Conventional Platinum-based Chemotherapy Research Articles

Evaluating the feasibility and predictive accuracy of biodynamic imaging to platinum-based chemotherapy response in esophageal adenocarcinoma

BackgroundEsophageal cancer management lacks reliable response predictors to chemotherapy. In this study we evaluated the feasibility and accuracy of Biodynamic Imaging (BDI), a technology that employs digital holography as a rapid predictor of chemotherapy sensitivity in locoregional esophageal adenocarcinoma.MethodsPre-treatment endoscopic pinch biopsies were collected from patients with esophageal adenocarcinoma during standard staging procedures. BDI analyzed the tumor samples and assessed in vitro chemotherapy sensitivity. BDI sensitivity predictions were compared to patients’ pathological responses, the gold standard for determining clinical response, in the surgically treated subset (n=18).ResultBDI was feasible with timely tissue acquisition, collection, and processing in all 30 enrolled patients and successful BDI analysis in 28/29 (96%) eligible. BDI accurately predicted chemotherapy response in 13/18 (72.2%) patients using a classifier for complete, marked, and partial/no-response. BDI technology had 100% negative predictive value for complete pathological response hence identifying patients unlikely to respond to treatment.ConclusionBDI technology can potentially predict patients’ response to platinum chemotherapy. Additionally, this technology represents a promising step towards optimizing treatment strategies for esophageal adenocarcinoma patients by pre-emptively identifying non-responders to conventional platinum-based chemotherapy.

Mutational Profiling by Next-Generation Sequencing in Patients with Metastatic Non-Small Cell Lung Carcinoma: Our Experience

Introduction According to GLOBOCAN 2020, overall lung cancer is the second most common cancer in both sexes (11.4%) accounting for highest cancer-related mortality (18%).1 Adenocarcinoma subtype of non-small cell lung cancer (NSCLC) is the most common subtype and is divided into further molecular subtypes based on oncogenic driver mutations. Overall survival in these patients is poor with the use of conventional platinum-based double chemotherapy and various recent studies on targeted therapy studies have showed improved survival. Therefore, broad panel-based testing like next-generation sequencing (NGS) is strongly recommended to identify these targetable driver mutations. Aims and Objectives The aim of this study was to evaluate the mutational profile in patients with metastatic NSCLC (mNSCLC) by NGS method. Materials and Methods A hospital-based prospective observational study done on 88 patients under the Department of Medical Oncology, State Cancer Institute during a period of 1 year. All patients above 18 years of age diagnosed as mNSCLC having Eastern Cooperative Oncology Group performance status 0 to 2 and evaluated for mutational profiling by NGS method were included. Five gene panel tests including endothelial growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK), BRAF, mesenchymal epithelial transition (MET), and ROS proto-oncogene 1 (ROS1) were used. Results and Observations Majority of mNSCLC cases were in the age group of 41 to 50 years (n = 30, 34.1%) with average age at presentation being 53.74 years. Male: female ratio was 1.14:1 and most patients were nonsmokers. Adenocarcinoma subtype of mNSCLC cases had the highest mutational burden (n = 55, 62.5%). EGFR (n = 32, 56.14%) was the most common mutation followed by EML4-ALK (n = 19, 33.33%). Most common EGFR mutation was in Exon 19. Other rare mutations were ROS1 (n = 4), BRAF V600E (n = 1), and MET (n = 1). Skeleton was the most common site of metastasis across all driver mutations. Conclusion EGFR and EML4-ALK were the commonest targetable mutations detected in the study. As there is very limited data from North Eastern region of India regarding mutational status in mNSCLC, this study opens up possibilities for further studies targeting multiple mutations to give us more comprehensive understanding of the mutational landscape of mNSCLC in this era of precision medicine.

Tumor-Stroma Proportion to Predict Chemoresistance in Patients With Ovarian Cancer

Platinum-based chemotherapy is the backbone of standard-of-care treatment for patients with advanced-stage, high-grade serous carcinoma (HGSC), the most common form of ovarian cancer; however, one-third of patients have or acquire chemoresistance toward platinum-based therapies. To demonstrate the utility of tumor-stroma proportion (TSP) as a predictive biomarker of chemoresistance of HGSC, progression-free survival (PFS), and overall survival (OS). This prognostic study leveraged tumors from patients with HGSC in The Cancer Genome Atlas (TCGA) cohort (1993-2013) and an independent cohort of resected clinical specimens from patients with HGSC (2004-2014) available in diagnostic and tissue microarray formats from the University of Tübingen in Germany. Data analysis was conducted from January 2021 to January 2024. Diagnosis of HGSC. Principal outcome measures were the ability of TSP to predict platinum chemoresistance, PFS, and OS. Using hematoxylin and eosin-stained slides from the Tübingen cohort (used for routine diagnostic assessment from surgical specimens) as well as tissue microarrays, representative sections of tumors for scoring of TSP were identified using previously evaluated cutoffs of 50% stroma or greater (high TSP) and less than 50% stroma (low TSP). Digitized slides from the TCGA Cohort were analyzed and scored in a similar fashion. Kaplan-Meier time-to-event functions were fit to estimate PFS and OS. The study included 103 patients (mean [SD] age, 61.6 [11.1] years) from the TCGA cohort and 192 patients (mean [SD] age at diagnosis, 63.7 [11.1] years) from the Tübingen cohort. In the TCGA cohort, there was no significant association of TSP levels with chemoresistance, PFS, or OS. However, in the Tübingen cohort, high TSP was associated with significantly shorter PFS (HR, 1.586; 95% CI, 1.093-2.302; P = .02) and OS (hazard ratio [HR], 1.867; 1.249-2.789; P = .002). Patients with chemoresistant tumors were twice as likely to have high TSP as compared to patients with chemosensitive tumors (HR, 2.861; 95% CI, 1.256-6.515; P = .01). In tissue microarrays from 185 patients from the Tübingen cohort, high TSP was again associated with significantly shorter PFS (HR, 1.675; 95% CI, 1.012-2.772 P = .04) and OS (HR, 2.491; 95% CI, 1.585-3.912; P < .001). In this prognostic study, TSP was a consistent and reproducible marker of clinical outcome measures of HGSC, including PFS, OS, and platinum chemoresistance. Accurate and cost-effective predictive biomarkers of platinum chemotherapy resistance are needed to identify patients most likely to benefit from standard treatments, and TSP can easily be implemented and integrated into prospective clinical trial design and adapted to identify patients who are least likely to benefit long-term from conventional platinum-based cytotoxic chemotherapy treatment at the time of initial diagnosis.

Prognostic nomogram based on pre-treatment HALP score for patients with advanced non-small cell lung cancer

BackgroundTo explore the correlation of pre-treatment Hemoglobin-Albumin-Lymphocyte-Platelet (HALP) score with the prognosis of patients with advanced Non-Small Cell Lung Cancer (NSCLC) undergoing first-line conventional platinum-based chemotherapy. MethodsIn this retrospective cohort study, 203 patients with advanced NSCLC were recruited from January 2017 to December 2021. The cut-off value for the HALP score was determined by Receiver Operating Characteristic (ROC) curve analysis. The baseline characteristics and blood parameters were recorded, and the Log-rank test and Kaplan-Meier curves were applied for the survival analysis. In the univariate and multivariate analyses, the Cox regression analysis was carried out. The predictive accuracy and discriminative ability of the nomogram were determined by the Concordance index (C-index) and calibration curve and compared with a single HALP score by ROC curve analysis. ResultsThe optimal cut-off value for the HALP score was 28.02. The lower HALP score was closely associated with poorer Progression-Free Survival (PFS) and Overall Survival (OS). The male gender and other pathological types were associated with shorter OS. Disease progression and low HALP were correlated with shorter OS and PFS. In addition, nomograms were established based on HALP scores, gender, pathology type and efficacy rating, and used to predict OS. The C-index for OS prediction was 0.7036 (95% CI 0.643 to 0.7643), which was significantly higher than the C-index of HALP at 6-, 12-, and 24-months. ConclusionThe HALP score is associated with the prognosis of advanced NSCLC patients receiving conventional platinum-based chemotherapy, and the nomogram established based on the HALP score has a better predictive capability for OS.

The Efficacy and Safety of Anlotinib Plus Etoposide with Cisplatin/Carboplatin in the First-Line Treatment of Lung Cancer: A Phase II Clinical Study.

Background: The primary aim of this phase II clinical study was to assess the safety and efficacy of combining anlotinib, etoposide, and platinum-based drugs as a first-line treatment for ES-SCLC. Methods: Patients underwent the standard chemotherapeutic regimen, consisting of four courses of etoposide plus cisplatin/carboplatin. Additionally, each patient received a 2-week intervention with anlotinib (12 mg/day, once daily). Anlotinib was continued until disease progression, occurrence of unbearable adverse events (AEs), or withdrawal from the research. Progression-free survival (PFS) served as the primary prognostic measure. Secondary measures included the disease control rate (DCR), objective response rate (ORR), overall survival time (OS), and the incidence of AEs. Results: The DCR and ORR were 97.6% and 91.0%, respectively. Estimated PFS and OS were 5.0 months (95% CI: 1.0-10.8 months) and 13.0 months (95% CI: 8.4-18.6 months), respectively. No unexpected adverse effects were reported during the trial. The most common adverse reactions included anemia (42.22%), hypertension (53.33%), alopecia (40.00%), elevated transaminase (24.40%), and elevated alkaline phosphatase (24.44%). Sixteen cases (35.56%) were classified as AEs of grades 3-5. No deaths attributed to treatment-related causes occurred in any patient during the trial. Conclusion: Combination chemotherapy is currently the first-line therapy for extensive small-cell lung cancer (ES-SCLC). Combining anlotinib with conventional platinum-based chemotherapy demonstrated promising therapeutic outcomes and prognosis in the management of ES-SCLC.

Targeted Treatment of Advanced Endometrial Cancer: Focus on Pembrolizumab.

Endometrial cancer (EC) accounts for 2% of all new cancers. Advanced forms have a poor prognosis with barely 17% 5-year survival. The last few years improved our knowledge of EC with a new molecular classification derived from The Cancer Genome Atlas (TCGA). They are now divided between POLE mutant, Microsatellite Instability High (MSI-H) or deficient in Mismatch Repair System (dMMR), TP53 mutant and no specific molecular profile. Until now, treatments for advanced EC have included conventional platinum-based chemotherapy or hormonotherapy. The revolution in oncology represented by the advent of immune checkpoints inhibitors (ICI) has also led to a major advance in the management of recurrent and metastatic EC. Pembrolizumab, a well-known anti PD-1, has firstly been approved as monotherapy in the second-line setting for dMMR/MSI-H advanced EC. More recently, a combination of lenvatinib with pembrolizumab offered a new effective option in the second line setting irrespectively of the MMR status, giving a new opportunity for these patients who had no actual standard of care before. This combination is currently being evaluated as frontline therapy. Despite exciting results, the main problem in identifying solid biomarkers remains unresolved and further investigations are required. New original combinations of pembrolizumab with other drugs including chemotherapy, poly ADPribose polymerase inhibitors (PARP-i) or tyrosine kinase inhibitors are being tested and promise exciting new therapeutic evolutions in a close future.

Zhengyuan capsules for the treatment of chemotherapy-induced cancer-related fatigue in stage IIIB-IV unresectable NSCLC: study protocol for a randomized, multi-center, double-blind, placebo-controlled clinical trial.

Patients with advanced non-small cell lung cancer (NSCLC) frequently experience cancer-related fatigue (CRF) during or after chemotherapy. Traditional Chinese medicine (TCM) can effectively relieve CRF, although the clinical evidence is insufficient due to the absence of extensive and rigorous clinical studies. Zhengyuan capsules have both tonifying and dispersing effects, and its ability to alleviate CRF has been verified in mice. This study aimed to provide evidence for the role of proprietary Chinese medicines in alleviating CRF in advanced NSCLC patients. A multi-center, randomized, double-blind, placebo-controlled clinical trial has been designed to evaluate the efficacy and safety of Zhengyuan capsules for CRF in stage IIIB-IV unresectable NSCLC patients undergoing chemotherapy. Thirty eligible participants will be randomized into two groups at a 1:1 ratio during chemotherapy using the centralized interactive web response system. All patients will receive conventional platinum-based dual-drug chemotherapy and Zhengyuan capsules or simulant for 42 consecutive days starting on the first day of the first week of chemotherapy. The primary outcome is the difference between baseline and post-treatment CRF in the two groups, which will be assessed using the Brief Fatigue Inventory (BFI) score. Secondary outcome measurements include the Revised Piper's Fatigue Scale (RPFS)-Chinese Version, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Module C30 (EORTC QLQ-C30) v3.0 combined with EORTC QLQ-LC13 (Lung Cancer 13), clinical symptom score, hematology exploratory index, and progression-free survival. And safety indicators such as blood, urine, fecal routine, liver and kidney function, coagulation, and electrocardiogram will be performed before chemotherapy. Data will be analyzed according to intention-to-treat (ITT) and per-protocol (PP) principles; Empowerstats and R will be applied for statistical analysis. This trial will provide data on the efficacy and safety of Zhengyuan capsules for treating CRF in stage IIIB-IV unresectable NSCLC patients undergoing chemotherapy. It will also provide a basis for the feasibility of a large-scale clinical trial. The clinical trial was registered on 19 November 2020 through https://www.chictr.org.cn (registration number: ChiCTR2000040061).

Mechanisms of chemotherapy resistance in ovarian cancer.

Ovarian cancer is one of the most lethal gynecologic cancers. The standard therapy for ovarian cancer has been the same for the past two decades, a combination treatment of platinum with paclitaxel. Recently, the FDA approved three new therapeutic drugs, two poly (ADP-ribose) polymerase inhibitors (olaparib and niraparib) and one vascular endothelial growth factor inhibitor (bevacizumab) as maintenance therapies for ovarian cancer. In this review, we summarize the resistance mechanisms for conventional platinum-based chemotherapy and for the newly FDA-approved drugs.

Novel Salvage Regimens Lead to Better Response and Survival in Relapsed Refractory Classic Hodgkin Lymphoma after Autologous Stem Cell Transplant

Novel Salvage Regimens Lead to Better Response and Survival in Relapsed Refractory Classic Hodgkin Lymphoma after Autologous Stem Cell Transplant

PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (CCC) exhibits an association with endometriosis, resistance to oxidative stress, and poor prognosis owing to its resistance to conventional platinum‐based chemotherapy. A greater understanding of the molecular characteristics and pathogenesis of ovarian cancer subtypes may facilitate the development of targeted therapeutic strategies, although the mechanism of drug resistance in ovarian CCC has yet to be determined. In this study, we assessed exome sequencing data to identify new therapeutic targets of mitochondrial function in ovarian CCC because of the central role of mitochondria in redox homeostasis. Copy number analyses revealed that chromosome 17q21‐24 (chr.17q21‐24) amplification was associated with recurrence in ovarian CCC. Cell viability assays identified an association between cisplatin resistance and chr.17q21‐24 amplification, and mitochondrion‐related genes were enriched in patients with chr.17q21‐24 amplification. Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species. Mouse xenograft models showed that inhibition of PDK2 with cisplatin inhibited tumor growth. This evidence suggests that targeting mitochondrial metabolism and redox homeostasis is an attractive therapeutic strategy for improving drug sensitivity in ovarian CCC.

Abstract 987: Ovarian carcinoma cells are susceptible to ferroptosis

Abstract Ovarian carcinoma (OC) is a malignancy with grave prognosis owing to its high recurrence rate and broad resistance to a variety of apoptosis-inducing chemotherapeutic agents. Induction of alternative, non-apoptotic cell death represents a novel strategy for anti-cancer therapies worldwide. Ferroptosis is a recently defined type of non-apoptotic cell death driven by the accumulation of iron-dependent lipid reactive oxygen species (ROS), resulting in membrane damage and cell rupture. Lines of evidence suggested that OC may be susceptible to ferroptosis. However, the exact effects mediated by ferroptosis and the underlying regulatory mechanisms in OC are not fully characterized. Herein, we sought to explore the susceptibility of a number of OC cell line models towards ferroptosis and investigate the possibility of enhancing conventional platinum-based chemotherapy with ferroptosis inducers. Ferroptosis inducers Erastin and RSL3 dose-dependently induced ferroptotic cell death in ovarian cancer cell lines OVCAR3 and TUOC1, hallmarked by a significant decrease of GSH level and increase of ROS and lipid peroxidation levels after treatment. Treatment by a lipid ROS scavenger ferrostatin-1 (Fer-1), but not by the apoptosis inhibitor Z-VAD-FMK, significantly rescued OVCAR3 and TUOC1 cells from Erastin- and RSL3- induced cell death. Additionally, Erastin and RSL3 could significantly promote cytotoxicity of cisplatin in a cisplatin-resistant ovarian cancer cells OVCA420. Collectively, our results indicate a crucial role of ferroptosis in susceptibility of ovarian carcinomas, suggesting a potential anticancer strategy. Citation Format: Jing Li, Oscar Gee Wong, Annie Nga Cheung. Ovarian carcinoma cells are susceptible to ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 987.

The Clinical Characteristics and Treatment Results in the Patients with Clear Cell Carcinoma of the Ovary

Background: It is well known that clear cell carcinoma of the ovary (CCC) demonstrates different clinical behaviors from other epithelial ovarian cancer and has strong association with endometriosis, thromboembolic complication, hypercalcemia, and large pelvic mass. The introduction of cisplatin-based chemotherapy significantly changed the postoperative management of ovarian cancer patients. Different studies showed a better response rate of CCC to chemotherapy with paclitaxel plus carboplatin regime than with the conventional platinum-based regimens. Aim: The purpose of this study was to evaluate the patients’ clinical characteristics and treatment results for clear cell carcinoma (CCC) of the ovary treated in paclitaxel-platinum chemotherapy in comparison with those treated in conventional platinum-based chemotherapy after primary surgery Methods: We retrospectively reviewed the medical records of 40 patients with CCC who received treatment in the department of obstetrics and gynecology, Samsung Medical Center from March, 1996 to April 2006. The clinical characteristics, treatment results and follow-up data were collected from medical records and/or telephone surveys. Results: Mean age was 47 years (range 30–72 years). Patients with age less than 50years were 62.5%. Tumors were 15% (6/40) stage IA, 2.5% (1/40) stage IB, 37.5% (15/40) stage IC, 5% (2/40) stage II, 32.5% (13/40) stage III, and 7.5% (3/40) stage IV. Patients with CCC were more likely to have FIGO stage I &amp; II disease than FIGO stage III &amp; IV (60% vs. 40%). Five-year progression-free survival and overall survival were 91% and 80% in stage I &amp; II, 36% and 55% in stage III &amp; IV, respectively (5-yr PFS; P&lt;0.01, 5-yr OS; P=0.03). With a median follow-up of 45 months (2-112 months), 75% (18/24) of stage I/II patients are alive, while 19% (3/16) of stage III/IV patients are alive. 37.5% (15/40) of the patients presented with endometriosis. Except for one patient who was referred by a local clinic, all patients underwent cytoreductive surgery. The rate of optimal debulking (≤ 1cm residual tumor diameter) was 90% (36/40). Overall, for women treated with platinum-based chemotherapy, 75% (27/36) had clinically complete responses to adjuvant chemotherapy. But there was no survival benefit according to chemotherapeutic differences in the patients who received cytoreductive surgery followed between conventional platinum-based chemotherapy (CAP or CP) and by paclitaxel and platinum-based chemotherapy (P=0.40). Univariate analysis showed that stage was the only favorable prognostic factor for women with clear cell carcinoma of the ovary (P=0.04). Conclusions: Our results suggest that CCC has a distinct clinical behavior, similar to previous studies, that frequently presents at early- stages and is associated with endometriosis. In addition, there was a close correlation between the level of CA-125 and survival, and there was no survival benefit according to chemotherapeutic differences. 〔CAP (CP) VS TP(TC)〕

Treatment Strategies for ARID1A-Deficient Ovarian Clear Cell Carcinoma.

Simple SummaryDeleterious mutations in SWI/SNF chromatin remodeling genes, such as ARID1A, are present in more than 50% of cases of ovarian clear cell carcinoma (OCCC), a histological subtype of ovarian cancer prevalent in Asian countries. To efficiently treat OCCC, which is refractory to conventional platinum-based chemotherapy, several therapeutic strategies based on SWI/SNF deficiency have been proposed, including gemcitabine-based chemotherapy, synthetic lethal therapy, and immune checkpoint blockade therapy. Implementation of these strategies would improve the prognosis of patients with this disease. Ovarian clear cell carcinoma (OCCC) is a histological subtype of ovarian cancer that is more frequent in Asian countries (~25% of ovarian cancers) than in US/European countries (less than 10%). OCCC is refractory to conventional platinum-based chemotherapy, which is effective against high-grade serous carcinoma (HGSC), a major histological subtype of ovarian cancer. Notably, deleterious mutations in SWI/SNF chromatin remodeling genes, such as ARID1A, are common in OCCC but rare in HGSC. Because this complex regulates multiple cellular processes, including transcription and DNA repair, molecularly targeted therapies that exploit the consequences of SWI/SNF deficiency may have clinical efficacy against OCCC. Three such strategies have been proposed to date: prioritizing a gemcitabine-based chemotherapeutic regimen, synthetic lethal therapy targeting vulnerabilities conferred by SWI/SNF deficiency, and immune checkpoint blockade therapy that exploits the high mutational burden of ARID1A-deficient tumor. Thus, ARID1A deficiency has potential as a biomarker for precision medicine of ovarian cancer.

Chemotherapy negatively impacts the tumor immune microenvironment in NSCLC: an analysis of pre- and post-treatment biopsies in the multi-center SAKK19/09 study

BackgroundOver the past few years, immune checkpoint inhibitors have changed the therapeutic landscape of non-small-cell lung cancer (NSCLC). Response to immune checkpoint inhibitors correlates with a pre-existing anti-tumoral immune response. Checkpoint inhibitors have been introduced as second-line therapy and are only very recently used as monotherapy or in combination with chemotherapy as first-line treatment of NSCLC. However, the effect of conventional first-line platinum-based chemotherapy on the immune infiltrate in the tumor is largely unknown.MethodsWe measured the gene expression of a custom set of 201 cancer- and immune-related genes in 100 NSCLC tumor biopsies collected before chemotherapy and 33 re-biopsies after platinum-based chemotherapy at the time point of progression. For 29 patients matched pre- and post-chemotherapy samples could be evaluated.ResultsWe identified a cluster of 47 co-expressed immune genes, including PDCD1 (PD1) and CD274 (PD-L1), along with three other co-expression clusters. Chemotherapy decreased the average gene expression of the immune cluster while no effect was observed on the other three cluster. Within this immune cluster, CTLA4, LAG3, TNFRSF18, CD80 and FOXP3 were found to be significantly decreased in patient-matched samples after chemotherapy.ConclusionOur results suggest that conventional platinum-based chemotherapy negatively impacts the immune microenvironment at the time point of secondary progression.

MP08-01 SETD2/MIR-378/OCT-4 PATHWAY REGULATES THE SELF-RENEWAL AND MOTILITY IN CD105(+) KIDNEY CANCER STEM CELLS

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I (MP08)1 Apr 2020MP08-01 SETD2/MIR-378/OCT-4 PATHWAY REGULATES THE SELF-RENEWAL AND MOTILITY IN CD105(+) KIDNEY CANCER STEM CELLS Guoliang Sun, Libin Yan, and Yue Ge* Guoliang SunGuoliang Sun More articles by this author , Libin YanLibin Yan More articles by this author , and Yue Ge*Yue Ge* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000828.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Renal cell carcinoma (RCC) is one of the few cancer types that are resistant to both radiotherapy and conventional platinum-based chemotherapy. Clear cell RCC (ccRCC) is the most common type and its 5-year survival rate can be as poor as 8% in high risk patients. What’s worse, cancer cells tend to be more and more drug resistant after many rounds of treatments. To this end, cancer stem cell model was brought to explain that a subpopulation within thousands of cancer cells represents as the origin of tumor relapse, progression and metastasis. Previously, we proved that CD105(+) cells possess the property of cancer initiating cells in ccRCC and might serve as a potential therapeutic target. Here, we aimed to uncover the mechanism of self-renewal and motility of CD105(+) renal cell stem cells (RCSCs). METHODS: Overexpression and interference plasmid were construct and transfected into cell lines. Scratch assay, modified 3D transwell assay, sphere formation assay and in vivo kidney cancer orthotopic model, etc. were conducted to explore the function of genes. RESULTS: A non-coding microRNA miR-378 was found to be downregulated in the CD105(+) RCSCs in a panel of 30 microRNAs we screened. Furthermore, artificial overexpression of miR-378 can not only significantly decrease the motility in scratch assay and a modified 3D transwell assay, but also decrease the self-renewal of RCSCs via sphere formation assay. In addition, the in vivo kidney cancer orthotopic model further validated that miR-378 can inhibit RCSCs’ tumorigenesis. Mechanistically, Oct-4 was verified to be a putative target of miR-378 while Oct-4, act as a transcriptional factor can also negatively regulates miR-378. The decrease in motility and sphere formation ability of RCSCs brought by miR-378 can be abrogated by Oct-4 overexpression. In the upstream of miR-378, SETD2 was validated to be one of its regulatory proteins mediating the histone methylation of miR-378, which was verified by ChIP. Also, miR-378 was found to be increased upon SETD2 downregulation. CONCLUSIONS: Collectively, SETD2/miR-378/Oct-4 regulatory pathway plays a critical role in RCSCs’ self-renewal and motility, which signifies its potential therapeutic application in targeting the stem cells in clear cell carcinoma. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e105-e105 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Guoliang Sun More articles by this author Libin Yan More articles by this author Yue Ge* More articles by this author Expand All Advertisement PDF downloadLoading ...

Acute kidney injury in cancer patients.

The increasing prevalence of neoplasias is associated with new clinical challenges, one of which is acute kidney injury (AKI). In addition to possibly constituting a clinical emergency, kidney failure significantly interferes with the choice and continuation of antineoplastic therapy, with prognostic implications in cancer patients. Some types of neoplasia are more susceptible to AKI, such as multiple myeloma and renal carcinoma. In cancer patients, AKI can be divided into pre-renal, renal (intrinsic), and post-renal. Conventional platinum-based chemotherapy and new targeted therapy agents against cancer are examples of drugs that cause an intrinsic renal lesion in this group of patients. This topic is of great importance to the daily practice of nephrologists and even constitutes a subspecialty in the field, the onco-nephrology.

Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma.

Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models.Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient-derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055.Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient-derived xenograft models.Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928-40. ©2018 AACR.

MiRNAs and their interplay with PI3K/AKT/mTOR pathway in ovarian cancer cells: a potential role in platinum resistance.

Ovarian cancer is a leading cause of death among gynecologic malignancies. This disappointing prognosis is closely related to intrinsic or acquired resistance to conventional platinum-based chemotherapy, which can affect a third of patients. As such, investigating relevant molecular targets is crucial in the fight against this disease. So far, many mutations involved in ovarian cancer pathogenesis have been identified. Among them, a few pathways were implicated. One such pathway is the P13K/AKT/mTOR with abnormalities found in many cases. This pathway is considered to have an instrumental role in proliferation, migration, invasion and, more recently, in chemotherapy resistance. Many miRNAs have been found to influence P13K/AKT/mTOR pathway with different potential role in tumor genesis and ovarian cancer behaviour. In particular, their biological function was recently investigated as regards chemoresistance, therefore, leading to the identification of potential specific indirect biomarker of platinum sensitivity in ovarian cancer.

Abstract B67: Antitumor effect of black tea pigments, theaflavin-3/3’-gallate, against cisplatin-resistant ovarian cancer cells

Abstract Ovarian cancer ranks fifth in cancer deaths among women in the United States, accounting for approximately 5% of all cancer deaths. Acquired resistance to conventional platinum-based chemotherapy drives the development of more selective anticancer drugs. Theaflavin-3-gallate (TF2a) and theaflavin-3’-gallate (TF2b) are the major bioactive components in black tea. In this study, we evaluated TF2a and TF2b as potential anticancer agents using human ovarian cancer cells. The cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum at 37˚C in a humidified incubator with 5% CO2. The [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, flow cytometry, and Western blot analysis were used to confirm that TF2a and TF2b exhibited a potent growth-inhibitory effect against cisplatin-resistant ovarian cancer A2780/CP70 cells. Treatment with TF2a and TF2b (10-40 μM) significantly decreased A2780/CP70 cell viability (p&amp;lt; 0.05). Treatment with TF2a and TF2b (5, 10 and 20 μM) increased the percentage of apoptotic cells in a concentration-dependent manner. Western blot analysis was used to evaluate the expression of proteins related to apoptosis in A2780/CP70 cells treated with designated concentrations (0, 5, 10, and 20 μM) of TF2a and TF2b for 24 h. The protein levels of procaspase-3/7 for TF2a-treated cells and procaspase 3 for TF2b-treated cells decreased significantly in A2780/CP70 cells (p&amp;lt; 0.05). Treatment with TF2a or TF2b significantly increased the protein levels of cleaved caspase-3/7, full-length PARP, and cleaved PARP in A2780/CP70 cells. Our study demonstrated that TF2a and TF2b are potential agents for treating platinum-resistant ovarian cancer by inducing apoptosis. Note: This abstract was not presented at the conference. Citation Format: Yi Charlie Chen. Antitumor effect of black tea pigments, theaflavin-3/3’-gallate, against cisplatin-resistant ovarian cancer cells. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B67.

Efficacy of mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) in patients with advanced pulmonary pleomorphic carcinoma

ObjectivesPulmonary pleomorphic carcinoma (PC) is a rare type of lung tumor with a dismal prognosis. There is no consensus on a chemotherapy regimen for PC, and conventional platinum-based chemotherapy has been associated with disappointing response rates and PFS. In searches for a new regimen, the sarcomatoid (spindle or giant cell) component has been assumed to be susceptible to chemotherapy used for soft tissue sarcoma. Materials and methodsThe medical records of 17 patients who received mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) for advanced PC between January 2010 and February 2017 were retrospectively analyzed for clinicopathological features and outcomes. Results and conclusionThe median age was 59 years. Sixteen patients were male, and only one patient had never smoked. Six patients achieved partial response to MAID, leading to an objective response rate of 35%. The median PFS was 2.8 months, and the median OS was 8.7 months. Hematologic toxicity-related adverse events were the most frequent, which comprised grade 3–4 anemia in 35% of patients, neutropenia in 47%, thrombocytopenia in 24%, and febrile neutropenia in 29%. No febrile neutropenia was reported in patients who received 5-day granulocyte-colony stimulating factor (G-CSF) prophylaxis. Most adverse events resolved without complications, except for one death due to sepsis.MAID is an effective, and possibly important, regimen for PC. MAID could be more safely used in clinical practice with appropriate dose modifications and G-CSF primary prophylaxis according to patients’ status.