-
Erika Martinelli, Teresa Troiani,
Elena D'Aiuto,
Floriana Morgillo,
Donata Vitagliano,
Anna Capasso,
Sara Costantino,
Loreta Pia Ciuffreda,
Francesco Merolla,
Loredana Vecchione,
Veerle De Vriendt,
Sabine Tejpar,
Anna Nappi,
Vincenzo Sforza,
Giulia Martini,
Liberato Berrino,
Raffaele De Palma,
Fortunato Ciardiello
[show abstract]
[hide abstract]
ABSTRACT: The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key regulators of proliferation and survival in human cancer cells. Selective inhibitors of different transducer molecules in these pathways have been developed as molecular targeted anti-cancer therapies. The in vitro and in vivo anti-tumor activity of pimasertib, a selective MEK 1/2 inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multi-targeted kinase inhibitors (sorafenib and regorafenib), that block also BRAF and CRAF, were tested in a panel of eight human lung and colon cancer cell lines. Following pimasertib treatment, cancer cell lines were classified as pimasertib-sensitive (IC50 for cell growth inhibition of 0.001µM) or pimasertib-resistant. Evaluation of basal gene expression profiles by microarrays identified several genes that were up-regulated in pimasertib-resistant cancer cells and that were involved in both RAS/RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or regorafenib were conducted, demonstrating a synergistic effect in cell growth inhibition and induction of apoptosis with sustained blockade in MAPK- and AKT-dependent signaling pathways in pimasertib-resistant human colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the combined treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) or with sorafenib caused significant tumor growth delays and increase in mice survival as compared to single agent treatment. These results suggest that dual blockade of MAPK and PI3K pathways could overcome intrinsic resistance to MEK inhibition. © 2013 Wiley Periodicals, Inc.
International Journal of Cancer 04/2013; · 5.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Introduction: A number of anti-EGFR monoclonal antibodies (mAbs) have been recently developed for the treatment of refractory metastatic colorectal cancer (mCRC). These mAbs, blocking ligand/receptor interactions, exert their biological activity via multiple mechanisms, including inhibition of cell cycle progression, potentiation of cell apoptosis, inhibition of angiogenesis, tumor cell invasion and metastasis and, potentially, induction of immunological effector mechanisms. Areas covered: Cetuximab is an anti-EGFR mAb currently used in mCRC treatment. Despite the evidence of efficacy of cetuximab in the treatment of mCRC patients, the observation of low response rates was the proof of concept of resistance to anti-EGFR mAbs treatment. An increasing number of molecular alterations have been more recently hypothesized to be involved in resistance to anti-EGFR mAbs in CRC: mutations in BRAF, NRAS and PIK3CA, loss of expression of PTEN and, now, activation of HER2 signaling through HER2 gene amplification and/or increased heregulin stimulation. Expert opinion: This review focuses on the development of new strategies such as combination with other agents blocking alternative escape pathways, cancer cell prioritization hyperactivating EGFR pathway, combination with immune system, development of nanotech devices to increase efficacy of antibody-based therapy and overcome the mechanisms of cancer cell resistance.
Expert opinion on biological therapy 01/2013; · 3.22 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The prognosis of patients with cancer remains poor in spite of the advances obtained in recent years with new therapeutic agents, new approaches in surgical procedures and new diagnostic methods. The discovery of a plethora of cellular targets and the rational generation of selective targeting agents has opened an era of new opportunities and extraordinary challenges. The specificity of these agents renders them capable of specifically targeting the inherent abnormalities of cancer cells, potentially resulting in less toxicity than traditional nonselective cytotoxics. Among the many new types of rationally designed agents are therapeutics targeting various strategic facets of growth signal transduction, malignant angiogenesis, survival, metastasis and cell-cycle regulation. The evaluation of these agents is likely to require some changes from the traditional drug development paradigms to realize their full potential. Inhibition of the epidermal growth factor receptor and the vascular endothelial growth factor have provided proof of principle that disruption of signal cascades in patients with colorectal cancer has therapeutic potential. This experience has also taught us that resistance to such rationally developed targeted therapeutic strategies is common. In this article, we review the role of signal transduction in colorectal cancer, introduce promising molecular targets, and outline therapeutic approaches under development.
Therapeutic advances in medical oncology. 01/2013; 5(1):51-72.
-
Floriana Morgillo,
Ferdinando Carlo Sasso,
Carminia Maria Della Corte,
Donata Vitagliano,
Elena D'aiuto, Teresa Troiani,
Erika Martinelli,
Ferdinando De Vita,
Michele Orditura,
Raffaele De Palma,
Fortunato Ciardiello
Clinical Cancer Research. 01/2013;
-
[show abstract]
[hide abstract]
ABSTRACT: The lack of valid clinical management options for patients affected by metastatic colorectal cancer, which has progressed after all approved standard treatments, has lead to research into new active molecules. Regorafenib is an oral small-molecule multi kinase inhibitor, binding to several intracellular kinases, with powerful inhibitory activity against vascular endothelial growth factor receptors (VEGFR-1,VEGFR-2, and VEGFR-3), platelet-derived growth factor receptor, fibroblast growth factor receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. The antitumor activity of regorafenib has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in several cancer models, particularly colorectal cancer and gastrointestinal stromal tumors. The most frequent adverse events of grade 3 or higher related to regorafenib were hand-foot skin reaction, fatigue, diarrhea, hypertension, and rash or desquamation. Only a few Phase I-II trials, and most recently a Phase III trial in pretreated colorectal cancer, have been carried out to date. Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy. At this point in time, regorafenib is the first small-molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients.
Cancer Management and Research 01/2013; 5:49-55.
-
[show abstract]
[hide abstract]
ABSTRACT: Introduction: Targeted agents have dramatically improved and enriched the therapeutical choices for patients with metastatic colorectal cancer (mCRC). By better understanding the role of the angiogenic pathway in colorectal cancer (CRC), new therapies have been developed. Bevacizumab, the first anti-angiogenetic agent approved for the treatment of mCRC provide a proof of concept since it has improved the progression-free survival and overall survival when combined with cytotoxic chemotherapy. Areas covered: This review is focused on the most recent findings on the VEGF signaling pathway and new therapeutic drugs explored in clinical trials. Expert opinion: Despite the advantage offered by bevacizumab, the median overall survival of mCRC patient exceeds 21 months; thus, investigational efforts are needed. Several antiangiogenic agents for the treatment of mCRC are being tested in preclinical and clinical Phase I/II trials. Unfortunately a discrete number of Phase III trials produced negative results. Recently aflibercept and regorafenib, two new antiangiogenic drugs, have been approved as the new-targeted agents for the treatment of mCRC, according to the positive findings from the VELOUR and the CORRECT studies. In order to maximize clinical impact it will be important to validate predictive biomarkers and best combination treatments to offer for mCRC patients; further research and intense investigation is still required.
Expert Opinion on Emerging Drugs 12/2012; · 3.21 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: INTRODUCTION: Treatment of colorectal cancer (CRC) has changed dramatically over the past decade, mainly due to the advent of molecularly targeted agents. In particular, an improved understanding of the role of the angiogenesis pathway in CRC has led to advancements in treatment. Bevacizumab has been shown to improve the progression-free survival and overall survival when combined with cytotoxic chemotherapy in patients with metastatic CRC (mCRC) and at present is the only antiangiogenesis agent approved for the treatment of this cancer. AREAS COVERED: In this review, the authors outline the most recent data on the VEGF signaling pathway and on new therapeutic reagents that target it, provide insight into their mechanisms, and describe results from recent clinical trials. EXPERT OPINION: In the new decade of 'modern therapy', an increasing number of antiangiogenic agents for the treatment of mCRC are being tested in preclinical models, and dozens of studies on these drugs are ongoing. Presently, eight novel antiangiogenic agents are in Phase III trials and a wide range of other candidates are being tested in Phase I/II trials. Given the preliminary positive results of two recent Phase III trials, aflibercept and regorafenib, probably, will be new-targeted agents approved for the treatment of mCRC. Furthermore, the list of potentially approved agents seems to increase in the next years and to maximize their potential clinical impact, is critically important to introduce efficient molecular diagnostic methodologies into the drug development process to indentify the subset of patients who would benefit most from their use.
Expert Opinion on Investigational Drugs 05/2012; 21(7):949-59. · 5.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The epidermal growth factor receptor (EGFR) autocrine pathway plays a crucial role in human cancer since it contributes to
relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death,
angiogenesis and metastatic spread. EGFR-blocking monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors
have been developed as anticancer drugs. Although anti-EGFR agents are active in a subset of cancer patients, constitutive
resistance in a large number of patients and the development of acquired resistance in initially responding patients are a
relevant clinical issue. A major problem is that intrinsic and/or acquired resistance can occur, and it could be due to the
activation of alternative cancer cell growth controlling pathways. One mechanism linked to acquired resistance to EGFR-inhibitor
treatment, in particular, is the activation of uncontrolled, tumor-induced angiogenesis through an increase in vascular endothelial
growth factor (VEGF) secretion by cancer cells. Significant and sustained antitumor activity in this context can be obtained
by combining selective anti-EGFR drugs with antiangiogenic agents. In this review, we focus on the preclinical and clinical
evidence showing that an approach combining anti-EGFR and antiangiogenic drugs is feasible and could represent a paradigm
for a rational combined multi-targeted treatment of cancer.
Targeted Oncology 04/2012; 1(3):123-129. · 0.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The understanding of the molecular mechanisms which regulate cancer cell sensitivity to epidermal growth factor receptor (EGFR) inhibitors is necessary for the optimal use of these drugs in cancer treatment. We developed an in vitro model of acquired resistance to two EGFR tyrosine kinase inhibitors (TKI), erlotinib and gefitinib, by continuously treating the human non-small cell lung cancer (NSCLC) cell line CALU-3 with escalating doses of each drug. In these two EGFR inhibitor-resistant cancer cell lines a significant increase in the expression of activated, phosphorylated AKT and of survivin compared to parental cells was observed. Treatment with several agents known to target directly or indirectly the AKT signalling pathway did not affect significantly EGFR inhibitor-resistant cancer cell proliferation. In contrast, bortezomib, a proteasome inhibitor, induced a significant inhibition of cancer cell growth and an increase in apoptosis in EGFR inhibitor-resistant cancer cells as compared to treatment with LY294002, a PI3K inhibitor, suggesting that, in addition to interference with AKT signalling, other mechanisms are involved in the pro-apoptotic effects of bortezomib. Bortezomib treatment activated endoplasmic reticulum (ER) stress-mediated apoptosis, as demonstrated by the induction of GADD153, an ER stress-inducible transcription factor, and of the death receptor DR5, in EGFR inhibitor-resistant cells, but not in parental cells. This effect resulted in the activation of the extrinsic apoptotic pathway, as shown by caspase 8 dependent-PARP and bid cleavage. Bortezomib significantly inhibited the growth of EGFR inhibitor-resistant CALU-3 cells which were established as subcutaneous tumor xenografts in athymic nude mice. These results suggest that bortezomib treatment could be a useful approach to overcome resistance to anti-EGFR therapies.
Lung cancer (Amsterdam, Netherlands) 03/2011; 71(3):283-90. · 3.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The amplification and expression of ERBB2 have been linked with prognosis and response to therapy with the anti-HER-2-humanised
monoclonal antibody, trastuzumab, in patients with advanced metastatic breast cancer. However, one of the major clinical problems
encountered with trastuzumab treatment is that metastatic breast cancer patients, who initially responded to trastuzumab,
showed disease progression within 1 year from treatment initiation. Several studies have already reported or speculated on
potential mechanisms of resistance to trastuzumab. Despite these important leads, there is/are no biomarker(s) that can reliably
predict lack of benefit from trastuzumab, which in turn can be used for subsequent clinical trial development and/or individual
therapeutic decisions.
01/2011: pages 51-60;
-
[show abstract]
[hide abstract]
ABSTRACT: Treatment of non small cell lung cancer (NSCLC) and colorectal cancer (CRC) have substantially changed in the last years with the introduction of epidermal growth factor receptor (EGFR) inhibitors in the clinical practice. The understanding of mechanisms which regulate cells sensitivity to these drugs is necessary for their optimal use.An in vitro model of acquired resistance to two tyrosine kinase inhibitors (TKI) targeting the EGFR, erlotinib and gefitinib, and to a TKI targeting EGFR and VEGFR, vandetanib, was developed by continuously treating the human NSCLC cell line CALU-3 and the human CRC cell line HCT116 with escalating doses of each drug. MTT, western blot analysis, migration, invasion and anchorage-independent colony forming assays were conducted in vitro and experiments with established xenografts in athymic nude mice were performed in vivo in sensitive, wild type (WT) and TKI-resistant CALU-3 and HCT116 cell lines.As compared to WT CALU-3 and HCT116 human cancer cells, TKI-resistant cell lines showed a significant increase in the levels of activated, phosphorylated AKT, MAPK, and of survivin. Considering the role of RAS and RAF as downstream signals of both the EGFR and VEGFR pathways, we treated resistant cells with sorafenib, an inhibitor of C-RAF, B-RAF, c-KIT, FLT-3, RET, VEGFR-2, VEGFR-3, and PDGFR-β. Sorafenib reduced the activation of MEK and MAPK and caused an inhibition of cell proliferation, invasion, migration, anchorage-independent growth in vitro and of tumor growth in vivo of all TKI-resistant CALU-3 and HCT116 cell lines.These data suggest that resistance to EGFR inhibitors is predominantly driven by the RAS/RAF/MAPK pathway and can be overcame by treatment with sorafenib.
PLoS ONE 01/2011; 6(12):e28841. · 4.09 Impact Factor
-
Erika Martinelli, Teresa Troiani,
Floriana Morgillo,
Gabriella Rodolico,
Donata Vitagliano,
Maria Pia Morelli,
Concetta Tuccillo,
Loredana Vecchione,
Anna Capasso,
Michele Orditura,
Ferdinando De Vita,
S Gail Eckhardt,
Massimo Santoro,
Liberato Berrino,
Fortunato Ciardiello
[show abstract]
[hide abstract]
ABSTRACT: Cancer cell survival, invasion, and metastasis depend on cancer cell proliferation and on tumor-induced angiogenesis. We evaluated the efficacy of the combination of sorafenib and erlotinib or cetuximab.
Sorafenib, erlotinib, and cetuximab, alone or in combination, were tested in vitro in a panel of non-small cell lung cancer (NSCLC) and colorectal cancer cell lines and in vivo in H1299 tumor xenografts.
Epidermal growth factor receptor (EGFR) ligand mRNAs were expressed in all NSCLC and colorectal cancer cell lines with variable levels ranging from 0.4- to 8.1-fold as compared with GEO colorectal cancer cells. Lung cancer cells had the highest levels of vascular endothelial growth factors (VEGF) A, B, and C, and of VEGF receptors as compared with colorectal cancer cells. Combined treatments of sorafenib with erlotinib or cetuximab produced combination index values between 0.02 and 0.5, suggesting a significant synergistic activity to inhibit soft agar colony formation in all cancer cell lines, which was accompanied by a marked blockade in mitogen-activated protein kinase and AKT signals. The in vitro migration of H1299 cells, which expressed high levels of both VEGF ligands and receptors, was inhibited by treatment with sorafenib, and this effect was significantly increased by the combination with anti-EGFR drugs. In nude mice bearing established human H1299 xenografts, treatment with the combination of sorafenib and erlotinib or cetuximab caused a significant tumor growth delay resulting in 70 to 90 days increase in mice median overall survival as compared with single-agent sorafenib treatment.
Combination treatment with sorafenib and erlotinib or cetuximab has synergistic antitumor effects in human colorectal and lung cancer cells.
Clinical Cancer Research 10/2010; 16(20):4990-5001. · 7.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Enzastaurin, an acyclic bisindolymaleimide, is a potent and selective competitive inhibitor of protein kinase Cbeta, which has been shown to inhibit cancer cell proliferation and angiogenesis in human cancer cell lines. Gemcitabine and pemetrexed are two cytotoxic drugs that are currently used in non-small cell lung cancer (NSCLC) therapy. In this study, we have investigated whether the addition of enzastaurin to gemcitabine or to pemetrexed is able to increase their antitumor activity to establish an effective schedule of combined treatment. The effects on cancer cell proliferation, cell cycle distribution, intracellular mitogenic and antiapoptotic signaling pathways, and induction of apoptosis were evaluated in three different combination sequences (concomitant treatment, sequential treatment with the cytotoxic drug followed by enzastaurin, or sequential treatment with enzastaurin followed by the cytotoxic drug) in a panel of human NSCLC cell lines. The combination of enzastaurin with either gemcitabine or pemetrexed caused different antiproliferative and proapoptotic effects depending on the treatment schedule. A synergistic antiproliferative and proapoptotic activity was only obtained when chemotherapy was followed by treatment with enzastaurin. These effects were accompanied by the arrest of the surviving cancer cells in the S phase, thus limiting their ability to proceed through the cell cycle, and by a maximum inhibition in the activated, phosphorylated forms of Akt and mitogen-activated protein kinase. In contrast, the concomitant treatments or the sequential treatments, in which enzastaurin was given before chemotherapy, resulted in significant antagonistic effects.
Molecular Cancer Therapeutics 07/2008; 7(6):1698-707. · 5.23 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mouse models of cancer have consistently been used to qualify new anti-cancer drugs for development of human clinical trials. The most used models are xenografts of human tumors grown subcutaneously in immunodeficient mice such as athymic (nude) or severe combined immune deficient (SCID) mice. However, the number of anti-cancer agents that fail in the clinic far outweighs those considered effective, suggesting that the selection procedure for progression of molecules into the clinic requires improvement. This has provoked considerable skepticism about the value of using such preclinical models. As a result, a shift has occurred towards developing and using spontaneous mouse tumor arising in transgenic and/or knockout mice engineered to recapitulate various genetic alterations thought to be causative of specific types of human cancers. Alternatively, the option has been to improve human tumor xenograft models by using orthotopic transplantation and, therefore, promotion of metastatic spread of the resultant 'primary' tumors. Here we review the value and the limitations of xenograft models and their role in developing new anti-cancer treatments.
Critical Reviews in Oncology/Hematology 04/2008; 65(3):200-11. · 4.41 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This in vivo study was designed to determine the optimal doses and schedules of vandetanib, a dual epidermal growth factor receptor (EGFR)-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with irinotecan in a murine xenograft model of human colon cancer.
HT-29 tumor-bearing nude mice were treated with two doses of vandetanib (12.5 and 25 mg/kg/d) with or without irinotecan (100 mg/kg) using either sequential or concurrent schedules for 30 days. Tumor size was measured using standard variables, whereas the antiangiogenic response was evaluated using dynamic contrast-enhanced magnetic resonance imaging. Additionally, effects on EGFR-dependent signal transduction pathways and proliferation were assessed using immunohistochemistry. These pharmacodynamic end points were then evaluated for associations with antitumor efficacy and/or to plasma/tumor concentrations of vandetanib.
The greatest antitumor efficacy was observed in the groups receiving the highest dose of vandetanib given continuously (concurrent schedule), alone or in combination with irinotecan. These dosing schedules resulted in significant effects on tumor vasculature, with decreased volume transfer constants, area under the curve, and permeability surface factor as well as increased gadolinium clearance after 30 days of treatment. In addition, these groups showed the greatest inhibition of EGFR signaling. Interestingly, tumor concentrations of vandetanib were increased by irinotecan in the concurrent schedule, possibly due to decreased tumor perfusion in this group.
These data suggest that higher, sustained concentrations of vandetanib (versus intermittent), alone and in combination with irinotecan, result in optimal antitumor efficacy in this model and may have implications for the design of future clinical studies with this drug.
Clinical Cancer Research 12/2007; 13(21):6450-8. · 7.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, is fundamental to support tumor growth. Inhibiting tumor angiogenesis is a promising strategy for treatment of cancer and has been successfully transferred from preclinical to clinical application in recent years. Due to its role in tumor angiogenesis, the vascular endothelial growth factor (VEGF) and its receptor have been a major focus of basic research and drug development in the field of oncology. Vandetanib, is an orally bioavailable inhibitor of VEGF receptor-2 tyrosine kinase activity that in preclinical studies has been shown to inhibit both VEGF-induced signalling in endothelial cells and tumourinduced angiogenesis. Consistent with inhibition of angiogenesis, vandetanib, produced significant broad-spectrum antitumour activity in a panel of histologically diverse human tumour xenografts. In addition to its antiangiogenic properties, vandetanib also has activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, which could impart a direct inhibitory effect on tumour cell growth and survival. Early clinical evaluation of this agent has demonstrated a safety profile and comprehensive series of phase II studies have clarify the value of this approach in the treatment of solid tumor. This review summarises preclinical and clinical studies with this unique agent.
Current Cancer Therapy Reviews 10/2007; 3(4):236-241.
-
[show abstract]
[hide abstract]
ABSTRACT: The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and in the progression of many human malignancies, including non-small-cell lung cancer (NSCLC). EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR is a valuable molecular approach in cancer therapy. This receptor is overexpressed in up to 80% of NSCLC cases. Thus, several molecules inhibiting this critical biologic pathway have been synthesized and tested as a single agent or in combination with other anticancer modalities in a wide of clinical trials, including reversible and irreversible small tyrosine kinase inhibitors, such as gefitinib and erlotinib, dual vascular endothelial growth factor receptor EGFR tyrosine kinase inhibitors, such as vandetanib (ZD-6474), and monoclonal antibodies, such as cetuximab, which have shown promising activity in patients with NSCLC. This review focuses on the preclinical and clinical results available with EGFR inhibitors in the treatment of NSCLC patients.
Expert Opinion on Drug Discovery 03/2007; 2(3):335-48. · 2.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hepatoid adenocarcinoma (HAC) is a peculiar type of extrahepatic adenocarcinoma generally characterized by adenocarcinomatous and hepatocellular carcinoma (HCC)-like foci. Stomach is the most frequent site where hepatoid adenocarcinoma occurs, although it has been described in many other organs. On the other side, liposarcoma is a rare, malignant tumor that develops from fat cells.
We describe here a case of hepatoid carcinoma in collision with a liposarcoma of the left colon serosa in a 71-year-old man. It presented as an abdominal mass involving several organs, falsely mimicking metastatic colonic adenocarcinoma. Recognition of this entity was evident on microscopic evaluation following surgery. The patient had an objective response following liposomal antracycline chemotherapy, with a 3-year overall survival.
To our knowledge, this is the first case of a hepatoid tumor colliding with a liposarcoma of the left colon serosa reported to date.
World Journal of Surgical Oncology 02/2007; 5:42. · 1.12 Impact Factor
-
Cataldo Bianco,
Elisa Giovannetti,
Fortunato Ciardiello,
Valentina Mey,
Sara Nannizzi,
Giampaolo Tortora, Teresa Troiani,
Francesco Pasqualetti,
Gail Eckhardt,
Mario de Liguoro,
Simona Ricciardi,
Mario Del Tacca,
David Raben,
Luca Cionini,
Romano Danesi
[show abstract]
[hide abstract]
ABSTRACT: Standard treatments have modest effect against pancreatic cancer, and current research focuses on agents targeting molecular pathways involved in tumor growth and angiogenesis. This study investigated the interactions between ZD6474, an inhibitor of tyrosine kinase activities of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor (EGFR), gemcitabine, and ionizing radiation in human pancreatic cancer cells and analyzed the molecular mechanisms underlying this combination.
ZD6474, ionizing radiation, and gemcitabine, alone or in combination, were given in vitro to MIA PaCa-2, PANC-1, and Capan-1 cells and in vivo to MIA PaCa-2 tumor xenografts. The effects of treatments were studied by the evaluation of cytotoxicity, apoptosis, cell cycle, EGFR and Akt phosphorylation, modulation of gene expression of enzymes related to gemcitabine activity (deoxycytidine kinase and ribonucleotide reductase), as well as vascular endothelial growth factor immunohistochemistry and microvessel count.
In vitro, ZD6474 dose dependently inhibited cell growth, induced apoptosis, and synergistically enhanced the cytotoxic activity of gemcitabine and ionizing radiation. Moreover, ZD6474 inhibited phosphorylation of EGFR and Akt and triggered cell apoptosis. PCR analysis showed that ZD6474 increased the ratio between gene expression of deoxycytidine kinase and ribonucleotide reductase. In vivo, ZD6474 showed significant antitumor activity alone and in combination with radiotherapy and gemcitabine, and the combination of all three modalities enhanced MIA PaCA-2 tumor growth inhibition compared with gemcitabine alone.
ZD6474 decreases EGFR and Akt phosphorylation, enhances apoptosis, favorably modulates gene expression in cancer cells, and acts synergistically with gemcitabine and radiotherapy to inhibit tumor growth. These findings support the investigation of this combination in the clinical setting.
Clinical Cancer Research 01/2007; 12(23):7099-107. · 7.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Colorectal cancer is the fourth most common malignant disease. Of newly diagnosed patients, 40% have metastatic disease at diagnosis, and approximately 25% of patients with localized disease at diagnosis will ultimately develop metastatic disease. The benefits of systemic chemotherapy in the treatment of metastatic colorectal cancer over best supportive care have been established. Panitumumab (ABX-EGF) is the first fully human monoclonal antibody developed for use in colorectal cancer that targets the extracellular domains of epidermal growth factor receptor.
The goal of this article is to review the published evidence for the use of panitumumab in the treatment of metastatic colorectal cancer to define its therapeutic potential.
The major evidence of panitumumab activity in colorectal cancer has appeared in meeting report abstracts. One phase II study in monotherapy, one in combination with chemotherapy, and one phase III study have included only patients with metastatic colorectal cancer.
To date, in phase II clinical studies panitumumab has demonstrated antitumor activity in advanced, refractory colorectal cancer. As monotherapy it resulted in a 10% response rate with 38% of patients having stable disease, and a 36% response rate with 46% stable disease when combined with chemotherapy. A phase III study indicates a clinically significant advantage of panitumumab as third-line monotherapy over best supportive care. Panitumumab appears to have a good tolerability profile, with no maximum tolerated dose yet defined.
Core Evidence 01/2007; 2(2):81-8.
