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ABSTRACT: The prognosis of patients affected by metastatic renal cell carcinoma (mRCC) has improved markedly with targeted therapies. Unfortunately, 20-25% of the patients are refractory to treatment at the first response assessment and most patients will acquire drug resistance during the treatment. Moreover, current data on the clinical activity of targeted agents in poor risk or non-clear-cell mRCC patients are inconclusive because of the absence of prospective trials. Therefore, there are still several patients in need of new therapeutic approaches to improve clinical outcomes. Kidney cancer is historically considered resistant to chemotherapy on the basis that the results of phase II trials have not always been promising. We carried out a systematic review of both monochemotherapy and polychemotherapy alone or combined with immunotherapy or targeted agents in mRCC to define the state of the art and to evaluate further clinical research fields. All retrospectives, phase I/dose finding, phase II and phase III studies on chemotherapy in mRCC, published in the literature from January 2003 to November 2012, with at least 20 patients enrolled, were evaluated. Although the results of clinical trials have often been disappointing, in selected cases of mRCC, chemotherapy may have a promising antitumor activity, particularly when there are sarcomatoid differentiation features, or in highly progressive disease where the combination of doxorubicine plus gemcitabine or capecitabine has yielded interesting results. Chemotherapy may play a role in mRCC, whereas targeted agents and immunotherapy have not yielded durable and satisfactory results; further studies are needed.
Anti-cancer drugs 04/2013; · 2.23 Impact Factor
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Sara Pilotto,
Umberto Peretti,
Silvia Novello,
Giulio Rossi,
Michele Milella,
Matteo Giaj Levra,
Ludovica Ciuffreda,
Francesco Massari,
Matteo Brunelli, Giampaolo Tortora,
Emilio Bria
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ABSTRACT: Introduction: In the recent years, the growing attention to the molecular background of non-small-cell lung cancer (NSCLC) led to the identification of different molecular subtypes according to genetic abnormalities driving the disease development and progression. Whereas the addicted pathways were successfully inhibited (such as the mutant epidermal growth factor receptor), clinicians have witnessed a dramatic survival improvement. In this regard, the molecular portrait of adenocarcinoma was recently enriched by the identification of a specific patients' subgroup characterized by abnormalities in the anaplastic lymphoma kinase (ALK), with unclear prognostic features but impressive response to specific inhibitors. Areas covered: In this article, updated data derived from the development and the use of crizotinib (the most advanced in development among tyrosine kinase ALK inhibitors) in comparison with standard second-line chemotherapy for patients affected by ALK-altered NSCLC are reviewed. Expert opinion: Taking into account the available data, pretreated NSCLC patients carrying the ALK-translocation require a selected targeted therapy which significantly improves activity, efficacy and symptoms control versus chemotherapy. In this context, the identification of this disease entity and the availability of such impressive therapeutic targeting represent a further step toward the understanding of the molecular complexity behind the adenocarcinoma of the lung.
Expert Opinion on Pharmacotherapy 03/2013; · 3.20 Impact Factor
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ABSTRACT: Although the interpretation of the data reported in meta-analyses may hide several issues, it is undoubtable that this methodological approach may significantly contribute to implement the results of clinical trials, and represent a useful and practical tool for the evidence-based medicine process. Indeed, level-one recommendations should consider well-conducted meta-analyses as well as large and adequately powered randomized trials as the main contributors for the definition of guidelines for clinical practice. In addition, the role of meta-analyses for issues whereas conflicting data (and/or unpowered results) are provided, is well established. In the field of lung cancer, meta-analyses already participated to change the current standard, and are now facing the challenging issues of predictive biomarkers of prognosis and/or efficacy of targeted agents. With this aim, the meta-analytic approach helped in the recent years to implement the quantification of the magnitude of the benefit of targeted agents, and added new insights by interpreting the data coming from clinical trials by integrating them with biomarkers. The treatment-interaction analyses according to putative predictive factors of efficacy may clarify unknown issues and generate new hypotheses for future perspectives. The current review attempts to put in the context of the clinical data of targeted agents for lung cancer all the pros and cons of the meta-analytic process published to date, and critically analyze all the potential perspectives which this methodology may add for both current practice and forthcoming research.
Targeted Oncology 01/2013; · 3.61 Impact Factor
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ABSTRACT: Pancreatic cancer remains one of the most lethal and poorly understood human malignancies and will continue to be a major unsolved health problem in the 21(st) century. Despite efforts over the past three decades to improve diagnosis and treatment, the prognosis for patients with pancreatic cancer is extremely poor with or without treatment, and incidence rates are virtually identical to mortality rates. Although advances have been made through the identification of relevant molecular pathways in pancreatic cancer, there is still a critical, unmet need for the translation of these findings into effective therapeutic strategies that could reduce the intrinsic drug resistance of this disease and for the integration of these molecularly targeted agents into established combination chemotherapy and radiotherapy regimens in order to improve patients' survival. Tumors are heterogeneous cellular entities whose growth and progression depend on reciprocal interactions between genetically altered neoplastic cells and a non-neoplastic microenvironment. To date, most of the mechanisms of resistance studied have been related to tumor cell-autonomous signaling pathways. However, recent data suggest a putative important role of tumor microenvironment in the development and maintenance of resistance to classic chemotherapeutic and targeted therapies. This present review is meant to describe and discuss some of the most important advances in the comprehension of the tumor cell-autonomous and tumor microenvironment-related molecular mechanisms responsible for the resistance of pancreatic cancer to the proapoptotic activity of the classic chemotherapeutic agents and to the most novel anti-angiogenic drugs. We present some of the emerging therapeutic targets for the modulation of this resistant phenotype.
Frontiers in pharmacology. 01/2013; 4:56.
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Eleonora Brunello,
Matteo Brunelli,
Giuseppe Bogina,
Anna Caliò,
Erminia Manfrin,
Alessia Nottegar,
Marco Vergine,
Annamaria Molino,
Emilio Bria,
Francesco Massari, Giampaolo Tortora,
Sara Cingarlini,
Serena Pedron,
Marco Chilosi,
Giuseppe Zamboni,
Keith Miller,
Guido Martignoni,
Franco Bonetti
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ABSTRACT: BACKGROUND: Lobular breast carcinoma usually shows poor responsiveness to chemotherapies and often lacks targeted therapies. Since FGFR1 expression has been shown to play pivotal roles in primary breast cancer tumorigenesis, we sought to analyze the status of FGFR1 gene in a metastatic setting of lobular breast carcinoma, since promising FGFR1 inhibitors has been recently developed. METHODS: Fifteen tissue metastases from lobular breast carcinomas with matched primary infiltrative lobular breast carcinoma were recruited. Eleven cases showed loco-regional lymph-nodal and four haematogenous metastases.FGFR-1 gene (8p12) amplification was evaluated by chromogenic in situ hybridization (CISH) analysis. Her-2/neu and topoisomerase-IIalpha gene status was assessed. E-cadherin and Hercept Test were also performed. We distinguished amplification (>6 or cluster of signals) versus gains (3--6 signals) of the locus specific FGFR-1 gene. RESULTS: Three (20%) primary lobular breast carcinomas showed >6 or cluster of FGFR1 signals (amplification), six cases (40%) had a mean of three (range 3--6) chromogenic signals (gains) whereas in 6 (40%) was not observed any abnormality. Three of 15 metastasis (20%) were amplified, 2/15 (13,4%) did not. The ten remaining cases (66,6%) showed three chromogenic signals.The three cases with FGFR-1 amplification matched with those primary breast carcinomas showing FGFR-1 amplification. The six cases showing FGFR-1 gains in the primary tumour again showed FGFR-1 gains in the metastases. Four cases showed gains of FGFR-1 gene signals in the metastases and not in the primary tumours. Her-2/neu gene amplification was not observed in all cases but one (6%) case. Topoisomerase-IIalpha was not amplified in all cases. CONCLUSIONS: 1) a subset of metastatic lobular breast carcinoma harbors FGFR-1 gene amplification or gains of chromogenic signals; 2) a minor heterogeneity has been observed after matching primary and metastatic carcinomas; 3) in the era of tailored therapies, patients affected by the lobular subtype of breast carcinoma with FGFR1 amplification could be approached to the new target biological therapy such as emerging FGFR-1 inhibitors.
Journal of Experimental & Clinical Cancer Research 12/2012; 31(1):103. · 2.15 Impact Factor
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Francesca Monteleone,
Roberta Rosa,
Monica Vitale,
Chiara D'Ambrosio,
Mariangela Succoio,
Luigi Formisano,
Lucia Nappi,
Maria Fiammetta Romano,
Andrea Scaloni, Giampaolo Tortora,
Roberto Bianco,
Nicola Zambrano
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ABSTRACT: Cetuximab is a chimeric antibody approved for the treatment of metastatic colorectal cancer that selectively targets epidermal growth factor receptor (EGFR) signalling. Treatment efficacy with this drug is often impaired by acquired resistance and poor information has been accumulated on the mechanisms underlying such a phenomenon. By taking advantage of a syngenic cellular system of sensitivity and acquired resistance to anti-EGFR therapy in the colorectal carcinoma GEO cell line, we profiled protein expression differences between Cetuximab-sensitive and resistant cells. Combined 2D-DIGE and MS analyses revealed a main proteomic signature resulting from selective deregulation of various metabolic enzymes, including glucose-6-phosphate dehydrogenase, transketolase, lactate dehydrogenase B and pyruvate dehydrogenase E1, which was also confirmed by western blotting experiments. Lactate dehydrogenase B down-regulation has been already related to an increased anaerobic utilization of glucose by tumor cells; accordingly, we verified that Cetuximab-resistant cells have a significantly higher production of lactate. Resistant cells also showed decreased NADPH levels. Observed protein deregulations were not related to functional alterations of the hypoxia-inducible factor 1-associated pathways. Our data demonstrate that increased anaerobic metabolism is a prominent feature observed in the GEO syngenic model of acquired resistance to anti-EGFR therapy in colorectal cancer.
Proteomics 12/2012; · 4.43 Impact Factor
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ABSTRACT: The rapid approval of several novel agents has given prostate cancer patients and their treating physicians many new and effective therapeutic options. Four new medical therapies were recently approved on the basis of prolonged overall survival in castration-resistant prostate cancer (CRPC) patients: sipuleucel-T, cabazitaxel, abiraterone acetate and MDV3100. Additionally, there are several other promising prostate cancer agents in late-stage development, including PROSTVAC-VF, orteronel and radium-223 chloride, each with a novel mechanism of action. The treatment paradigm for these patients is rapidly evolving, with future study needed to define the optimal sequencing and potential combinations of these new agents. In this review, we discuss the recent progress in understanding the biology of this disease and examine the development of a variety of new agents with promising activity and a favorable toxicity profile, that have been investigated in the setting of hormonal, cytotoxic, immune and targeted therapy. In this new therapeutic setting of CRPC, clinicians will have an opportunity to balance benefits and harms of these new agents in an individual context.
Anti-cancer agents in medicinal chemistry 12/2012;
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ABSTRACT: With seven targeted agents, directed against the VEGF/VEGF receptor (VEGFR) axis or the mTOR pathway, approved for the treatment of metastatic renal cell carcinoma and more active agents in advanced phase of clinical testing, questions have arisen with regard to their optimal use, either in combination or in sequence. One of the most compelling (and debated) issues is whether continued VEGF/VEGFR inhibition with agents hitting the same targets (TKI-TKI) affords better results than switching mechanisms of action by alternating VEGFR and mTOR inhibition (TKI-mTOR). In this article, the authors review the (little) available evidence coming from randomized Phase III clinical trials and try to fill in the (many) remaining gaps using evidence from small-size, single-arm Phase II studies and retrospective series, as well as reviewing preclinical evidence supporting either strategy.
Expert Review of Anti-infective Therapy 12/2012; 12(12):1545-57. · 2.65 Impact Factor
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ABSTRACT: In the recent years, the improved understanding of the biological relevance of angiogenesis as a major cancer hallmark led to the development of a heterogeneous group of agents targeting this key process. Among the anti-angiogenic drugs (including monoclonal antibodies such as Bevacizumab, and other molecules with different mechanism of action, such as the vascular disrupting agents Vadimezan), the tyrosine kinase inhibitors (TKIs, Sorafenib, Sunitinib, Pazopanib, and Axitinib), are commonly thought to inhibit angiogenesis through a most rational and promising approach. In this regard, many tyrosine kinase inibitors, such as Sorafenib, are multi-targeted, which allows for the inhibition of those multiple functional pathways which are considered to be critical for both tumor development and progression. Besides, this multi-targeted activity may theoretically increase efficacy but also toxicity. As a member of this group, Sorafenib has already been approved for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma not suitable for locoregional treatment, and it is currently under investigation for advanced non small cell lung cancer (NSCLC), either alone or in combination with other biological/cytotoxic agents.
Expert Opinion on Investigational Drugs 07/2012; 21(10):1445-8. · 5.27 Impact Factor
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ABSTRACT: The epidermal growth factor receptor (EGFR) autocrine pathway plays a crucial role in human cancer, contributing to a number
of highly relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell
death, angiogenesis, and metastatic spread. For these reasons, the EGFR is one of the most studied and exploited targets for
molecular cancer therapy. Two classes of anti-EGFR agents have entered clinical practice: monoclonal antibodies and small
molecules targeting the receptor tyrosine kinase. They have shown activity alone and in combination with conventional antitumor
treatments, such as chemotherapy or radiation therapy. However, preclinical and clinical studies have demonstrated the occurrence
of spontaneous or acquired resistance to these drugs. Since EGFR is implicated in a wide array of intracellular functions,
the phenomenon of resistance to its inhibitors may result from the derangement of different molecular pathways, including
autocrine/paracrine production of ligands, receptor mutations, constitutive activation of downstream signaling proteins, and
activation of alternative pathways. This review presents the experimental evidence underlying the main mechanisms of resistance
to EGFR inhibitors.
Targeted Oncology 04/2012; 2(1):31-37. · 0.46 Impact Factor
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ABSTRACT: Pancreatic ductal adenocarcinoma (referred here as pancreatic cancer) is a lethal disease with the worst prognosis among all solid tumors. Surgical resection represents the only hope for cure but it is possible only in patients that present with local disease (about 20% of cases). Whether dismal prognosis of pancreatic cancer is a result of late diagnosis or early dissemination to distant organ is still a debate. Moreover, this disease shows an intrinsic chemotherapeutic resistance that has been mainly ascribed to the presence of a dense stromal reaction that significantly impairs drugs delivery. Clinical management of pancreatic cancer patients relies on few molecular markers (e.g., the diagnostic marker CA19-9) that, however, present several limitations to their use. The clinical usefulness of somatic alterations in well-characterized genes (such as KRAS and TP53), whose detection is technically feasible in different biological samples, has been extensively investigated leading to inconsistent results. Furthermore, none of the candidate molecular markers identified in recent years has shown an appropriate clinical performance and therefore none is routinely used. This depicts a scenario where the identification of novel and effective clinical biomarkers is mandatory. Very recent genome-wide comprehensive studies have shed light on the high degree of genetic complexity and heterogeneity of the pancreatic cancers. Although far from being introduced into the clinical settings, results from those studies are expected to change definitively the perspective through which we look at the clinical management of pancreatic cancer patients towards a personalized cancer medicine.
Current drug targets 03/2012; 13(6):744-52. · 3.93 Impact Factor
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Fotios Loupakis,
Chiara Cremolini,
Lisa Salvatore,
Marta Schirripa,
Sara Lonardi,
Vanja Vaccaro,
Federica Cuppone,
Diana Giannarelli,
Vittorina Zagonel,
Francesco Cognetti, Giampaolo Tortora,
Alfredo Falcone,
Emilio Bria
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ABSTRACT: Antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies (MoAbs) are indicated for the treatment of metastatic colorectal cancer patients, but some scientific issues concerning their efficacy are currently unsolved.
A literature-based meta-analysis was conducted. Hazard ratios (HRs) were extracted from randomized trials for progression-free survival (PFS) and overall survival (OS); the event-based risk ratio was derived for response. Sensitivity analyses to look for interactions according to KRAS status and chemotherapy association regimens were performed.
Eight trials (6609 patients) were identified. A significant interaction according to KRAS status was found for PFS (wild type vs mutant, P = .001) and response rate (wild type vs mutant, P < .0001). The addition of an anti-EGFR MoAb to first-line chemotherapy increased PFS in the KRAS wild-type population (HR, 0.91; 95% confidence interval [CI], 0.84-0.99; P = .03), and had a detrimental effect in the KRAS mutant population (HR, 1.13; 95% CI, 1.03-1.25; P = .013). A significant increase in the probability of achieving a response was evident in KRAS wild-type patients (relative risk, 1.17; 95% CI, 1.04-1.33; P = .011). In this population, the interaction in response rate according to adopted chemotherapy favored irinotecan-containing regimens (P = .01), and at meta-regression analysis the relative increase in response rate was significantly related to PFS (P = .00001) and OS (P = .00193) benefit.
The addition of an anti-EGFR MoAb to first-line chemotherapy produces a clear benefit in response rate. This advantage is restricted to KRAS wild-type patients and translates into a small benefit in PFS. At present, irinotecan-based backbone chemotherapy could be a preferable option. The correlation between activity and survival parameters corroborates the hypothesis that anti-EGFR MoAbs might be more suitable for patients needing tumoral shrinkage.
Cancer 03/2012; 118(6):1523-32. · 4.77 Impact Factor
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Matteo Brunelli,
Emilio Bria,
Alessia Nottegar,
Sara Cingarlini,
Francesca Simionato,
Anna Caliò,
Albino Eccher,
Claudia Parolini,
Antonio Iannucci,
Eliana Gilioli, [......],
Francesco Massari, Giampaolo Tortora,
Ioana Borze,
Sakari Knuutila,
Stefano Gobbo,
Antonio Santo,
Luca Tondulli,
Francesco Calabrò,
Guido Martignoni,
Marco Chilosi
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ABSTRACT: Squamous lung carcinoma lacks specific "ad hoc" therapies. Amplification of chromosome 3q is the most common genomic aberration and this region harbours genes having role as novel targets for therapeutics. There is no standard definition on how to score and report 3q amplification. False versus true 3q chromosomal amplification in squamous cell lung carcinoma may have tremendous impact on trials involving drugs which target DNA zones mapping on 3q. Forty squamous lung carcinomas were analyzed by FISH to assess chromosome 3q amplification. aCGH was performed as gold-standard to avoid false positive amplifications. Three clustered patterns of fluorescent signals were observed. Eight cases out of 40 (20%) showed ≥8 3q signals. Twenty out of 40 (50%) showed from 3 to 7 signals. The remaining showed two fluorescent signals (30%). When corrected by whole chromosome 3 signals, only cases with ≥8 signals maintained a LSI 3q/CEP3 ratio >2. Only the cases showing 3q amplification by aCGH (+3q25.3-3q27.3) showed ≥8 fluorescent signals at FISH evidencing a 3q/3 ratio >2. The remaining cases showed flat genomic portrait at aCGH on chromosome 3. We concluded that: 1) absolute copy number of 3q chromosomal region may harbour false positive interpretation of 3q amplification in squamous cell carcinoma; 2) a case results truly "amplified for chromosome 3q" when showing ≥8 fluorescent 3q signals; 3) trials involving drugs targeting loci on chromosome 3q in squamous lung carcinoma therapy have to consider false versus true 3q chromosomal amplification.
PLoS ONE 01/2012; 7(12):e49689. · 4.09 Impact Factor
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ABSTRACT: Adjuvant chemotherapy for non-small-cell lung carcinoma (NSCLC) is a debated issue in clinical oncology. Although it is considered a standard for resected stage II-IIIA patients according to the available guidelines, many questions are still open. Among them, it should be acknowledged that the treatment for stage IB disease has shown so far a limited (if sizable) efficacy, the role of modern radiotherapies requires to be evaluated in large prospective randomized trials and the relative impact of age and comorbidities should be weighted to assess the reliability of the trials' evidences in the context of the everyday-practice. In addition, a conclusive evidence of the best partner for cisplatin is currently awaited as well as a deeper investigation of the fading effect of chemotherapy over time. The limited survival benefit since first studies were published and the lack of reliable prognostic and predictive factors beyond pathological stage, strongly call for the identification of bio-molecular markers and classifiers to identify which patients should be treated and which drugs should be used. Given the disappointing results of targeted therapy in this setting have obscured the initial promising perspectives, a biomarker-selection approach may represent the basis of future trials exploring adjuvant treatment for resected NSCLC.
Journal of Experimental & Clinical Cancer Research 12/2011; 30:115. · 2.15 Impact Factor
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Roberta Rosa,
Davide Melisi,
Vincenzo Damiano,
Roberto Bianco,
Sonia Garofalo,
Teresa Gelardi,
Sudhir Agrawal,
Federica Di Nicolantonio,
Aldo Scarpa,
Alberto Bardelli, Giampaolo Tortora
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ABSTRACT: K-Ras somatic mutations are a strong predictive biomarker for resistance to epidermal growth factor receptor (EGFR) inhibitors in patients with colorectal and pancreatic cancer. We previously showed that the novel Toll-like receptor 9 (TLR9) agonist immunomodulatory oligonucleotide (IMO) has a strong in vivo activity in colorectal cancer models by interfering with EGFR-related signaling and synergizing with the anti-EGFR monoclonal antibody cetuximab.
In the present study, we investigated, both in vitro and in vivo, the antitumor effect of IMO alone or in combination with cetuximab in subcutaneous colon and orthotopic pancreatic cancer models harboring K-Ras mutations and resistance to EGFR inhibitors.
We showed that IMO was able to significantly restore the sensitivity of K-Ras mutant cancer cells to cetuximab, producing a marked inhibition of cell survival and a complete suppression of mitogen-activated protein kinase phosphorylation, when used in combination with cetuximab. IMO interfered with EGFR-dependent signaling, modulating the functional interaction between TLR9 and EGFR. In vivo, IMO plus cetuximab combination caused a potent and long-lasting cooperative antitumor activity in LS174T colorectal cancer and in orthotopic AsPC1 pancreatic cancer. The capability of IMO to restore cetuximab sensitivity was further confirmed by using K-Ras mutant colorectal cancer cell models obtained through homologous recombination technology.
We showed that IMO markedly inhibits growth of K-Ras mutant colon and pancreatic cancers in vitro and in nude mice and cooperates with cetuximab via multiple mechanisms of action. Therefore, we propose IMO plus cetuximab as a therapeutic strategy for K-Ras wild-type as well for K-Ras mutant, cetuximab-resistant colorectal and pancreatic cancers.
Clinical Cancer Research 09/2011; 17(20):6531-41. · 7.74 Impact Factor
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ABSTRACT: INTRODUCTION: Pancreatic cancer treatment remains a challenge for clinicians and researchers. Despite undisputable advances in the comprehension of the molecular mechanisms underlying cancer development and progression, early disease detection and clinical management of patients has made little, if any, progress in the past 20 years. Clinical development of targeted agents directed against validated pathways, such as the EGF/EGF receptor axis, the mutant KRAS protein, MMPs, and VEGF-mediated angiogenesis, alone or in combination with gemcitabine-based standard chemotherapy, has been disappointing. AREAS COVERED: This review explores the preclinical rationale for clinical approaches aimed at targeting the TGF-β, IGF, Hedgehog, Notch and NF-κB signaling pathways, to develop innovative therapeutic strategies for pancreatic cancer. EXPERT OPINION: Although some of the already clinically explored approaches (particularly EGFR and KRAS targeting) deserve further clinical consideration, by employing more innovative and creative clinical trial designs than the gemcitabine-targeted agent paradigm that has thus far invariably failed, the targeting of emerging and relatively unexplored signaling pathways holds great promise to increase our understanding of the complex molecular biology and to advance the clinical management of pancreatic cancer.
Expert opinion on therapeutic targets 08/2011; 15(10):1183-96. · 3.72 Impact Factor
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ABSTRACT: The combination of EGFR inhibitors and anti-angiogenic drugs has a strong pre-clinical rationale, yet its use has produced controversial clinical results. We conducted two sequential phase I trials to evaluate the feasibility and the recommended dose of erlotinib when combined with fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab. A total of 21 metastatic colorectal cancer (mCRC) patients were treated in two sequential phase I trials. In the first trial, 12 patients were treated with escalating doses of erlotinib plus FOLFOX. In the second, 9 patients were treated with escalating doses of erlotinib combined with oxaliplatin, capecitabine and bevacizumab. No MTD was reached in either of the trials. The only dose-limiting toxicities observed were neutropenia and diarrhea. No unexpected toxicities were noted. Hematological toxicity was the most frequently noted adverse event with infusional 5FU therapy, while gastrointestinal toxicity was the most common adverse event. In the second trial most patients withdrew from treatment due to toxicity, and less than half completed the therapeutic program as per protocol, mostly due to toxicity. In conclusion, the present study confirms the disappointing results of the double combination of EGFR inhibitors and anti-angiogenic drugs in mCRC patients.
Experimental and therapeutic medicine 01/2011; 2(3):449-455.
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Donata Vitagliano,
Valentina De Falco,
Anna Tamburrino,
Sabrina Coluzzi,
Giancarlo Troncone,
Gennaro Chiappetta,
Fortunato Ciardiello, Giampaolo Tortora,
James A Fagin,
Anderson J Ryan,
Francesca Carlomagno,
Massimo Santoro
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ABSTRACT: Oncogenic conversion of the RET tyrosine kinase is a frequent feature of medullary thyroid carcinoma (MTC). ZD6474 (vandetanib) is an ATP-competitive inhibitor of RET, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptors kinases. In this study, we have studied ZD6474 mechanism of action in TT and MZ-CRC-1 human MTC cell lines, carrying cysteine 634 to tryptophan (C634W) and methionine 918 to threonine (M918T) RET mutation respectively. ZD6474 blunted MTC cell proliferation and RET, Shc and p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation. Single receptor knockdown by RNA interference showed that MTC cells depended on RET for proliferation. Adoptive expression of the ZD6474-resistant V804M RET mutant rescued proliferation of TT cells under ZD6474 treatment, showing that RET is a key ZD6474 target in these MTC cells. Upon RET inhibition, adoptive stimulation of EGFR partially rescued TT cell proliferation, MAPK signaling, and expression of cell-cycle-related genes. This suggests that simultaneous inhibition of RET and EGFR by ZD6474 may overcome the risk of MTC cells to escape from RET blockade through compensatory over-activation of EGFR.
Endocrine Related Cancer 10/2010; 18(1):1-11. · 4.36 Impact Factor
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A Teresa Alberobello,
Vittoria D'Esposito,
Daniela Marasco,
Nunzianna Doti,
Menotti Ruvo,
Roberto Bianco, Giampaolo Tortora,
Iolanda Esposito,
Francesca Fiory,
Claudia Miele,
Francesco Beguinot,
Pietro Formisano
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ABSTRACT: Insulin-like growth factor-1 (IGF-1) signaling system exerts a broad antiapoptotic function and plays a crucial role in resistance to anticancer therapies. Exposure of MCF-7 breast cancer cells to IGF-1 rapidly and transiently induced tyrosine phosphorylation and activation of phosphoinositide-dependent kinase-1 (PDK1). This was paralleled by Akt/protein kinase B and protein kinase C-zeta phosphorylation, at Thr(308) and Thr(410), respectively. IGF-1 treatment also enhanced PDK1 interaction with IGF-1 receptor (IGF-1R) in intact MCF-7 cells. Pulldown assays revealed that PDK1 bound IGF-1R in vitro and that the region encompassing amino acids 51-359 of PDK1 was necessary for the interaction. Synthetic peptides corresponding to IGF-1R C terminus amino acids 1295-1337 (C43) and to PDK1 amino acids 114-141 reduced in vitro IGF-1R/PDK1 interaction in a concentration-dependent manner. Loading of fluoresceinated-C43 (fluorescein isothiocyanate (FITC)-C43) into MCF-7 cells significantly reduced IGF-1R/PDK1 interaction and phosphorylation of PDK1 substrates. Moreover, FITC-C43 intracellular loading reverted the protective effect of IGF-1 on growth factor deprivation-induced cell death. Finally, the inhibition of IGF-1R/PDK1 interaction and signaling by FITC-C43 was accompanied by 2-fold enhanced killing capacity of cetuximab in human GEO colon adenocarcinoma cells and was sufficient to restore cell death in cetuximab-resistant cell clones. Thus, disruption of PDK1 interaction with IGF-1R reduces IGF-1 survival effects in cancer cells and may enhance cell death by anticancer agents.
Journal of Biological Chemistry 02/2010; 285(9):6563-72. · 4.77 Impact Factor
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Vincenzo Damiano,
Sonia Garofalo,
Roberta Rosa,
Roberto Bianco,
Rosa Caputo,
Teresa Gelardi,
Gerardina Merola,
Luigi Racioppi,
Corrado Garbi,
Ekambar R Kandimalla,
Sudhir Agrawal, Giampaolo Tortora
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ABSTRACT: Resistance to anti-HER2 monoclonal antibody trastuzumab is a relevant issue in breast cancer patients. Among the mechanisms implicated in trastuzumab resistance, increasing evidence supports a role of tumor microenvironment. We previously found that a novel toll-like receptor 9 agonist, referred to as immune modulatory oligonucleotide (IMO) and currently under clinical investigation, acts through epidermal growth factor receptor (EGFR) and shows direct antiangiogenic effects by cooperating with anti-EGFR or anti-VEGF drugs, thus interfering with cancer cells and microenvironment.
In this study, we used KPL-4 and JIMT-1 trastuzumab-resistant breast cancer cells to evaluate the combination IMO plus trastuzumab as a therapeutic option for trastuzumab-resistant breast cancers.
IMO inhibits KPL-4 and JIMT-1 xenografts growth and potentiates trastuzumab antitumor effect, with complete suppression of tumor growth, potent enhancement of trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity, and strong inhibition of EGFR/HER2-related signaling. In KPL-4 xenografts, IMO alone interferes with HER signal transduction, whereas trastuzumab is ineffective. IMO induces an HER-dependent signal inhibition also in vitro by modulating a functional interaction between toll-like receptor 9 and HER receptors occurring at membrane level. Finally, IMO plus trastuzumab produces a cooperative antiangiogenic effect related to suppression of endothelial HER-related signaling.
We showed a cooperative effect of IMO plus trastuzumab in trastuzumab-resistant breast cancers due to IMO direct antitumor and antiangiogenic activity and antibody-dependent cell-mediated cytotoxicity enhancement. Moreover, we provided first evidence of a toll-like receptor 9/HER interaction at membrane level as novel mechanism of action. Altogether, we propose IMO plus trastuzumab as an effective strategy in trastuzumab-resistant breast cancers.
Clinical Cancer Research 11/2009; 15(22):6921-30. · 7.74 Impact Factor
