Browsing Over 1605 Presentations
3P - Beyond first-line therapy in metastatic adrenal cortical cancer (ACC): Is it time to move on from chemotherapy?
- Abhenil Mittal (New Delhi, India)
Abstract
Background
Metastatic ACC is a rare and aggressive tumor with limited treatment options beyond first-line chemotherapy. Unfortunately, survival outcomes are poor with 2nd line chemotherapy, which is frequently adopted for treatment. Data on outcomes with non-chemotherapeutic approaches including immunotherapy is scarce.
Methods
A retrospective review (2002-2020) of metastatic ACC patients treated at Princess Margaret Cancer Center was performed. Patients who received any 2nd line therapy and beyond were identified. Descriptive statistics were used to summarize clinical and demographic data. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Survival outcomes were compared using log-rank test.
Results
Out of 84 patients with metastatic ACC, 30 (20.7%) had de novo and 54 (37.2%) recurrent disease after local definitive therapy; 51 (60.7%) and 30 (58.8%) received 1st and 2nd line systemic therapy respectively. Median age was 49 years (36-58); 18 (60%) were female,14 (47%) had functional tumors, 4 (13.3%), 25 (83.3%), and 1 (3.3%) were ECOG 0, 1 and 2 respectively. One patient had MMR deficiency out of 16 patients in which it was evaluated. Seventeen patients (56.6%) received chemotherapy (14-gemcitabine capecitabine, 1-gemcitabine, 2-etoposide doxorubicin and cisplatin rechallenge) and 13 patients (43.4%) received non chemotherapy treatment (8- clinical trial, 4-sunitinib, 1-pembrolizumab ). Mitotane was continued in 16 of 22 (72.7%) patients for which data was available. Baseline characteristics and disease control rate were similar between the two groups (18% for chemotherapy vs 31% for non -chemotherapy, p=0.46). Median PFS was similar (2.6 months (2-4) and 3 months (1.7-4.5), p=0.48), however OS was numerically better with non- chemotherapy (6.6 months (4.9-13.1) vs 10.2 months (5.9-22.7) p=0.08.
Conclusions
This study shows favorable outcomes with non-chemotherapy approaches compared to chemotherapy. Although this needs to be confirmed in larger studies, given the lack of randomized data for superiority of chemotherapy, non-chemotherapy approaches including immunotherapy and clinical trials should be considered where appropriate.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
4P - Immune checkpoint inhibitors in adrenocortical carcinoma: A meta-analysis
- Obada Ababneh (Irbid, Jordan)
Abstract
Background
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with few treatment options. The use of immune checkpoint inhibitors (ICI) has revolutionized the way many malignancies are treated. However, its role in ACC is still unclear. Thus, we performed a meta-analysis to summarize the efficacy of ICI in patients with ACC.
Methods
A systematic review was performed for studies published in PubMed, Scopus, CENTRAL, ASCO, and ESMO meeting abstracts. Studies that reported overall survival (OS), progression-free survival (PFS), or objective response rate (ORR) and were with at least 5 patients were included in the meta-analysis. We estimated the proportions for ORR, disease control rate (DCR), PFS, OS and adverse events using the fixed-effect model.
Results
We included 9 studies with a total number of 168 patients. Six studies used anti-PD(L)-1 monotherapy (n=113), 2 studies used anti-PD(L)-1 and anti-CTLA4 combination therapy (n=24) and 2 studies used anti-PD1 combined with chemotherapy (n=31). Patients’ median age across studies ranged from 43 to 62 with 60.6% being females. The pooled ORR was 10% (95% CI: 4.6%-15.6%, I2 = 0%) for anti-PD(L)-1 monotherapy, 8.7% (95% CI: 0%-20%, I2 = 0%) for anti-PD(L)-1 and anti-CTLA4 combination therapy, and 9.9% (95%CI: 0%-20.1%, I2 = 0%). For the pooled DCR, it was 45.4% (95% CI: 36.3%-54.4%, I2 = 0%) for anti-PD(L)-1 monotherapy, 54.9% (95% CI: 34.4%-75.5%, I2 = 0%) for anti-PD(L)-1 and anti-CTLA4 combination therapy, and 70.5% (95%CI: 26.5%-100%, I2 = 90.3%) for anti-PD1 combined with chemotherapy. The median PFS was 1.88 months (95%CI: 1.08-2.69, I2 = 0%) for anti-PD(L)-1 monotherapy. The was not enough data regarding PFS and OS for further analyses. Pooled all grades adverse events were 24.0% (95%CI: 12.9%-35.2%, I2 = 92.41%) for anti-PD(L)-1 monotherapy and 39.1% (95%CI: 9%-69.2%, I2 = 94.7%) for anti-PD1 combined with chemotherapy. Grade 3/4 adverse events were 17% (95%CI: 10.1%-24.%, I2 = 0%) for anti-PD(L)-1 monotherapy and 11.8% (95%CI: 5.5%-18.1% , I2 = 0%) for anti-PD1 combined with chemotherapy.
Conclusions
Combination therapy showed a similar ORR and safety profile but higher DCR compared to single-agent anti-PD(L)-1. Survival data were scarce and should be reported more in future combination-based ICI trials.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
5P - Application of a novel machine learning model in predicting survival in adrenocortical cancer (ACC)
- Diana G. Varghese (Bethesda, United States of America)
Abstract
Background
Machine Learning has the potential to revolutionize cancer care, however, its application is lacking in rare cancers such as ACC. ACC has a dismal prognosis and in need of effective therapies and prognostic tools. Here we applied a novel AI-assisted technology utilizing 18F-FDG PET scans using a scoring system to characterize metabolic signatures that correlates with survival.
Methods
69 patients with at least two 18F-FDG PET scans were analyzed, 67% female and 33% male, median age is 50 (80% metastatic [59% with lung metastasis], 16% localized and 4% NED on follow-up). All lesions were contoured for both the baseline and follow-up 18F-FDG PET scans. Lesions were quantified and matched between timepoints using TRAQinform IQ technology (AIQ Solutions) and TRAQinform Profile was calculated. Imaging features were extracted from each patient, including basic features (SUVmax, SUVmean, total lesion glycolysis, and number of lesions at baseline), basic response features (baseline, follow up, and change in basic features), location features (number of lesions in different organs) and heterogeneity (intrapatient heterogeneity of disease and response) features. Univariate predictive power of overall survival prediction of each measure was determined using Cox regression models. The TRAQinform Profile was calculated to predict overall survival using 3-fold cross-validation of a random survival forest. The model performance was evaluated using the c-index.
Results
The overall disease burden at the baseline has the strongest predictor to overall survival (c-index = 0.68), followed by disease burden at follow-up (0.65), number of lesions in the lungs at follow-up (0.62), and number of lesions with increasing disease burden (0.62). TRAQinform Profile was able to predict the responder’s vs suboptimal responders to the standard of care treatment (c-index = 0.76).
Conclusions
Machine Learning algorithms are rapidly evolving and new tools using AI are being added to the repertoire of cancer management. Here we present an AI-assisted technology that can help predict the prognosis of ACC patients disease based on the analysis of the lesions present in the 18F-FDG-PET. This can be translated to tailoring the treatment options to a more personalized approach.
Legal entity responsible for the study
The authors.
Funding
National Cancer Institute.
Disclosure
O. Lokre, R. Munian-Govindan, T. Perk: Financial Interests, Full or part-time Employment: AIQ Solutions, Inc. All other authors have declared no conflicts of interest.
6P - Sensitization of pancreatic and colorectal cancer to radiotherapy, chemotherapy and inhibition of PD-1 expression by newly developed proprotein convertase inhibitors
- Simon Pernot (Boulogne-Billancourt, France)
Abstract
Background
The pancreatic ductal adenocarcinoma (PDAC) and advanced colorectal cancer (CRC) have a bad prognosis with delayed diagnosis that significantly impedes the use of therapeutic resection. In these situation, palliative chemotherapy has modest activity, and Immune checkpoint inhibitors or radiotherapy failed to improve survival. The proprotein convertases (PCs) are enzymes involved in the biological activation/maturation of various protein precursors crucial for the malignant phenotype of PDAC and CRC tumors, and the resistance to various anticancer treatments.
Methods
Using computer-aided virtual screening, we identified among a collection of 2082 small molecules, those with inhibitory activity against Furin, the only PCs with published crystallographic structure. 15 molecules with significant inhibitory activity. Identified molecules where then tested in vivo in syngenic murine colorectal cancer model (CT26) and on PDAC and CRC organoids generated from cells line (Capan-1, Capan-2, Panc-1 HT29, CT26) and from cancer cells from patient tumors, alone or concomitant with chemotherapy (Gemcitabine or 5-Fluorouracil), or radiotherapy. PD-1 expression was analysed in activated T cells or patients PBMCs cultured with these Furin inhibitors by flow cytometry.
Results
We identified 15 molecules with significant inhibitory activity against Furin with computered screening. Among these, 5 generated molecules ( I0, I1, I10, I13, I9), significantly reduced tumor progression and enhanced survival and sensitivity to radiotherapy in syngenic mice. Using cancer organoids in the presence of some of these molecules, the latter were more sensitive to radiotherapy and chemotherapy. Treatment of activated T cells or PBMCs with these Furin inhibitors repressed significantly PD-1 expression.
Conclusions
These findings suggest the potential efficacy of Furin inhibitors in the sensitization of PDAC and CRC to drug resistance, and the potential immune sensitization through inhibition of T cells exhaustion, that may contribute to the development of efficient therapeutic strategies and to in patients with these cancers.
Legal entity responsible for the study
The authors.
Funding
Planète Végétal.
Disclosure
S. Pernot: Financial Interests, Personal, Invited Speaker: Amgen, BMS, Merck, Sanofi, Servier, Pierre Fabre. All other authors have declared no conflicts of interest.
7P - HIFA1 inhibition as a therapeutic strategy for overcoming castration resistance in PTEN-deficient prostate cancer
- Julie Terzic (Geneva, Switzerland)
Abstract
Background
Prostate cancer (PCa) is the second most commonly diagnosed neoplasia in men worldwide. The growth of prostate cancer cells is initially dependent of the activity of the androgen receptor (AR) and AR is the target of first-line prostate cancer systemic treatments. The benefit of adding neoadjuvant and adjuvant androgen deprivation therapy is well established for men with high-risk localized and advanced disease. However, some patients develop castration resistant prostate cancer, for which curative options are limited. PTEN is the most often tumor suppressor gene mutated in PCa patients. Hypoxic regions have been found in prostate adenocarcinoma, and elevated expression of hypoxia markers, including HIF1a (hypoxia-inducible factor 1A), have been shown to identify PCa patients with elevated risk of biochemical recurrence.
Methods
Prostate tumors of sham-operated and castrated Pten(i)pe-/- mice, which have a prostatic luminal cell-specific inactivation of PTEN after puberty, were analyzed by droplet-based single cell-RNA sequencing. Moreover, the impact of genetic and pharmacological Hif1a inhibition was determined in castrated Pten(i)pe-/- mice by histological analyses.
Results
To gain insights on pathways driving androgen-independence in prostate tumor, we analyzed Pten(i)pe-/- mice which develop tumors that are resistant to castration. Droplet based single cell-RNA sequencing of 17265 cells from dissociated tumors of castrated and sham-operated Pten(i)pe-/- mice revealed that androgen deprivation enhances hypoxia signaling in luminal cells. Importantly, this is accompanied by the emergence of an immune-cell-related gene signature in luminal cells of castrated mice, indicating that activation of hypoxic signaling and induction of cellular plasticity are involved in castration resistance. Importantly, genetic ablation of Hif1a in prostatic tumors sensitizes them to castration, and pharmacological inhibition of Hif1a together with androgen deprivation leads to durable anti-tumoral response.
Conclusions
Androgen deprivation in combination with HIF1 signaling inhibition is a promising therapeutic strategy for overcoming castration resistance in PTEN-deficient prostatic tumors.
Legal entity responsible for the study
Daniel Metzger.
Funding
Centre National de la Recherche Scientifique (CNRS) Institut National de la Santé et de la Recherche Médicale (INSERM) Université de Strasbourg Fondation pour la Recherche Médicale grant EQU201903007800 ITMO Cancer within the funds of the Cancer Plan 2014-2019 (administrated by INSERM) and with a collaborative support from the French national cancer Institute Agence Nationale de la Recherche grant ANR-10-LABX-0030-INRT under the frame program Investissements d’Avenir labeled ANR-10-IDEX-0002-02 Fondation ARC pour la Recherche sur le Cancer ITMO Cancer Aviesan / Inserm / Cancer 2020 through the “Formation à la Recherche Fondamentale et Translationnelle en Cancérologie” program.
Disclosure
All authors have declared no conflicts of interest.
8P - The TTYH3/MK5 positive feedback loop via GSK3-β/β-catenin signaling regulates hepatocellular carcinoma progression
- Chengzhan Zhu (Qingdao, China)
Abstract
Background
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and identification of novel targets is necessary for its diagnosis and treatment. This study aimed to investigate the biological function and clinical significance of tweety homolog 3 (TTYH3) in HCC.
Methods
The biological function of TTYH3 was investigated in vitro and in vivo through its overexpression and knockdown in HCC cell lines. The molecular mechanism by which TTYH3 regulates HCC cell invasion and metastasis was explored. The expression and clinical significance of TTYH3 was analyzed in HCC tissues. DNA methylation in
Results
TTYH3 overexpression promoted cell proliferation, migration, and invasion and inhibited HCCM3 and Hep3B cell apoptosis. TTYH3 promoted tumor formation and metastasis in vivo. TTYH3 upregulated calcium influx and intracellular chloride concentration, thereby promoting cellular migration and regulating epithelial-mesenchymal transition-related protein expression. The interaction between TTYH3 and MK5 was identified through co-immunoprecipitation assays and protein docking. TTYH3 promoted the expression of MK5, which then activated the GSK3β/β-catenin signaling pathway.
Conclusions
We identified TTYH3 regulates tumor development and progression via MK5/GSK3-β/β-catenin signaling in HCC and promotes itself expression in a positive feedback loop.
Legal entity responsible for the study
Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University.
Funding
The National Natural Science Foundation of China (grant number 81600490), the Taishan Scholars Program of Shandong Province (grant number 2019010668), the Shandong Higher Education Young Science and Technology Support Program (grant number 2020KJL005), and National Natural Science Foundation of Shandong Province (grant number ZR2021MH171).
Disclosure
All authors have declared no conflicts of interest.
9P - The role of ICAM1 in glioblastoma tumor associated macrophages under hypoxia
- Kaviya Devaraja (Toronto, Canada)
Abstract
Background
Glioblastoma (GBM) is an aggressive and fatal brain cancer in adults with ineffective existing treatment methods. Intracellular adhesion molecule 1 (ICAM1) is a cell adhesion molecule expressed by tumor associated macrophages (TAMs) in GBM. TAMs enhance tumor growth and proliferation, particularly within the characteristic hypoxic tumor microenvironment (TME) of GBM. Hypothesis: I hypothesize that the expression of ICAM1 on the surface of TAMs contributes to GBM cell invasiveness, especially in the hypoxic TME, by enhancing the interaction between tumor cells and macrophages, thereby facilitating the migration, proliferation and invasion of the tumor cells.
Methods
Assess the expression levels of ICAM1 in primary and immortalized human and mouse macrophages under hypoxic conditions (1% O2, 0.2% O2, and HIF stabilizing drug IOX4). Analyze the effect of ICAM1 deficiency, knockdown, and overexpression and hypoxic conditions on macrophage behaviour including migration, proliferation, and adhesion to tumor cells. Intracranially inject ICAM1 deficient mouse model with GBM followed by analysis of tumor growth, overall survival and the composition of the tumor microenvironment.
Results
ICAM1 is highly expressed in different cell types within the GBM microenvironment, including TAMs. The expression is particularly enhanced when primary or immortalized macrophages are treated with tumor cell-conditioned medium in vitro and is further exacerbated upon incubation of these cells in a hypoxic chamber at 1% and 0.2% oxygen levels and treatment of HIF-stabilizing drug IOX4. The migration levels and proliferation rate of macrophages is higher in wild type cells than in ICAM1 deficient cells. Macrophage migration and proliferation levels increase when co-cultured with tumor cell condition media and is further exacerbated upon incubation of these cells in hypoxic conditions. ICAM1 deficient mice succumbed to GBM more quickly than wild type mice.
Conclusions
It is evident that the hypoxic tumor microenvironment increases the expression of ICAM1 in macrophages. The expression of ICAM1 in TAMs in hypoxic TME promotes GBM cell invasiveness and migration.
Legal entity responsible for the study
Gelareh Zadeh.
Funding
CIHR.
Disclosure
The author has declared no conflicts of interest.
10P - Sodium selenite presents a great antitumor activity against pancreatic cancer by AIF activation and potentiates gemcitabine by p38 pathway: In vitro and in vivo study
- Kevin Doello (Granada, Spain)
Abstract
Background
Sodium selenite is a selective cytotoxic agent for tumor cells. This cytotoxicity is due to the depletion of reduced glutathione and thioredoxin, leaving the cell defenseless against oxidative stress. Pancreatic cancer is the ninth most frequent and the fourth deadliest. It has a low response to treatment (chemotherapy), which makes it necessary to develop new therapeutic strategies. The objective of this study is to demonstrate in vitro and in vivo antitumor ability of sodium selenite against pancreatic cancer.
Methods
Pancreatic adenocarcinoma cell lines PANC-1 (human) and Pan02 (murine) were exposed to selenite and selenite + gemcitabine (GMZ) both in monolayer culture and after the generation of multicellular spheroids (MTS). In vivo studies were performed by generating tumors in C57BL mice after subcutaneous inoculation of the Pan02 line. In addition, immunofluorescence, Western-Blot and mitochondrial membrane potential studies were performed to elucidate the molecular mechanisms by which sodium selenite acts. Finally, the effect of treatment on cancer stem cells (CSCs) derived from tumor lines was assessed.
Results
The results showed an IC50 of 5.6 μM and 4.6 μM in PANC-1 and Pan02 lines, respectively, and a synergistic effect when associated with GMZ. The antitumor effect of sodium selenite involved apoptosis-inducing factor (AIF) in monotherapy and phospho-p38 expression in combination with GMZ. In addition, sodium selenite alone and in association with GMZ significantly decreased migration and colony forming ability, reduced tumor viability in multicellular tumor spheroids (MTS) and decreased CSCs sphere formation. In vivo studies showed that the combined therapy inhibits tumor growth (65%) compared to the untreated group and also compared to sodium selenite or GMZ used as monotherapy (up to 40%), increasing mice survival. These results were supported by analysis of C57BL/6 albino mice bearing a Pan02-generated tumor using the IVIS system.
Conclusions
In conclusion, sodium selenite is a potential agent for the treatment of pancreatic cancer and could be considered for future clinical trials in humans.
Legal entity responsible for the study
UGR.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
11P - WU-NK-101: An enhanced NK cell therapy optimized for function in the tumor microenvironment (TME)
- Sergio Rutella (Nottingham, United Kingdom)
Abstract
Background
The efficacy of adoptive cell therapies against solid tumors has been limited by the immune-suppressive TME, which aids immune escape. WU-NK-101, manufactured using the MONETATM platform, is an NK product derived from healthy donor NK cells that addresses challenges of adoptive cell therapy in the setting of an adverse TME.
Methods
Cell phenotypes were evaluated by mass cytometry. Cytotoxicity was assessed
Results
WU-NK-101 has a unique phenotype
Conclusions
WU-NK-101 has potent cytotoxicity against tumor cells and enhanced/adaptive metabolic fitness contributing to resilience toward the immunosuppressive TME, relative to cNK cells. mAb addition further enhances anti-tumor activity by improved NK trafficking and tumor penetration, taking advantage of these enhanced metabolic features of WU-NK-101. These data suggest that WU-NK-101 may overcome the limitations of adoptive cellular therapy and supports clinical development in the setting of solid tumor.
Legal entity responsible for the study
The authors.
Funding
Wugen, Inc.
Disclosure
S. Rutella: Financial Interests, Institutional, Research Grant: Wugen. J. Muth A. Carter: Non-Financial Interests, Institutional, Full or part-time Employment: Wugen, Inc. M.E. Mathyer, B.R. Tumala K. Magee: Non-Financial Interests, Institutional, Full or part-time Employment: Wugen. J. Baughman: Financial Interests, Personal, Other, Clinical Research Consultant: Wugen; Financial Interests, Personal, Stocks/Shares: MacroGenics, Inc. M. Kiebish: Financial Interests, Institutional, Full or part-time Employment: BERG LLC; Financial Interests, Institutional, Stocks/Shares: BERG LLC. M.L. Cooper: Financial Interests, Personal, Ownership Interest: Wugen; Financial Interests, Personal, Full or part-time Employment: Wugen; Financial Interests, Personal, Royalties: Washington University. M. Berrien-Elliott: Financial Interests, Personal, Ownership Interest, Equity: Wugen; Financial Interests, Personal, Royalties, Possible Royalties Based on Inventorship: Wugen; Financial Interests, Personal, Other, Consulting: Wugen; Financial Interests, Institutional, Licensing Fees, Licensing Fees and Possible Royalties: Wugen; Financial Interests, Institutional, Other, John Dipersio also has equity interest: Wugen. T.A. Fehniger: Financial Interests, Personal, Ownership Interest, Equity: Wugen; Financial Interests, Personal, Other, Possible Royalties Based on Patents by Washington University: Wugen; Financial Interests, Personal, Advisory Board, Consulting: Wugen, Takeda; Financial Interests, Institutional, Funding, SRA and Partial Clinical Trial Funding: Wugen; Financial Interests, Institutional, Other, John DiPersio also has Ownership interest, possible royalties: Wugen; Financial Interests, Personal, Ownership Interest, SAB: OrcaBio, Indapta; Financial Interests, Institutional, Funding, SRA: Affimed, HCW Biologics; Financial Interests, Institutional, Funding, Clinical trial funding: ImmunityBio; Financial Interests, Personal, Advisory Board, SAB: Affimed. J.K. Davidson-Moncada: Financial Interests, Personal and Institutional, Stocks/Shares: Wugen. All other authors have declared no conflicts of interest.
12P - In vitro and in vivo investigations of anlotinib in bladder cancer treatment
- Zeji Meng (Xi'an, China)
Abstract
Background
Anlotinib is a potent oral, multi-target tyrosine kinase inhibitor with a favorable safety which mainly targets vascular endothelial growth factor receptor (VEGFR), FGFR, platelet-derived growth factor receptors, and c-kit. This study aims to investigate the role of anlotinib in bladder cancer compared with FGFR3 inhibitor erdafitinib in vitro and in vivo.
Methods
MTT, colony formation, and Transwell assays were performed on bladder cancer cells (SW780 and UMUC14) to confirm the effects of anlotinib and erdafitinib on proliferation, migration and invasion. Apoptotic effect was evaluated by Annexin V/propidium iodide double staining, and the levels of the protein and mRNA were examined by RNA-seq, Western blotting and RT-qPCR. Finally, mice with palpable xenografts were treated either with anlotinib and erdafitinib for 8 days before they were sacrificed for measuring the sizes and weights of the tumors.
Results
To assess the roles of anlotinib in bladder cancer, we treated SW780 cell line which had FGFR3-BALAP2L1 fusion mutation and UMUC-14 cell line which had a FGFR3 (MuS247C) mutation with DMSO, anlotinib and erdafitinib. As seen in MTT, colony formation and Transwell assays, anlotinib repressed cell proliferation, migration and invasion as erdafitinib. Compared with vehicle, Anlotinib promoted cell apoptosis of bladder cancer cells. To further explore the mechanism, anlotinib and erdafitinib suppressed p-Erk1/2 and p-AKT, while only anlotinib inhibited the expression of VEGF-a. Compared with erdafitinib, the inhibitory ability of anlotinib was weaker than that of erdafitinib in cell line with FGFR3 (MuS247C) mutation, on the contrary, it was much stronger in cell line with FGFR3-BALAP2L1 fusion mutation. In addition, the
Conclusions
Anlotinib could repress the proliferation, migration and invasion of bladder cancer cells by inhibiting the phosphorylation of Erk1/2 and AKT, and the suppression VEGF-a expression, whose effects was better than erdafitinib in bladder cancer with FGFR3 fusion mutation. Therefore, anlotinib might be a potential novel targeted agent to treat the bladder cancer patients with FGFR3 fusion mutations.
Clinical trial identification
ALTER-UC-002.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
13P - Berberine associated to SGLT2i dapagliflozin synergistically reduces cardiac cell apoptosis during exposure to trastuzumab through induction of pAMPK and reduction of NLRP3 inflammasome, IL-6, methylglyoxal and leukotrienes-B4 levels
- Annamaria Bonelli (Napoli, Italy)
Abstract
Background
Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer, but it can induce left ventricular dysfunction with reduced ejection fraction or HF during treatment. Dapagliflozin is a SGLT2i with cardio-renal benefits. In the DAPA-HF trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin decreased the risk of worsening HF events and cardiovascular death in patients with HF and reduced ejection fraction. Berberine,a nutraceutical, significantly reduces myocardial infarct size and the incidence of ventricular arrhythmia, improves cardiac function, ameliorates myocardial apoptosis.
Methods
Human fetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration of trastuzumab (200 nM) alone or co-incubated with Berberine (200 mM) or Dapagliflozin (50 nM) or both in combination for 48 h. After the incubation period, we performed the following tests: cell viability, apoptosis, expression of NLRP3, methylglyoxal and leukotrienes-B4. Expression of pAMPK and IL-6 were performed through western blot.
Results
Berberine and Dapagliflozin increased significantly the cell viability of cardiomyocytes exposed to Trastuzumab. When combined, Berberine and Dapagliflozin increased synergistically cell viability of cardiac cells (p<0.001 vs Trastuzumab). Cell apoptosis was reduced of 32.5, 41.8 and 72.7% for berberine, dapagliflozin and both combined (vs trastuzumab group). Methylglyoxal was strongly reduced compared to untreated cells. Western blot analysis clearly demonstrate that pAMPK was induced by berberine and Dapagliflozin. No significant changes in Leukotriene B4 expression were seen. IL-6 levels were reduced of 46.3, 62.7 and 86.3% for berberine, dapagliflozin and both combined (vs trastuzumab group).
Conclusions
Berberine and Dapagliflozin exerts significant cardioprotective effects in cardiac cells exposed to the HER2-bloking agent Trastuzumab. Berberine and Dapagliflozin in combination induces an anti-inflammatory phenotype to myocardial cells through the reduction of biomarkers involved in heart failure and apoptosis.
Legal entity responsible for the study
The authors.
Funding
Ricerca Corrente Project, Ministero della Salute.
Disclosure
All authors have declared no conflicts of interest.
14P - Sacubitril-valsartan increases pAMPK and reduces NLRP3, MyD88, interleukin-6 and galectin-3 in short-term doxorubicin-treated mice improving longitudinal strain and ejection fraction
- Antonietta Caronna (Napoli, Italy)
Abstract
Background
Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril-valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction. We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function.
Methods
Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), LCZ-696 at 60 mg/kg (LCZ, n=6) or doxorubicin combined to LCZ-696 (DOXO-LCZ, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100), pAMPK, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified through ELISA and western blot methods.
Results
LCZ 696 improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88, DAMPs and NF-kB in cardiac tissues was seen in DOXO-LCZ group compared to DOXO mice (p<0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with LCZ-696 indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in LCZ-696-DOXO compared to DOXO group. Levels of Calgranulin S100 and galectine-3 were strongly enhanced in DOXO group; on the other hand their expression were reduced by 47.7 and 52.3% in LCZ-696-DOXO group vs DOXO (p<0.005).
Conclusions
In this preclinical study, LCZ-696 is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis. The overall picture of the study pushes the use of Sacubitril-valsartan in prevention of cardiomyopathies induced by anthracyclines in cancer patients.
Legal entity responsible for the study
The authors.
Funding
Ricerca Corrente, Ministero della Salute.
Disclosure
All authors have declared no conflicts of interest.