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Russo M.,University of Turin | Russo M.,Candiolo Cancer Institute FPO | Bardelli A.,University of Turin | Bardelli A.,Candiolo Cancer Institute FPO
Cold Spring Harbor Perspectives in Medicine | Year: 2017

Precision oncology relies on targeted drugs, such as kinase inhibitors, that are presently administered based on molecular profiles obtained from surgical or bioptic tissue samples. The inherent ability of human tumors to molecularly evolve in response to drug pressures represents a daunting diagnostic challenge. Circulating freeDNA(cfDNA) released from primary and metastatic lesions can be used to draw molecular maps that can be continuously updated to match each tumor’s evolution. We will present evidence that liquid biopsies can effectively interrogate how targeted therapies drive lesion-specific drug-resistance mechanisms. The impact of drug-induced molecular heterogeneity on subsequent lines of treatment will also be discussed. © 2017 Cold Spring Harbor Laboratory Press. All rights reserved.


Grignani G.,Candiolo Cancer Institute FPO | Palmerini E.,IRCCS Instituto Ortopedico Rizzoli | Ferraresi V.,Italian National Cancer Institute | D'Ambrosio L.,Candiolo Cancer Institute FPO | And 19 more authors.
The Lancet Oncology | Year: 2015

Background: Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. Methods: We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. Findings: We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Interpretation: Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater. © 2015 Elsevier Ltd.


VanSchaeybroeck S.,Queen's University of Belfast | Kalimutho M.,Queen's University of Belfast | Dunne P.,Queen's University of Belfast | Carson R.,Queen's University of Belfast | And 13 more authors.
Cell Reports | Year: 2014

There are currently no approved targeted therapies for advanced KRAS mutant (KRASMT) colorectal cancer (CRC). Using a unique systems biology approach, we identified JAK1/2-dependent activation of STAT3 as the key mediator of resistance toMEK inhibitors in KRASMT CRC invitro and invivo.Further analyses identified acute increases in c-MET activity following treatment with MEK inhibitors in KRASMT CRC models, which was demonstrated to promote JAK1/2-STAT3-mediated resistance. Furthermore, activation of c-MET following MEK inhibition was found tobe due to inhibition of the ERK-dependent metalloprotease ADAM17, which normally inhibits c-MET signaling by promoting shedding of its endogenous antagonist, soluble "decoy" MET. Most importantly, pharmacological blockade of this resistance pathway with either c-MET or JAK1/2 inhibitors synergisticallyincreased MEK-inhibitor-induced apoptosis and growth inhibition invitro and invivo in KRASMT models, providing clear rationales for the clinical assessment of these combinations in KRASMT CRC patients. © 2014 The Authors.


Xenopoulos P.,Sloan Kettering Institute | Kang M.,Sloan Kettering Institute | Kang M.,Cornell University | Puliafito A.,Candiolo Cancer Institute FPO | And 2 more authors.
Cell Reports | Year: 2015

The pluripotent epiblast (EPI) is the founder tissue of almost all somatic cells. EPI and primitive endoderm (PrE) progenitors arise from the inner cell mass (ICM) of the blastocyst-stage embryo. The EPI lineage isdistinctly identified by its expression of pluripotency-associated factors. Many of these factors have been reported to exhibit dynamic fluctuations of expression in embryonic stem cell cultures. Whether these fluctuations correlating with ICM fate choice occur invivo remains an open question. Using single-cell resolution quantitative imaging of a Nanog transcriptional reporter, we noted an irreversible commitment to EPI/PrE lineages invivo. A period of apoptosis occurred concomitantly with ICM cell-fate choice, followed by a burst of EPI-specific cell proliferation. Transitions were occasionally observed from PrE-to-EPI, but not vice versa, suggesting that they might be regulated and not stochastic. We propose that the rapid timescale of early mammalian embryonic development prevents fluctuations in cell fate. © 2015 The Authors.


Van Emburgh B.O.,Candiolo Cancer Institute FPO | Van Emburgh B.O.,FIRC Institute of Molecular Oncology IFOM | Sartore-Bianchi A.,Niguarda Cancer Center | Di Nicolantonio F.,Candiolo Cancer Institute FPO | And 4 more authors.
Molecular Oncology | Year: 2014

Cetuximab and panitumumab are anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies used as therapies for metastatic colorectal cancer patients. Intrinsic mechanisms of resistance, such as RAS mutations, can prevent patients from having a response with clinical benefit. The clinical efficacy of EGFR targeted antibodies is limited by the development of acquired (secondary) resistance, which typically occurs within 3-12 months from the start of therapy. Preclinical models and analyses of clinical samples have uncovered some of the alterations that confer a selective advantage to tumor cells when under the pressure of anti-EGFR therapy. Molecular profiling of clinical specimens confirmed that genetic alterations of genes in the EGFR-RAS-RAF-MEK signaling pathway and of receptor tyrosine kinases are mechanisms of acquired resistance to anti-EGFR antibodies. The escape from anti-EGFR blockade appears to converge on the (re)activation of MEK-ERK or AKT as revealed in preclinical studies. Circulating tumor DNA and patient derived xenografts have proven useful tools to monitor patients for resistance to anti-EGFR therapy and test combination therapies to overcome or reverse resistance. © 2014 Published by Elsevier B.V.


Misale S.,University of Turin | Misale S.,Candiolo Cancer Institute FPO | Di Nicolantonio F.,University of Turin | Di Nicolantonio F.,Candiolo Cancer Institute FPO | And 5 more authors.
Cancer Discovery | Year: 2014

The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in K RAS, N RAS, and B RAF and amplifi-cation of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment. Recently, the emergence of alterations in the same genes was detected in patients who responded to EGFR blockade and then relapsed. These results illuminate a striking overlap between genes that, when mutated, drive primary and secondary resistance to anti-EGFR antibodies. Remarkably, although the mechanisms of resistance are genetically heterogeneous, they biochemically converge on key signaling pathways. This knowledge is being translated in the rational design of additional lines of therapy.Significance: Anti-EGFR-targeted therapies are used for the treatment of metastatic colorectal cancer. Molecular heterogeneity impairs their efficacy by fuelling de novo and acquired resistance. In this review, we highlight how genetically distinct resistance mechanisms biochemically converge on a limited number of signaling pathways that can be therapeutically intercepted. © 2014 American Association for Cancer Research.


Siravegna G.,University of Turin | Siravegna G.,Candiolo Cancer Institute FPO | Bardelli A.,University of Turin | Bardelli A.,Candiolo Cancer Institute FPO | Bardelli A.,FIRC Institute of Molecular Oncology IFOM
Clinical Cancer Research | Year: 2014

A blood-based molecular test might direct recommendations for systemic therapies in patients with earlystage breast cancer undergoing surgery with curative intent. A new study suggests that droplet digital PCR (ddPCR) can be used to detect cancer-specific DNA alterations in plasma with sensitivity suitable for monitoring minimal residual disease. © 2014 American Association for Cancer Research.


Lamba S.,University of Turin | Lamba S.,Candiolo Cancer Institute FPO | Russo M.,University of Turin | Russo M.,Candiolo Cancer Institute FPO | And 12 more authors.
Cell Reports | Year: 2014

KRAS is the most frequently mutated oncogene in human cancer, yet no therapies are available to treat KRAS mutant cancers. We used two independent reverse genetic approaches to identify components of the RAS-signaling pathways required for growth of KRAS mutant tumors. Small interfering RNA (siRNA) screening of 37 KRAS mutant colorectal cancer cell lines showed that RAF1 suppression was synthetic lethal with MEK inhibition. An unbiased kinome short hairpin RNA (shRNA)-based screen confirmed this synthetic lethal interaction in colorectal as well as in lung cancer cells bearing KRAS mutations. Compounds targeting RAF kinases can reverse resistance to the MEK inhibitor selumetinib. MEK inhibition induces RAS activation and BRAF-RAF1 dimerization and sustains MEK-ERK signaling, which is responsible for intrinsic resistance to selumetinib. Prolonged dual blockade of RAF and MEK leads to persistent ERK suppression and efficiently induces apoptosis. Our data underlie the relevance of developing combinatorial regimens of drugs targeting the RAF-MEK pathway in KRAS mutant tumors. © 2014 The Authors.


Fiori A.,Candiolo Cancer Institute FPO | Mignone A.,5T S.r.l. | Rospo G.,Candiolo Cancer Institute FPO
Information Sciences | Year: 2016

Automatic Vehicle Monitoring (AVM) systems are exploited by public transport companies to manage and control their fleet of vehicles. However, these systems are usually based on the background knowledge of the transport network which can change during the time and in some cases can be missing or erroneous. GPS data and other information captured by the vehicles during their work can be exploited to update the network knowledge. This paper presents a novel approach, namely DeCoClu (Density Consensus Clustering), that aims at mining the topology of a public transport network by means of a consensus clustering density-based approach. In particular, the method exploits static information from time series of positioning signals (i.e., GPS data) to infer geographical locations of stops by means of a consensus clustering strategy based on a new distance function. Moreover, the logical pathway of a route (i.e., stops sequence) is defined by an Hamiltonian cycle. Experiments performed on real-data collections provided by a public transport company demonstrate the effectiveness of the proposed approach. © 2015 Elsevier Inc. All rights reserved.


Amplification of the MET oncogene occurs in 2–4% of gastroesophageal cancers and defines a small and aggressive subset of tumors. Although in vitro studies have given very promising results, clinical trials with MET inhibitors have been disappointing, showing few and short lasting responses. The aim of the work was to exploit a MET-amplified patient-derived xenograft model to optimize anti-MET therapeutic strategies in gastroesophageal cancer. We found that despite the high MET amplification level (26 gene copies), in the absence of qualitative or quantitative alterations of EGFR, MET inhibitors induced only tumor growth inhibition, whereas dual MET/EGFR inhibition led to complete tumor regression. Importantly, the combo treatment completely prevented the onset of resistance, which quite rapidly appeared in tumors treated with MET monotherapy. We found that this secondary resistance was due to EGFR activation and could be overcome by dual MET/EGFR inhibition. Similar results were also obtained in a MET-addicted, established gastric cancer cell line. In vitro experiments performed on tumor-derived primary cells confirmed that MET inhibitors were not able to abrogate the activation of downstream transducers and that only the combined MET/EGFR treatment completely shut off the signaling. Previously reported cases, as well as those described here, showed only partial and transient sensitivity to anti-MET therapy. The finding that combined anti-MET/EGFR therapy—even in the absence of EGFR genetic alterations—induced complete and durable response, represents a proof of concept and guarantees further investigations, opening a new perspective of treatment for these patients.Oncogene advance online publication, 15 August 2016; doi:10.1038/onc.2016.283. © 2016 Macmillan Publishers Limited, part of Springer Nature.

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