outline the currently available therapies for the first-line treatment of metastatic adenocarcinoma that do not possess a driver mutation and provide a recommended approach and algorithm by which to select the best first-line therapy.

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