Publications by authors named "Stefano Indraccolo"

119 Publications

Role of next generation sequencing-based liquid biopsy in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: impact of STK11, KRAS and TP53 mutations and co-mutations on outcome.

Transl Lung Cancer Res 2021 Jan;10(1):202-220

Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.

Background: Characterization of tumor-related genetic alterations is promising for the screening of new predictive markers in non-small cell lung cancer (NSCLC). Aim of the study was to evaluate prognostic and predictive role of most frequent tumor-associated genetic alterations detected in plasma before starting immune checkpoint inhibitors (ICIs).

Methods: Between January 2017 and October 2019, advanced NSCLC patients were prospectively screened with plasma next-generation sequencing (NGS) while included in two trials: VISION (NCT02864992), using Guardant360 test, and MAGIC (Monitoring Advanced NSCLC through plasma Genotyping during Immunotherapy: Clinical feasibility and application), using Myriapod NGS-IL 56G Assay. A control group of patients not receiving ICIs was analyzed.

Results: A total of 103 patients receiving ICIs were analyzed: median overall survival (OS) was 20.8 (95% CI: 16.7-24.9) months and median immune-related progression free disease (irPFS) 4.2 (95% CI: 2.3-6.1) months. TP53 mutations in plasma negatively affected OS both in patients treated with ICIs and in control group (P=0.001 and P=0.009), indicating a prognostic role. STK11 mutated patients (n=9) showed a trend for worse OS only if treated with ICIs. The presence of KRAS/STK11 co-mutation and KRAS/STK11/TP53 co-mutation affected OS only in patients treated with ICIs (HR =10.936, 95% CI: 2.337-51.164, P=0.002; HR =17.609, 95% CI: 3.777-82.089, P<0.001, respectively), indicating a predictive role.

Conclusions: Plasma genotyping demonstrated prognostic value of TP53 mutations and predictive value of KRAS/STK11 and KRAS/STK11/TP53 co-mutations.
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http://dx.doi.org/10.21037/tlcr-20-674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867770PMC
January 2021

Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts.

Cells 2021 Feb 5;10(2). Epub 2021 Feb 5.

Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy.

Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of PDK1 silencing on growth, angiogenesis and metabolic features of tumor xenografts formed by highly glycolytic OC316 and OVCAR3 ovarian cancer cells. Notably, at variance with the moderate antiproliferative effects observed in vitro, we found a dramatic negative impact of PDK1 silencing on tumor growth. These findings were associated with reduced angiogenesis and increased necrosis in the OC316 and OVCAR3 tumor models, respectively. Analysis of viable tumor areas uncovered increased proliferation as well as increased apoptosis in PDK1-silenced OVCAR3 tumors. Moreover, RNA profiling disclosed increased glucose catabolic pathways-comprising both oxidative phosphorylation and glycolysis-in PDK1-silenced OVCAR3 tumors, in line with the high mitotic activity detected in the viable rim of these tumors. Altogether, our findings add new evidence in support of a link between tumor metabolism and angiogenesis and remark on the importance of investigating net effects of modulations of metabolic pathways in the context of the tumor microenvironment.
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http://dx.doi.org/10.3390/cells10020325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915933PMC
February 2021

Detection of Low-Frequency Mutations in cfDNA From -Mutated NSCLC Patients After First-Line EGFR Tyrosine Kinase Inhibitors.

Front Oncol 2020 15;10:607840. Epub 2021 Jan 15.

Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.

Background: Molecular profiling of advanced mutated NSCLC has recently demonstrated the co-existence of multiple genetic alterations. Specifically, co-existing -mutations in NSCLCs have been described, despite their prevalence at progression and their role in the response to tyrosine kinase inhibitors (TKIs) remain marginally explored. Aim of our study was to investigate the prevalence of co-existing mutations at the time of progressive disease and explore their impact on clinical outcome.

Materials And Methods: We retrospectively analyzed by digital droplet PCR prevalence of co-mutations in 106 plasma samples of mutated NSCLC patients, in progressive disease after TKI treatment as first-line therapy.

Results: co-mutations (codon 12 and 13) were identified in 3 patients (2.8% of analyzed samples), with low allelic frequency (<0.2%), and had a negative impact on clinical outcome to first-line TKI.

Conclusion: Detection of mutations in cell-free DNA of mutant NSCLC patients at progression after first or second generation TKI is a rare event. Due to their low abundance, the negative impact of mutations on the response to TKI remains to be confirmed in larger studies.
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http://dx.doi.org/10.3389/fonc.2020.607840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844327PMC
January 2021

Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia.

Theranostics 2021 1;11(4):1594-1608. Epub 2021 Jan 1.

Institut de Recherche en Cancérologie de Montpellier (IRCM), Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, 34298, Cedex 5, France.

The Notch pathway is highly active in almost all patients with T-cell acute lymphoblastic leukemia (T-ALL), but the implication of Notch ligands in T-ALL remains underexplored. We used a genetic mouse model of Notch ligand delta like 4 (DLL4)-driven T-ALL and performed thymectomies and splenectomies in those animals. We also used several patient-derived T-ALL (PDTALL) models, including one with DLL4 expression on the membrane and we treated PDTALL cells and with demcizumab, a blocking antibody against human DLL4 currently being tested in clinical trials in patients with solid cancer. We show that surgical removal of the spleen abrogated T-ALL development in our preclinical DLL4-driven T-ALL mouse model. Mechanistically, we found that the spleen, and not the thymus, promoted the accumulation of circulating CD4CD8 T cells before T-ALL onset, suggesting that DLL4-driven T-ALL derives from these cells. Then, we identified a small subset of T-ALL patients showing higher levels of DLL4 expression. Moreover, in mice xenografted with a DLL4-positive PDTALL model, treatment with demcizumab had the same therapeutic effect as global Notch pathway inhibition using the potent γ-secretase inhibitor dibenzazepine. This result demonstrates that, in this PDTALL model, Notch pathway activity depends on DLL4 signaling, thus validating our preclinical mouse model. DLL4 expression in human leukemic cells can be a source of Notch activity in T-ALL, and the spleen plays a major role in a genetic mouse model of DLL4-driven T-ALL.
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http://dx.doi.org/10.7150/thno.48067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778594PMC
January 2021

Genetic perturbation of IFN-α transcriptional modulators in human endothelial cells uncovers pivotal regulators of angiogenesis.

Comput Struct Biotechnol J 2020 2;18:3977-3986. Epub 2020 Dec 2.

Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, via Gattamelata 64, 35128 Padova, Italy.

Interferon-α (IFN-α) comprises a family of 13 cytokines involved in the modulation of antiviral, immune, and anticancer responses by orchestrating a complex transcriptional network. The activation of IFN-α signaling pathway in endothelial cells results in decreased proliferation and migration, ultimately leading to suppression of angiogenesis. In this study, we knocked-down the expression of seven established or candidate modulators of IFN-α response in endothelial cells to reconstruct a gene regulatory network and to investigate the antiangiogenic activity of IFN-α. This genetic perturbation approach, along with the analysis of interferon-induced gene expression dynamics, highlighted a complex and highly interconnected network, in which the angiostatic chemokine C-X-C Motif Chemokine Ligand 10 (CXCL10) was a central node targeted by multiple modulators. IFN-α-induced secretion of CXCL10 protein by endothelial cells was blunted by the silencing of Signal Transducer and Activator of Transcription 1 (STAT1) and of Interferon Regulatory Factor 1 (IRF1) and it was exacerbated by the silencing of Ubiquitin Specific Peptidase 18 (USP18). sprouting assay, which mimics angiogenesis, confirmed STAT1 as a positive modulator and USP18 as a negative modulator of IFN-α-mediated sprouting suppression. Our data reveal an unprecedented physiological regulation of angiogenesis in endothelial cells through a tonic IFN-α signaling, whose enhancement could represent a viable strategy to suppress tumor neoangiogenesis.
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http://dx.doi.org/10.1016/j.csbj.2020.11.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734228PMC
December 2020

Filling the Gap Between Risk Assessment and Molecular Determinants of Tumor Onset.

Carcinogenesis 2020 Dec 15. Epub 2020 Dec 15.

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Via Giustiniani.

In the past two decades, a ponderous epidemiological literature has causally linked tumor onset to environmental exposure to carcinogens. As consequence, risk assessment studies have been carried out with the aim to identify both predictive models of estimating cancer risks within exposed populations and establishing rules for minimizing hazard when handling carcinogenic compounds. The central assumption of these works is that neoplastic transformation is directly related to the mutational burden of the cell without providing further mechanistic clues to explain increased cancer onset after carcinogen exposure. Nevertheless, in the last few years, a growing number of studies have implemented the traditional models of cancer aetiology, proposing that neoplastic transformation is a complex process in which several parameters and crosstalk between tumor and microenvironmental cells must be taken into account and integrated with mutagenesis. In this conceptual framework, the current strategies of risk assessment that are solely based on the "mutator model" require an urgent update and revision to keep pace with advances in our understanding of cancer biology. We will approach this topic revising the most recent theories on the biological mechanisms involved in tumor formation in order to envision a roadmap leading to a future regulatory framework for a new, protective policy of risk assessment.
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http://dx.doi.org/10.1093/carcin/bgaa135DOI Listing
December 2020

A Multi-Center, Real-Life Experience on Liquid Biopsy Practice for EGFR Testing in Non-Small Cell Lung Cancer (NSCLC) Patients.

Diagnostics (Basel) 2020 09 28;10(10). Epub 2020 Sep 28.

SOC Anatomia Patologica, Azienda Sanitaria UniversitariaFriuli Centrale, 33100 Udine, Italy.

Background: circulating tumor DNA (ctDNA) is a source of tumor genetic material for EGFR testing in NSCLC. Real-word data about liquid biopsy (LB) clinical practice are lacking. The aim of the study was to describe the LB practice for EGFR detection in North Eastern Italy.

Methods: we conducted a multi-regional survey on ctDNA testing practices in lung cancer patients.

Results: Median time from blood collection to plasma separation was 50 min (20-120 min), median time from plasma extraction to ctDNA analysis was 24 h (30 min-5 days) and median turnaround time was 24 h (6 h-5 days). Four hundred and seventy five patients and 654 samples were tested. One hundred and ninety-two patients were tested at diagnosis, with 16% EGFR mutation rate. Among the 283 patients tested at disease progression, 35% were T790M+. Main differences in LB results between 2017 and 2018 were the number of LBs performed for each patient at disease progression (2.88 vs. 1.2, respectively) and the percentage of T790M+ patients (61% vs. 26%).
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http://dx.doi.org/10.3390/diagnostics10100765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601690PMC
September 2020

Metabolic Profiling of Ovarian Cancer Tumor Xenografts: A Digital Pathology Approach.

Front Oncol 2020 19;10:1277. Epub 2020 Aug 19.

Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto, IOV-IRCCS, Padua, Italy.

Metabolic profiling of cancer is a rising interest in the field of biomarker development. One bottleneck of its clinical exploitation, however, is the lack of simple and quantitative techniques that enable to capture the key metabolic traits of tumor from archival samples. In fact, liquid chromatography associated with mass spectrometry is the gold-standard technique for the study of tumor metabolism because it has high levels of accuracy and precision. However, it requires freshly frozen samples, which are difficult to collect in large multi-centric clinical studies. For this reason, we propose here to investigate a set of established metabolism-associated protein markers by exploiting immunohistochemistry coupled with digital pathology. As case study, we quantified expression of MCT1, MCT4, GLS, PHGDH, FAS, and ACC in 17 patient-derived ovarian cancer xenografts and correlated it with survival. Among these markers, the glycolysis-associated marker MCT4 was negatively associated with survival of mice. The algorithm enabling a quantitative analysis of these metabolism-associated markers is an innovative research tool that can be exported to large sets of clinical samples and can remove the variability of individual interpretation of immunohistochemistry results.
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http://dx.doi.org/10.3389/fonc.2020.01277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466758PMC
August 2020

Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study.

Cancers (Basel) 2020 Aug 14;12(8). Epub 2020 Aug 14.

Department of Oncology, Oncology 1, Veneto Institute of oncology-IRCCS, 35128 Padua, Italy.

Introduction: Pembrolizumab demonstrated promising results in hypermutated tumors of diverse origin. Immunohistochemical loss of mismatch repair (MMR) proteins has been suggested as a surrogate of hypermutation in high-grade gliomas (HGG). We evaluated the efficacy and safety of pembrolizumab in relapsing HGGs with immunohistochemical loss of at least 1 MMR protein. Molecular biomarkers of pembrolizumab activity were also analyzed.

Methods: Consecutive patients with recurrent HGG and partial or complete loss of MMR protein expression were prospectively enrolled; they received pembrolizumab 200 mg once every 3 weeks until disease progression. The primary endpoint was disease control rate (DCR). Post hoc exploratory analyses included next-generation sequencing to assess tumor mutational burden (TMB), and immunostaining for CD8+ T-cells and CD68+ macrophages.

Results: Among 310 HGG patients screened, 13 cases with MMR loss were enrolled: eight glioblastoma, four anaplastic astrocytoma, and one anaplastic oligodendroglioma. Median age was 43 years. DCR was 31%: four patients had stable disease and no patient had complete or partial response. TMB ranged between 6.8 and 23.4 mutations/megabase. Neither TMB nor gene mutations, nor CD8+ T-cell and CD68+ macrophage content, were associated with pembrolizumab activity.

Conclusions: pembrolizumab showed no apparent benefit in these patients. No molecular biomarker was found to be associated with pembrolizumab activity.
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http://dx.doi.org/10.3390/cancers12082283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464918PMC
August 2020

A molecular signature associated with prolonged survival in glioblastoma patients treated with regorafenib.

Neuro Oncol 2021 Feb;23(2):264-276

Department of Neurosciences, Biomedicine, and Movement, University of Verona, Verona, Italy.

Background: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival (OS) benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug.

Methods: Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and micro (mi)RNA profiles were associated with patients' OS and progression-free survival.

Results: In the first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. In the second step, a mini-signature of 2 gene transcripts (HIF1A, CDKN1A) and 3 miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range, 10.6-20.8 mo).

Conclusions: The study provides evidence that a signature based on the expression of 5 biomarkers could help identify a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Although the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guide the clinical decision among regorafenib and other treatments in patients with relapsing GBM.
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http://dx.doi.org/10.1093/neuonc/noaa156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906066PMC
February 2021

Metabolism in the Tumor Microenvironment.

Adv Exp Med Biol 2020 ;1263:1-11

Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy.

From a general perspective, in the context of solid tumors, we can distinguish metabolic alterations of cancer cells from those of the stroma. These two components interact with each other and with the extracellular matrix (ECM), and these interactions can take the form of either metabolic competition or metabolic symbiosis. The aim of this chapter is to overview the canonical metabolic alterations of tumor and stroma cells and to present specific examples of metabolic competition and symbiosis. We will also discuss the complexity and plasticity of metabolism, which pose indeed a serious threat to our ability to target selective metabolic features of tumor microenvironment with drugs. Finally, we will highlight some limitations of state-of-the-art techniques used to study tumor metabolism and propose some innovative solutions to investigate the clinical relevance of metabolic alterations for patient management and treatment.
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http://dx.doi.org/10.1007/978-3-030-44518-8_1DOI Listing
July 2020

Phosphorylated Acetyl-CoA Carboxylase Is Associated with Clinical Benefit with Regorafenib in Relapsed Glioblastoma: REGOMA Trial Biomarker Analysis.

Clin Cancer Res 2020 Sep 9;26(17):4478-4484. Epub 2020 Jun 9.

Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.

Purpose: Preclinical studies show that antiangiogenic therapy exacerbates tumor glycolysis and activates liver kinase B1/AMP kinase (AMPK), a pathway involved in the regulation of tumor metabolism. We investigated whether certain metabolism-related biomarkers could predict benefit to regorafenib in the phase II randomized REGOMA trial.

Patients And Methods: IHC and digital pathology analysis were used to investigate the expression in glioblastoma (GBM) sections of monocarboxylate transporter 1 and 4 (MCT1 and MCT4), associated with OXPHOS and glycolysis, respectively, phosphorylated AMPK (pAMPK), and phosphorylated acetyl-CoA carboxylase (pACC), a canonical target of AMPK activity. The status of each biomarker was associated with clinical endpoints, including overall survival (OS) and progression-free survival (PFS) in patients with relapsed GBM treated either with regorafenib or lomustine.

Results: Between November 2015 and February 2017, 119 patients were enrolled ( = 59 regorafenib and = 60 lomustine) and stratified for surgery at recurrence, and baseline characteristics were balanced. Biomarker analysis was performed in 84 patients (71%), including 42 patients of the regorafenib arm and 42 patients of the lomustine arm. Among all markers analyzed, only pACC showed predictive value in terms of OS. In fact, median OS was 9.3 months [95% confidence interval (CI), 5.6-13.2] for regorafenib and 5.5 months (95% CI, 4.2-6.6) for lomustine for pACC-positive patients, HR, 0.37 (95% CI, 0.20-0.70); log rank = 0.0013; test for interaction = 0.0453. No statistically significant difference was demonstrated for PFS according to pACC status.

Conclusions: We found that AMPK pathway activation is associated with clinical benefit from treatment with regorafenib in relapsed GBM.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4055DOI Listing
September 2020

mutations are not associated with the efficacy of first-line and second-line chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC): a post hoc analysis of the TAILOR trial.

ESMO Open 2020 05;5(3):e000748

Unit of Thoracic Oncology, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Lombardia, Italy.

Purpose: In patients with advanced lung adenocarcinoma, the impact of mutations on cytotoxic chemotherapy efficacy remains poorly explored. Here, we aimed at investigating the potential impact of mutational status on chemotherapy efficacy in advanced non-small-cell lung cancer (NSCLC) patients enrolled in the TArceva Italian Lung Optimisation tRial (TAILOR) trial.

Methods: The multicenter TAILOR trial randomised patients with -wild type (wt) advanced NSCLC progressing on/after previous platinum-based chemotherapy to receive docetaxel or erlotinib. Here, we evaluated the impact of mutational status on progression-free survival (PFS) and overall survival (OS) in patients treated with second-line docetaxel/erlotinib or during prior platinum-based chemotherapy.

Results: Out of 222 patients randomised in the TAILOR trial, left-over tumour tissues were available for 188 patients, and 120 patients with evaluable status were included. Of them, 17 (14.17%) patients had -mutated tumours, while 103 (85.83%) had wt disease. During second-line treatment, PFS and OS were not statistically significantly different in patients with mutated when compared with wt NSCLC (adjusted HR (aHR)=1.29, 95% CI 0.75 to 2.21; p=0.364 and aHR=1.41, 95% CI 0.82 to 2.44; p=0.218, respectively). Similarly, we found no significant association between mutations and patient PFS or OS during prior first-line platinum-based chemotherapy (aHR=1.04, 95% CI 0.55 to 1.97; p=0.910 and aHR=0.83, 95% CI 0.42 to 1.65; p=0.602, respectively).

Conclusion: Among advanced NSCLC patients receiving two lines of systemic therapy, mutations were not associated with PFS or OS during second-line docetaxel or prior first-line platinum-based chemotherapy. While larger prospective trials are needed to confirm our findings, cytotoxic chemotherapy remains the backbone of investigational combination strategies in this patient population.
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http://dx.doi.org/10.1136/esmoopen-2020-000748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259832PMC
May 2020

SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia.

Leukemia 2021 02 7;35(2):377-388. Epub 2020 May 7.

Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA.

Folate metabolism enables cell growth by providing one-carbon (1C) units for nucleotide biosynthesis. The 1C units are carried by tetrahydrofolate, whose production by the enzyme dihydrofolate reductase is targeted by the important anticancer drug methotrexate. 1C units come largely from serine catabolism by the enzyme serine hydroxymethyltransferase (SHMT), whose mitochondrial isoform is strongly upregulated in cancer. Here we report the SHMT inhibitor SHIN2 and demonstrate its in vivo target engagement with C-serine tracing. As methotrexate is standard treatment for T-cell acute lymphoblastic leukemia (T-ALL), we explored the utility of SHIN2 in this disease. SHIN2 increases survival in NOTCH1-driven mouse primary T-ALL in vivo. Low dose methotrexate sensitizes Molt4 human T-ALL cells to SHIN2, and cells rendered methotrexate resistant in vitro show enhanced sensitivity to SHIN2. Finally, SHIN2 and methotrexate synergize in mouse primary T-ALL and in a human patient-derived xenograft in vivo, increasing survival. Thus, SHMT inhibition offers a complementary strategy in the treatment of T-ALL.
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http://dx.doi.org/10.1038/s41375-020-0845-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647950PMC
February 2021

Early assessment of KRAS mutation in cfDNA correlates with risk of progression and death in advanced non-small-cell lung cancer.

Br J Cancer 2020 07 7;123(1):81-91. Epub 2020 May 7.

Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.

Background: Liquid biopsy has the potential to monitor biological effects of treatment. KRAS represents the most commonly mutated oncogene in Caucasian non-small-cell lung cancer (NSCLC). The aim of this study was to explore association of dynamic plasma KRAS genotyping with outcome in advanced NSCLC patients.

Methods: Advanced NSCLC patients were prospectively enrolled. Plasma samples were collected at baseline (T1), after 3 or 4 weeks, according to treatment schedule (T2) and at first radiological restaging (T3). Patients carrying KRAS mutation in tissue were analysed in plasma with droplet digital PCR. Semi-quantitative index of fractional abundance of mutated allele (MAFA) was used.

Results: KRAS-mutated cohort included 58 patients, and overall 73 treatments (N = 39 chemotherapy and N = 34 immune checkpoint inhibitors) were followed with longitudinal liquid biopsy. Sensitivity of KRAS detection in plasma at baseline was 48.3% (95% confidence interval (CI): 35.0-61.8). KRAS mutation at T2 was associated with increased probability of experiencing progressive disease as best radiological response (adjusted odds ratio: 7.3; 95% CI: 2.1-25.0, p = 0.0016). Increased MAFA (T1-T2) predicted shorter progression-free survival (adjusted hazard ratio (HR): 2.1; 95% CI: 1.2-3.8, p = 0.0142) and overall survival (adjusted HR: 3.2; 95% CI: 1.2-8.4, p = 0.0168).

Conclusions: Longitudinal analysis of plasma KRAS mutations correlated with outcome: its early assessment during treatment has great potentialities for monitoring treatment outcome in NSCLC patients.
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http://dx.doi.org/10.1038/s41416-020-0833-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341732PMC
July 2020

Evolving use of liquid biopsy in non-small-cell-lung cancer patients.

Int J Biol Markers 2020 Feb;35(1_suppl):23-25

Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.

Liquid biopsy is routinely used to detect epidermal growth factor receptor mutations in advanced or metastatic lung cancer, due to some limitations of tissue genotyping, especially at relapse. However, the existence of a non-marginal proportion of oncogene-addicted lung cancers that can benefit from target therapy is rapidly expanding clinical relevance of plasma genotyping. Apart from static assessment of mutations in circulating free DNA, the fact that liquid biopsy is minimally invasive and can be repeated several times makes it a suitable assay for the dynamic monitoring of cancer response to treatment. It is likely that quantitative mutation assessment by liquid biopsy will be increasingly included in the design of innovative clinical trials for patient stratification purposes.
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http://dx.doi.org/10.1177/1724600820905614DOI Listing
February 2020

Assessment of chromosomal rearrangements helps to differentiate multiple lung primary cancers from metastases.

Transl Lung Cancer Res 2019 Dec;8(Suppl 4):S435-S438

Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV IRCCS, Padova, Italy.

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http://dx.doi.org/10.21037/tlcr.2019.11.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987365PMC
December 2019

Comparison of the Genomic Profile of Cancer Stem Cells and Their Non-Stem Counterpart: The Case of Ovarian Cancer.

J Clin Med 2020 Jan 29;9(2). Epub 2020 Jan 29.

Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy.

The classical cancer stem cell (CSC) model places CSCs at the apex of a hierarchical scale, suggesting different genetic alterations in non-CSCs compared to CSCs, since an ill-defined number of cell generations and time intervals separate CSCs from the more differentiated cancer cells that form the bulk of the tumor. Another model, however, poses that CSCs should be considered a functional state of tumor cells, hence sharing the same genetic alterations. Here, we review the existing literature on the genetic landscape of CSCs in various tumor types and as a case study investigate the genomic complexity of DNA obtained from matched CSCs and non-CSCs from five ovarian cancer patients, using a genome-wide single-nucleotide polymorphism (SNP) microarray.
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http://dx.doi.org/10.3390/jcm9020368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073612PMC
January 2020

Detection of Loss of Heterozygosity in cfDNA of Advanced - or -Mutated Non-Small-Cell Lung Cancer Patients.

Int J Mol Sci 2019 Dec 20;21(1). Epub 2019 Dec 20.

Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Via Gattamelata 64, 35128 Padova, Italy.

Liquid biopsy is currently approved for management of epidermal growth factor receptor ()-mutated non-small-cell lung cancer (NSCLC) patients. However, one unanswered question is whether the rate of cell-free DNA (cfDNA)-negative samples is due to technical limitations rather than to tumor genetic characteristics. Using four microsatellite markers that map specific chromosomal loci often lost in lung cancer, we conducted a pilot study to investigate whether other alterations, such as loss of heterozygosity (LOH), could be detected in -negative cfDNA. We analyzed -mutated NSCLC patients ( = 24) who were positive or negative for mutations in cfDNA and compared the results with a second cohort of 24 patients bearing -mutated cancer, which served as a representative control population not exposed to targeted therapy. The results showed that in -negative post-tyrosine-kinase-inhibitor (TKI) cfDNAs, LOH frequency was significantly higher than in both pre- and post-TKI -positive cfDNAs. By contrast, no association between status in cfDNA and number of LOH events was found. In conclusion, our study indicates the feasibility of detecting LOH events in cfDNA from advanced NSCLC and suggests LOH analysis as a new candidate molecular assay to integrate mutation-specific assays.
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http://dx.doi.org/10.3390/ijms21010066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981934PMC
December 2019

Rewiring of Lipid Metabolism and Storage in Ovarian Cancer Cells after Anti-VEGF Therapy.

Cells 2019 12 9;8(12). Epub 2019 Dec 9.

Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy.

Anti-angiogenic therapy triggers metabolic alterations in experimental and human tumors, the best characterized being exacerbated glycolysis and lactate production. By using both Liquid Chromatography-Mass Spectrometry (LC-MS) and Nuclear Magnetic Resonance (NMR) analysis, we found that treatment of ovarian cancer xenografts with the anti-Vascular Endothelial Growth Factor (VEGF) neutralizing antibody bevacizumab caused marked alterations of the tumor lipidomic profile, including increased levels of triacylglycerols and reduced saturation of lipid chains. Moreover, transcriptome analysis uncovered up-regulation of pathways involved in lipid metabolism. These alterations were accompanied by increased accumulation of lipid droplets in tumors. This phenomenon was reproduced under hypoxic conditions in vitro, where it mainly depended from uptake of exogenous lipids and was counteracted by treatment with the Liver X Receptor (LXR)-agonist GW3965, which inhibited cancer cell viability selectively under reduced serum conditions. This multi-level analysis indicates alterations of lipid metabolism following anti-VEGF therapy in ovarian cancer xenografts and suggests that LXR-agonists might empower anti-tumor effects of bevacizumab.
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http://dx.doi.org/10.3390/cells8121601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953010PMC
December 2019

LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective.

Oxid Med Cell Longev 2019 31;2019:8730816. Epub 2019 Oct 31.

Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.

Inactivating mutations of the tumor suppressor gene Liver Kinase B1 () are frequently detected in non-small-cell lung cancer (NSCLC) and cervical carcinoma. Moreover, LKB1 expression is epigenetically regulated in several tumor types. LKB1 has an established function in the control of cell metabolism and oxidative stress. Clinical and preclinical studies support a role of LKB1 as a central modifier of cellular response to different stress-inducing drugs, suggesting LKB1 pathway as a highly promising therapeutic target. Loss of LKB1-AMPK signaling confers sensitivity to energy depletion and to redox homeostasis impairment and has been associated with an improved outcome in advanced NSCLC patients treated with chemotherapy. In this review, we provide an overview of the interplay between LKB1 and its downstream targets in cancer and focus on potential therapeutic strategies whose outcome could depend from LKB1.
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http://dx.doi.org/10.1155/2019/8730816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874879PMC
April 2020

Clinical Features and Progression Pattern of Acquired T790M-positive Compared With T790M-negative EGFR Mutant Non-small-cell Lung Cancer: Catching Tumor and Clinical Heterogeneity Over Time Through Liquid Biopsy.

Clin Lung Cancer 2020 01 5;21(1):1-14.e3. Epub 2019 Aug 5.

Department of Oncology 2, Istituto Oncologico Veneto - IRCCS, Padova, Italy. Electronic address:

Background: Clinical-pathologic predictors of acquired T790M epidermal growth factor receptor (EGFR) mutation in Caucasian patients with non-small-cell lung cancer (NSCLC) progressing after first-/second-generation tyrosine kinase inhibitors (TKIs) is an open field for research. Similarly, the best time point for T790M detection by liquid or tissue biopsy after disease progression is currently matter of debate.

Patients And Methods: This is an observational study at 7 Italian centers enrolling patients with EGFR-mutant NSCLC progressing after first-/second-generation EGFR TKIs, between 2014 and 2018, aiming at comparing baseline clinical-pathologic features and progression patterns in acquired T790M-positive compared with T790M-negative cases.

Results: A total of 235 patients received first-line treatment with gefitinib (N = 126; 53%), erlotinib (N = 51; 22%), or afatinib (N = 58; 25%). In 120 (51%) cases, T790M was detected in liquid biopsy, tissue biopsy, or both. Age younger than 65 years (P = .037), the presence of common mutations (P = .004), and better response to first-line TKI (P = .023) were correlated with T790M positivity. T790M detection was associated with higher number of new progressing sites (P = .04), liver progression (P = .002), and a lower frequency of lung metastases (P = .027). When serial liquid biopsies were performed (N = 15), an oligoprogressive disease was correlated with a negative test outcome, whereas systemic progression was observed at the time of T790M positivity.

Conclusion: This study on a Caucasian population showed that age, type of EGFR mutation at diagnosis, response to first-line treatment, and peculiar progression pattern are associated with T790M status. Serial liquid biopsy might be useful for treatment selection, especially when tissue rebiopsy is not feasible.
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http://dx.doi.org/10.1016/j.cllc.2019.07.009DOI Listing
January 2020

Dissecting molecular mechanisms of resistance to NOTCH1-targeted therapy in T-cell acute lymphoblastic leukemia xenografts.

Haematologica 2020 05 29;105(5):1317-1328. Epub 2019 Aug 29.

Istituto Oncologico Veneto IOV - IRCCS, Padova

Despite substantial progress in treatment of T-cell acute lymphoblastic leukemia (T-ALL), mortality remains relatively high, mainly due to primary or acquired resistance to chemotherapy. Further improvements in survival demand better understanding of T-ALL biology and development of new therapeutic strategies. The Notch pathway has been involved in the pathogenesis of this disease and various therapeutic strategies are currently under development, including selective targeting of NOTCH receptors by inhibitory antibodies. We previously demonstrated that the NOTCH1-specific neutralizing antibody OMP52M51 prolongs survival in TALL patient-derived xenografts bearing mutations. However, acquired resistance to OMP52M51 eventually developed and we used patient-derived xenografts models to investigate this phenomenon. Multi-level molecular characterization of T-ALL cells resistant to NOTCH1 blockade and serial transplantation experiments uncovered heterogeneous types of resistance, not previously reported with other Notch inhibitors. In one model, resistance appeared after 156 days of treatment, it was stable and associated with loss of Notch inhibition, reduced mutational load and acquired mutations potentially affecting the stability of the heterodimerization domain. Conversely, in another model resistance developed after only 43 days of treatment despite persistent down-regulation of Notch signaling and it was accompanied by modulation of lipid metabolism and reduced surface expression of NOTCH1. Our findings shed light on heterogeneous mechanisms adopted by the tumor to evade NOTCH1 blockade and support clinical implementation of antibody-based target therapy for Notch-addicted tumors.
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http://dx.doi.org/10.3324/haematol.2019.217687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193477PMC
May 2020

Silencing of miR-182 is associated with modulation of tumorigenesis through apoptosis induction in an experimental model of colorectal cancer.

BMC Cancer 2019 Aug 20;19(1):821. Epub 2019 Aug 20.

Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.

Background: miR-182-5p (miR-182) is an oncogenic microRNA (miRNA) found in different tumor types and one of the most up-regulated miRNA in colorectal cancer (CRC). Although this microRNA is expressed in the early steps of tumor development, its role in driving tumorigenesis is unclear.

Methods: The effects of miR-182 silencing on transcriptomic profile were investigated using two CRC cell lines characterized by different in vivo biological behavior, the MICOL-14 cell line (dormant upon transfer into immunodeficient hosts) and its tumorigenic variant, MICOL-14. Apoptosis was studied by annexin/PI staining and cleaved Caspase-3/PARP analysis. The effect of miR-182 silencing on the tumorigenic potential was addressed in a xenogeneic model of MICOL-14 transplant.

Results: Endogenous miR-182 expression was higher in MICOL-14 than in MICOL-14 cells. Interestingly, miR-182 silencing had a strong impact on gene expression profile, and the positive regulation of apoptotic process was one of the most affected pathways. Accordingly, annexin/PI staining and caspase-3/PARP activation demonstrated that miR-182 treatment significantly increased apoptosis, with a prominent effect in MICOL-14 cells. Moreover, a significant modulation of the cell cycle profile was exerted by anti-miR-182 treatment only in MICOL-14 cells, where a significant increase in the fraction of cells in G0/G1 phases was observed. Accordingly, a significant growth reduction and a less aggressive histological aspect were observed in tumor masses generated by in vivo transfer of anti-miR-182-treated MICOL-14 cells into immunodeficient hosts.

Conclusions: Altogether, these data indicate that increased miR-182 expression may promote cell proliferation, suppress the apoptotic pathway and ultimately confer aggressive traits on CRC cells.
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http://dx.doi.org/10.1186/s12885-019-5982-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700772PMC
August 2019

Overcoming platinum-acquired resistance in ovarian cancer patient-derived xenografts.

Ther Adv Med Oncol 2019 24;11:1758835919839543. Epub 2019 Jun 24.

Department of Oncology, Laboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Background: Epithelial ovarian cancer is the most lethal gynecological cancer and the high mortality is due to the frequent presentation at advanced stage, and to primary or acquired resistance to platinum-based therapy.

Methods: We developed three new models of ovarian cancer patient-derived xenografts (ovarian PDXs) resistant to cisplatin (cDDP) after multiple drug treatments. By different and complementary approaches based on integrated metabolomics (both targeted and untargeted mass spectrometry-based techniques), gene expression, and functional assays (Seahorse technology) we analyzed and compared the tumor metabolic profile in each sensitive and their corresponding cDDP-resistant PDXs.

Results: We found that cDDP-sensitive and -resistant PDXs have a different metabolic asset. In particular, we found, through metabolomic and gene expression approaches, that glycolysis, tricarboxylic acid cycle and urea cycle pathways were deregulated in resistant sensitive PDXs. In addition, we observed that oxygen consumption rate and mitochondrial respiration were higher in resistant PDXs than in sensitive PDXs under acute stress conditions. An increased oxidative phosphorylation in cDDP-resistant sublines led us to hypothesize that its interference could be of therapeutic value. Indeed, treatment of metformin and cDDP was able to partially reverse platinum resistance.

Conclusions: Our data strongly reinforce the idea that the development of acquired cDDP resistance in ovarian cancer can bring about a rewiring of tumor metabolism, and that this might be exploited therapeutically.
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http://dx.doi.org/10.1177/1758835919839543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591669PMC
June 2019

Editorial on "The AvaALL Randomized Clinical Trial".

J Thorac Dis 2019 May;11(Suppl 9):S1237-S1240

Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.

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http://dx.doi.org/10.21037/jtd.2019.02.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560574PMC
May 2019

LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer.

Int J Mol Sci 2019 Apr 16;20(8). Epub 2019 Apr 16.

Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV- IRCCS, 35128 Padova, Italy.

Liver kinase B1 () is a tumor suppressor gene whose inactivation is frequent in different tumor types, especially in lung adenocarcinoma (about 30% of cases). LKB1 has an essential role in the control of cellular redox homeostasis by regulating ROS production and detoxification. Loss of LKB1 makes the tumor cell more sensitive to oxidative stress and consequently to stress-inducing treatments, such as chemotherapy and radiotherapy. LKB1 loss triggers complex changes in tumor microenvironment, supporting a role in the regulation of angiogenesis and suggesting a potential role in the response to anti-angiogenic treatment. On the other hand, LKB1 deficiency can promote an immunosuppressive microenvironment and may be involved in primary resistance to anti-PD-1/anti-PD-L1, as it has been reported in lung cancer. The aim of this review is to discuss interactions of LKB1 with the tumor microenvironment and the potential applications of this knowledge in predicting response to treatment in lung cancer.
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http://dx.doi.org/10.3390/ijms20081874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514929PMC
April 2019

PD-1/PD-L1 immune-checkpoint inhibitors in glioblastoma: A concise review.

Crit Rev Oncol Hematol 2019 Mar 1;135:128-134. Epub 2019 Feb 1.

Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy.

Glioblastoma is the most aggressive and most common primary brain tumor in adults, with a very poor prognosis, due to limited therapeutic efficacy of available treatments. The promising data deriving from the use of immune checkpoint inhibitors (ICI) in other cancers have prompted evaluation of its efficacy and possible use in patients with glioblastoma. In this review, we analyzed the available data about these drugs in glioblastoma. Although data are not yet mature and preliminary studies do not show a clear-cut benefit, we are far from excluding the concrete possibility of using ICI as potential treatment in patients with glioblastoma. Moreover, many molecular and immunological aspects of this approach have yet to be clarified. For this reason, it is essential to identify potential predictive biomarkers for the selection of patients who will benefit most from treatment with ICI. Additional effort is needed to better understand the mechanisms that will allow us to establish whether ICI have a place in the treatment of patients with glioblastoma.
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http://dx.doi.org/10.1016/j.critrevonc.2018.12.002DOI Listing
March 2019

Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma.

J Hepatol 2019 04 14;70(4):700-709. Epub 2018 Dec 14.

Department of Molecular Medicine, University of Padua, Padova, Italy; International Center for Digestive Health (ICDH), University of Milan-Bicocca, Milan, Italy; Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA. Electronic address:

Background & Aims: In cholangiocarcinoma, early metastatic spread via lymphatic vessels often precludes curative therapies. Cholangiocarcinoma invasiveness is fostered by an extensive stromal reaction, enriched in cancer-associated fibroblasts (CAFs) and lymphatic endothelial cells (LECs). Cholangiocarcinoma cells recruit and activate CAFs by secreting PDGF-D. Herein, we investigated the role of PDGF-D and liver myofibroblasts in promoting lymphangiogenesis in cholangiocarcinoma.

Methods: Human cholangiocarcinoma specimens were immunostained for podoplanin (LEC marker), α-SMA (CAF marker), VEGF-A, VEGF-C, and their cognate receptors (VEGFR2, VEGFR3). VEGF-A and VEGF-C secretion was evaluated in human fibroblasts obtained from primary sclerosing cholangitis explants. Using human LECs incubated with conditioned medium from PDGF-D-stimulated fibroblasts we assessed migration, 3D vascular assembly, transendothelial electric resistance and transendothelial migration of cholangiocarcinoma cells (EGI-1). We then studied the effects of selective CAF depletion induced by the BH3 mimetic navitoclax on LEC density and lymph node metastases in vivo.

Results: In cholangiocarcinoma specimens, CAFs and LECs were closely adjacent. CAFs expressed VEGF-A and VEGF-C, while LECs expressed VEGFR2 and VEGFR3. Upon PDGF-D stimulation, fibroblasts secreted increased levels of VEGF-C and VEGF-A. Fibroblasts, stimulated by PDGF-D induced LEC recruitment and 3D assembly, increased LEC monolayer permeability, and promoted transendothelial EGI-1 migration. These effects were all suppressed by the PDGFRβ inhibitor, imatinib. In the rat model of cholangiocarcinoma, navitoclax-induced CAF depletion, markedly reduced lymphatic vascularization and reduced lymph node metastases.

Conclusion: PDGF-D stimulates VEGF-C and VEGF-A production by fibroblasts, resulting in expansion of the lymphatic vasculature and tumor cell intravasation. This critical process in the early metastasis of cholangiocarcinoma may be blocked by inducing CAF apoptosis or by inhibiting the PDGF-D-induced axis.

Lay Summary: Cholangiocarcinoma is a highly malignant cancer affecting the biliary tree, which is characterized by a rich stromal reaction involving a dense population of cancer-associated fibroblasts that promote early metastatic spread. Herein, we show that cholangiocarcinoma-derived PDGF-D stimulates fibroblasts to secrete vascular growth factors. Thus, targeting fibroblasts or PDGF-D-induced signals may represent an effective tool to block tumor-associated lymphangiogenesis and reduce the invasiveness of cholangiocarcinoma.
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http://dx.doi.org/10.1016/j.jhep.2018.12.004DOI Listing
April 2019

Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial.

Lancet Oncol 2019 01 3;20(1):110-119. Epub 2018 Dec 3.

Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. Electronic address:

Background: Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma.

Methods: REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up.

Findings: Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8-18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8-12·0) in the regorafenib group and 5·6 months (4·7-7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33-0·75; log-rank p=0·0009). Grade 3-4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand-foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related.

Interpretation: REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study.

Funding: Veneto Institute of Oncology and Bayer Italy.
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http://dx.doi.org/10.1016/S1470-2045(18)30675-2DOI Listing
January 2019