Cancer Diagnosis and Targeted Therapy

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 January 2011) | Viewed by 198933

Special Issue Editor


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Guest Editor
1. NF-kB, Differenciation and Cancer, University Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France
2. Faculté de Pharmacie, 4 Avenue de l'Observatoire, 75006 Paris, France
Interests: interface between signal transduction and cancer with a focus on the alternative NF-kappaB signaling pathway, how it is regulated, and its contributions towards tumor development and resistance to conventional cancer therapies
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Special Issue Information

Dear Colleagues,

Although mortality rates have declined in recent years, the majority of cancers are still difficult to treat and the medical need for better cancer treatment is evident. The current anticancer armamentarium includes many active agents that are applied across tumor types, and most drugs have a small therapeutic index and barely discriminate between malignant and normal cells. In recent years the focus has shifted to the development of rationally designed, molecularly-targeted therapy for the treatment of a specific cancer, therefore offering the promise of greater specificity coupled with reduced systemic toxicity. Another challenge has been the development of prognostic and pharmacogenomic biomarkers that enable the targeting of individualized treatments to those patients most likely to benefit.

This special issue will explore the routes from cancer research and oncogenomics into the development of novel mechanism-based cancer therapeutics and biomarkers.

We invite research and review papers in any area of oncology that are related, but not limited to, fundamental understanding of oncogenomics and cancer signaling pathways, diagnostic, prognostic and pharmacogenomic biomarkers, molecular diagnosis by gene expression profiling, molecular targets driving the progression of human cancers, cancer drug development on these targets, clinical trial with new agents, validation in animal models.

Dr. Veronique Baud
Guest Editor

Keywords

  • cancer targeted diagnosis
  • cancer targeted therapeutics
  • solid tumors
  • hematological malignancies
  • oncogenomics
  • gene expression profiling
  • molecular targets
  • mechanism-based drug development
  • biomarkers
  • miRNA
  • ubiquitin-proteasome pathway
  • clinical trials
  • animal models

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Published Papers (20 papers)

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Research

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236 KiB  
Article
Different Aspects of Self-Reported Quality of Life in 450 German Melanoma Survivors
by Annika Waldmann, Sandra Nolte, Ron Pritzkuleit, Eckhard W. Breitbart and Alexander Katalinic
Cancers 2011, 3(2), 2316-2332; https://doi.org/10.3390/cancers3022316 - 11 May 2011
Cited by 11 | Viewed by 8288
Abstract
The present study was aimed at assessing quality of life (QoL) in a total of 450 melanoma patients who filled out the EORTC QLQ-C30 (Q1; 15 months post diagnosis) as part of the OVIS Study. Follow-up questionnaires (Q2) were administered two years after [...] Read more.
The present study was aimed at assessing quality of life (QoL) in a total of 450 melanoma patients who filled out the EORTC QLQ-C30 (Q1; 15 months post diagnosis) as part of the OVIS Study. Follow-up questionnaires (Q2) were administered two years after Q1. The analyses presented herein were based on the following assumptions: QoL of melanoma patients is worse than that of a German reference population. Further, both tumor location and tumor stage have an influence on self-reported QoL, with patients with tumors located on face, head, neck, and advanced tumor stage (T3/T4) reporting the worst QoL levels. Finally, patients’ QoL improves over time based on the theory of disease adaptation. In contrast to the above assumptions, with the exception of global health/QoL scores, differences between OVIS and the reference population were below the minimal clinical important difference of ten points. Furthermore, no clinically meaningful differences were found between patients after stratifying our data by tumor location and tumor stage. Finally, no clinically relevant changes were seen between Q1 and Q2 across all scales of the EORTC QLQ-C30. However, when data were stratified by patients with stable disease versus those with progression, clinically relevant differences were found between Q1 and Q2 predominantly in women in the latter group regarding emotional function, insomnia, dyspnoea, and fatigue. The lack of clinically meaningful differences across strata (tumor location; tumor stage), time, and patients compared to a reference population is surprising. However, it is possible that the instrument used, a generic QoL instrument, is generally not sensitive enough to detect differences in melanoma patients. Our findings may further be explained by the fact that all patients included in our sample had been diagnosed well before Q1, i.e., main illness adaptation processes may have occurred before study entry. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Article
Inferences for the Lead Time in Breast Cancer Screening Trials under a Stable Disease Model
by Justin Shows and Dongfeng Wu
Cancers 2011, 3(2), 2131-2140; https://doi.org/10.3390/cancers3022131 - 26 Apr 2011
Cited by 3 | Viewed by 7216
Abstract
We estimated the effects on the lead time for women participating in a long-term breast cancer screening program when the screening sensitivities and disease progression are independent of age. The lead time, or time by which a diagnosis is advanced by screening, is [...] Read more.
We estimated the effects on the lead time for women participating in a long-term breast cancer screening program when the screening sensitivities and disease progression are independent of age. The lead time, or time by which a diagnosis is advanced by screening, is one of the major concerns of any cancer screening program, which we consider to include both a mammogram and physical examination. Using estimates of test sensitivities and mean sojourn times previously calculated by other authors from observed data, we estimated properties of the lead time. We utilized the model for the lead time derived by other authors and ran simulations for different screening program designs, concentrating on screening interval lengths of 0.5 years, 1 year, 1.5 years, and 2 years. These estimates were based on a long-term screening program from age 50 to 80. For each six-month decrease in screening interval length, we estimated the percent increase in mean lead time, as well as the percent increase in the proportion of clinical patients who will have their cancer detected at a screening exam. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Article
A Methodological Framework for Evaluating the Evidence for Complementary and Alternative Medicine (CAM) for Cancer
by Robert Zachariae and Helle Johannessen
Cancers 2011, 3(1), 773-788; https://doi.org/10.3390/cancers3010773 - 23 Feb 2011
Cited by 5 | Viewed by 9316
Abstract
In spite of lacking evidence for effects on cancer progression itself, an increasing number of cancer patients use various types of complementary and alternative medicine (CAM). There is disagreement between CAM practitioners, researchers and clinical oncologists, as to how evidence concerning effects of [...] Read more.
In spite of lacking evidence for effects on cancer progression itself, an increasing number of cancer patients use various types of complementary and alternative medicine (CAM). There is disagreement between CAM practitioners, researchers and clinical oncologists, as to how evidence concerning effects of CAM can and should be produced, and how the existing evidence should be interpreted. This represents a considerable challenge for oncologists; both in terms of patient needs for an informed dialogue regarding CAM, and because some types of CAM may interact with standard treatments. There is a need for insight into which kinds of CAM may work, for whom they work, what the possible effects and side-effects are, and in what ways such effects may come about. The present article presents a framework for evaluating effects of CAM by suggesting a taxonomy of different levels of evidence related to different types of research questions and discussing the relevance of different research methodologies for different types of effects. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)

Review

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263 KiB  
Review
Epidermal to Mesenchymal Transition and Failure of EGFR-Targeted Therapy in Glioblastoma
by Andrej Pala, Georg Karpel-Massler, Richard Eric Kast, Christian Rainer Wirtz and Marc-Eric Halatsch
Cancers 2012, 4(2), 523-530; https://doi.org/10.3390/cancers4020523 - 8 May 2012
Cited by 25 | Viewed by 8650
Abstract
Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is almost never curable with the current standard treatment consisting of surgical resection, irradiation and temozolomide. The prognosis remains poor despite undisputable advances in the understanding of this tumor’s molecular biology and [...] Read more.
Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is almost never curable with the current standard treatment consisting of surgical resection, irradiation and temozolomide. The prognosis remains poor despite undisputable advances in the understanding of this tumor’s molecular biology and pathophysiology, which unfortunately has so far failed to translate into a meaningful clinical benefit. Dysregulation and a resulting prominent pathophysiological role of the epidermal growth factor receptor (EGFR) have been identified in several different malignant tumor entities, GBM among them. The EGFR is overexpressed in about 40% of GBM cases, and half of these coexpress a mutant, constitutively activated subtype, EGFRvIII. Unfortunately, recent trials studying with therapeutic approaches targeted against the EGFR and EGFRvIII have failed to meet expectations, with only a minority of patients responding despite evidence of good in vitro and rodent model activity. Having potentially high relevance within this context, epithelial to mesenchymal transition (EMT) is a phenomenon associated with early stages of carcinogenesis, cancer invasion and recurrence. During EMT, epithelial cells lose many of their epithelial characteristics, prominently E-cadherin expression, and acquire properties that are typical for mesenchymal cells such as the expression of vimentin. Epithelial to mesenchymal transition has been specifically demonstrated in GBM. In this review, we summarize the evidence that EMT may precipitate GBM resistance to EGFR-targeted therapy, and may thus be among the principal factors contributing to the clinical failure of targeted therapy against EGFR and EGFRvIII. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Review
Transcription Inhibition as a Therapeutic Target for Cancer
by Christine M. Stellrecht and Lisa S. Chen
Cancers 2011, 3(4), 4170-4190; https://doi.org/10.3390/cancers3044170 - 23 Nov 2011
Cited by 28 | Viewed by 10719
Abstract
During tumorigenesis the transformed cells lose their normal growth control mechanisms and become dependent on oncogenes’ products and pathways for survival. Treatments tailored to block the expression or function of transforming genes have shown efficacy in eliminating neoplastic cells. The mRNAs of many [...] Read more.
During tumorigenesis the transformed cells lose their normal growth control mechanisms and become dependent on oncogenes’ products and pathways for survival. Treatments tailored to block the expression or function of transforming genes have shown efficacy in eliminating neoplastic cells. The mRNAs of many oncogenes, as well as regulators of other key processes such as cell proliferation, angiogenesis, and apoptosis, typically have shorter half-lives. Agents that impede mRNA synthesis are expected to selectively hinder the expression of these genes and, therefore, be detrimental to neoplastic cells that are physiologically dependent on them. In addition to exploiting the tumor cells’ dependency on short-lived transcripts, RNA-directed agents also take advantage of the differential sensitivity between transformed and non-transformed cells, as the cytotoxic effects of inhibiting RNA synthesis have not been seen in non-transformed cells. The abrogation of the formation of oncotranscripts provides a new concept in cancer therapeutics and numerous agents have been developed which are able to target transcription. The focus of this review is to give an overview of transcription and the different inhibitory strategies that target various aspects of the transcriptional process. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Review
Targeted Radionuclide Therapy
by Devrim Ersahin, Indukala Doddamane and David Cheng
Cancers 2011, 3(4), 3838-3855; https://doi.org/10.3390/cancers3043838 - 11 Oct 2011
Cited by 72 | Viewed by 12947
Abstract
Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the [...] Read more.
Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Review
An Evidence-Based Approach to the Use of Predictive Biomarkers in the Treatment of Non- Small Cell Lung Cancer (NSCLC)
by Cindy Quinton and Peter M. Ellis
Cancers 2011, 3(3), 3506-3524; https://doi.org/10.3390/cancers3033506 - 13 Sep 2011
Cited by 5 | Viewed by 7858
Abstract
Recent advances in the treatment of non-small cell lung cancer (NSCLC) have led to improvements in patient survival and quality of life. It is unclear whether molecular abnormalities associated with NSCLC cell survival, growth and proliferation are useful in predicting treatment benefit. We [...] Read more.
Recent advances in the treatment of non-small cell lung cancer (NSCLC) have led to improvements in patient survival and quality of life. It is unclear whether molecular abnormalities associated with NSCLC cell survival, growth and proliferation are useful in predicting treatment benefit. We conducted a systematic review to establish which biomarkers contribute meaningfully to the management of NSCLC. A team of researchers searched PubMed and conference proceedings (ASCO, ESMO, IASLC, USCAP) using MESH terms for NSCLC and randomized trials (RCT), plus keywords for variables of interest. Evidence from multiple RCTs confirmed that histologic subtype is prognostic for survival and predictive of treatment efficacy and/or toxicity in NSCLC. Likewise, activating mutations of the epidermal growth factor receptor (EGFR) are associated with benefit from EGFR tyrosine kinase inhibitors in patients with advanced non-squamous NSCLC and should be assessed routinely. No biomarkers to date reliably predict response to anti-Vascular Endothelial Growth Factor (VEGF) therapies. There are inconsistent data on the role of ERCC1, BRCA, Beta tubulin III, RRM1, K-RAS, or TP-53 in treatment decisions. These tests should not be routinely used in selecting treatment at this time, whereas EML4/ALK translocations predict responses to specific targeted agents, the optimal assessment of this molecular abnormality has yet to be established. Personalized care of patients with NSCLC based on biomarkers is increasingly important to both clinical practice and research. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Review
TRAF4, at the Crossroad between Morphogenesis and Cancer
by Adrien Rousseau, Marie-Christine Rio and Fabien Alpy
Cancers 2011, 3(2), 2734-2749; https://doi.org/10.3390/cancers3022734 - 21 Jun 2011
Cited by 17 | Viewed by 8518
Abstract
Tumor Necrosis Factor Receptor-Associated Factor 4 (TRAF4) is a gene whose expression is altered in cancers. It is overexpressed in a variety of carcinomas of different origins, often as a consequence of amplification. TRAF4 encodes an adaptor protein that belongs to the TRAF [...] Read more.
Tumor Necrosis Factor Receptor-Associated Factor 4 (TRAF4) is a gene whose expression is altered in cancers. It is overexpressed in a variety of carcinomas of different origins, often as a consequence of amplification. TRAF4 encodes an adaptor protein that belongs to the TRAF protein family. While most TRAF proteins influence immune and inflammation processes, TRAF4 is mainly involved in developmental and morphogenic processes. Interestingly, this protein has been shown to be linked to crucial cellular functions such as cell polarity and the regulation of reactive oxygen species production. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Review
Enhancing Photodynamyc Therapy Efficacy by Combination Therapy: Dated, Current and Oncoming Strategies
by Ilaria Postiglione, Angela Chiaviello and Giuseppe Palumbo
Cancers 2011, 3(2), 2597-2629; https://doi.org/10.3390/cancers3022597 - 9 Jun 2011
Cited by 103 | Viewed by 9575
Abstract
Combination therapy is a common practice in many medical disciplines. It is defined as the use of more than one drug to treat the same disease. Sometimes this expression describes the simultaneous use of therapeutic approaches that target different cellular/molecular pathways, increasing the [...] Read more.
Combination therapy is a common practice in many medical disciplines. It is defined as the use of more than one drug to treat the same disease. Sometimes this expression describes the simultaneous use of therapeutic approaches that target different cellular/molecular pathways, increasing the chances of killing the diseased cell. This short review is concerned with therapeutic combinations in which PDT (Photodynamyc Therapy) is the core therapeutic partner. Besides the description of the principal methods used to assess the efficacy attained by combinations in respect to monotherapy, this review describes experimental results in which PDT was combined with conventional drugs in different experimental conditions. This inventory is far from exhaustive, as the number of photosensitizers used in combination with different drugs is very large. Reports cited in this work have been selected because considered representative. The combinations we have reviewed include the association of PDT with anti-oxidants, chemotherapeutics, drugs targeting topoisomerases I and II, antimetabolites and others. Some paragraphs are dedicated to PDT and immuno-modulation, others to associations of PDT with angiogenesis inhibitors, receptor inhibitors, radiotherapy and more. Finally, a look is dedicated to combinations involving the use of natural compounds and, as new entries, drugs that act as proteasome inhibitors. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Review
Differentiation Therapy of Acute Myeloid Leukemia
by Elzbieta Gocek and Ewa Marcinkowska
Cancers 2011, 3(2), 2402-2420; https://doi.org/10.3390/cancers3022402 - 16 May 2011
Cited by 36 | Viewed by 11140
Abstract
Acute Myeloid Leukemia (AML) is a predominant acute leukemia among adults, characterized by accumulation of malignantly transformed immature myeloid precursors. A very attractive way to treat myeloid leukemia, which is now called ‘differentiation therapy’, was proposed as in vitro studies have shown that [...] Read more.
Acute Myeloid Leukemia (AML) is a predominant acute leukemia among adults, characterized by accumulation of malignantly transformed immature myeloid precursors. A very attractive way to treat myeloid leukemia, which is now called ‘differentiation therapy’, was proposed as in vitro studies have shown that a variety of agents stimulate differentiation of the cell lines isolated from leukemic patients. One of the differentiation-inducing agents, all-trans retinoic acid (ATRA), which can induce granulocytic differentiation in myeloid leukemic cell lines, has been introduced into clinics to treat patients with acute promyelocytic leukemia (APL) in which a PML-RARA fusion protein is generated by a t(15;17)(q22;q12) chromosomal translocation. Because differentiation therapy using ATRA has significantly improved prognosis for patients with APL, many efforts have been made to find alternative differentiating agents. Since 1,25-dihydroxyvitamin D3 (1,25D) is capable of inducing in vitro monocyte/macrophage differentiation of myeloid leukemic cells, clinical trials have been performed to estimate its potential to treat patients with AML or myelodysplastic syndrome (MDS). Unfortunately therapeutic concentrations of 1,25D can induce potentially fatal systemic hypercalcemia, thus limiting clinical utility of that compound. Attempts to overcome this problem have focused on the synthesis of 1,25D analogs (VDAs) which retain differentiation inducing potential, but lack its hypercalcemic effects. This review aims to discuss current problems and potential solutions in differentiation therapy of AML. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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260 KiB  
Review
Targeted Therapy in Nonmelanoma Skin Cancers
by Giulia Spallone, Elisabetta Botti and Antonio Costanzo
Cancers 2011, 3(2), 2255-2273; https://doi.org/10.3390/cancers3022255 - 3 May 2011
Cited by 17 | Viewed by 8365
Abstract
Nonmelanoma skin cancer (NMSC) is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC), representing around 75% of NMSC and Squamous Cell Carcinomas (SCC). The incidence of these tumors is continuously growing. It was found that the overall [...] Read more.
Nonmelanoma skin cancer (NMSC) is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC), representing around 75% of NMSC and Squamous Cell Carcinomas (SCC). The incidence of these tumors is continuously growing. It was found that the overall number of procedures for NMSC in US rose by 76%, from 1,158,298 in 1992 to 2,048,517 in 2006. Although mortality from NMSC tends to be very low, clearly the morbidity related to these skin cancers is very high. Treatment options for NMSC include both surgical and nonsurgical interventions. Surgery was considered the gold standard therapy, however, advancements in the knowledge of pathogenic mechanisms of NMSCs led to the identification of key targets for drug intervention and to the consequent development of several targeted therapies. These represent the future in treatment of these common forms of cancer ensuring a high cure rate, preservation of the maximal amount of normal surrounding tissue and optimal cosmetic outcome. Here, we will review recent advancements in NMSC targeted therapies focusing on BCC and SCC. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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229 KiB  
Review
Targeted Therapy for Biliary Tract Cancer
by Junji Furuse and Takuji Okusaka
Cancers 2011, 3(2), 2243-2254; https://doi.org/10.3390/cancers3022243 - 3 May 2011
Cited by 12 | Viewed by 8206
Abstract
It is necessary to establish effective chemotherapy to improve the survival of patients with biliary tract cancer, because most of these patients are unsuitable candidates for surgery, and even patients undergoing curative surgery often have recurrence. Recently, the combination of cisplatin plus gemcitabine [...] Read more.
It is necessary to establish effective chemotherapy to improve the survival of patients with biliary tract cancer, because most of these patients are unsuitable candidates for surgery, and even patients undergoing curative surgery often have recurrence. Recently, the combination of cisplatin plus gemcitabine was reported to show survival benefits over gemcitabine alone in randomized clinical trials conducted in the United Kingdom and Japan. Thus, the combination of cisplatin plus gemcitabine is now recognized as the standard therapy for unresectable biliary tract cancer. One of the next issues that need to be addressed is whether molecular targeted agents might also be effective against biliary tract cancer. Although some targeted agents have been investigated as monotherapy for first-line chemotherapy, none were found to exert satisfactory efficacy. On the other hand, monoclonal antibodies such as bevacizumab and cetuximab have also been investigated in combination with a gemcitabine-based regimen and have been demonstrated to show promising activity. Furthermore, clinical trials using new targeted agents for biliary tract cancer are also proposed. This cancer is a relatively rare and heterogeneous tumor consisting of cholangiocarcinoma and gallbladder carcinoma. Therefore, a large randomized clinical trial is necessary to confirm the efficacy of chemotherapy, and international collaboration is important. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Review
Cell Autonomous and Non-Autonomous Functions of IKKβ and NF-κB during the Pathogenesis of Gastrointestinal Tumors
by Hsin-Yu Fang and Florian R. Greten
Cancers 2011, 3(2), 2214-2222; https://doi.org/10.3390/cancers3022214 - 28 Apr 2011
Cited by 6 | Viewed by 11209
Abstract
Genetic studies describing a link between cancer and inflammation have increased recently. Activation of the transcription factor nuclear factor-κB (NF-κB) and its effector pathways has been proposed to be the missing link between these two processes. NF-κB is persistently activated in several types [...] Read more.
Genetic studies describing a link between cancer and inflammation have increased recently. Activation of the transcription factor nuclear factor-κB (NF-κB) and its effector pathways has been proposed to be the missing link between these two processes. NF-κB is persistently activated in several types of tumors. However, NF-κB has a distinct role in cancer cells and in inflammatory cells. While in tumor cells NF-κB controls cell survival, in inflammatory cells NF-κB activates genes that encode pro-inflammatory cytokines which further act in a paracrine manner within the tumor microenvironment to contribute to tumorigenesis. Inactivation of NF-κB can also reduce chemoresistance and radioresistance of cancer cells. Therefore, specific NF-κB inhibition in combination with cytotoxic drugs and/or irradiation represents a very promising strategy for cancer therapy. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Review
EGFR-Targeting as a Biological Therapy: Understanding Nimotuzumab’s Clinical Effects
by Rolando Perez, Ernesto Moreno, Greta Garrido and Tania Crombet
Cancers 2011, 3(2), 2014-2031; https://doi.org/10.3390/cancers3022014 - 18 Apr 2011
Cited by 36 | Viewed by 10021
Abstract
Current clinical trials of epidermal growth factor receptor (EGFR)-targeted therapies are mostly guided by a classical approach coming from the cytotoxic paradigm. The predominant view is that the efficacy of EGFR antagonists correlates with skin rash toxicity and induction of objective clinical response. [...] Read more.
Current clinical trials of epidermal growth factor receptor (EGFR)-targeted therapies are mostly guided by a classical approach coming from the cytotoxic paradigm. The predominant view is that the efficacy of EGFR antagonists correlates with skin rash toxicity and induction of objective clinical response. Clinical benefit from EGFR-targeted therapies is well documented; however, chronic use in advanced cancer patients has been limited due to cumulative and chemotherapy-enhanced toxicity. Here we analyze different pieces of data from mechanistic and clinical studies with the anti-EGFR monoclonal antibody Nimotuzumab, which provides several clues to understand how this antibody may induce a biological control of tumor growth while keeping a low toxicity profile. Based on these results and the current state of the art on EGFR-targeted therapies, we discuss the need to evaluate new therapeutic approaches using anti-EGFR agents, which would have the potential of transforming advanced cancer into a long-term controlled chronic disease. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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444 KiB  
Review
Neuropilins: A New Target for Cancer Therapy
by Camille Grandclement and Christophe Borg
Cancers 2011, 3(2), 1899-1928; https://doi.org/10.3390/cancers3021899 - 8 Apr 2011
Cited by 83 | Viewed by 12614
Abstract
Recent investigations highlighted strong similarities between neural crest migration during embryogenesis and metastatic processes. Indeed, some families of axon guidance molecules were also reported to participate in cancer invasion: plexins/semaphorins/neuropilins, ephrins/Eph receptors, netrin/DCC/UNC5. Neuropilins (NRPs) are transmembrane non tyrosine-kinase glycoproteins first identified as [...] Read more.
Recent investigations highlighted strong similarities between neural crest migration during embryogenesis and metastatic processes. Indeed, some families of axon guidance molecules were also reported to participate in cancer invasion: plexins/semaphorins/neuropilins, ephrins/Eph receptors, netrin/DCC/UNC5. Neuropilins (NRPs) are transmembrane non tyrosine-kinase glycoproteins first identified as receptors for class-3 semaphorins. They are particularly involved in neural crest migration and axonal growth during development of the nervous system. Since many types of tumor and endothelial cells express NRP receptors, various soluble molecules were also found to interact with these receptors to modulate cancer progression. Among them, angiogenic factors belonging to the Vascular Endothelial Growth Factor (VEGF) family seem to be responsible for NRP-related angiogenesis. Because NRPs expression is often upregulated in cancer tissues and correlated with poor prognosis, NRPs expression might be considered as a prognostic factor. While NRP1 was intensively studied for many years and identified as an attractive angiogenesis target for cancer therapy, the NRP2 signaling pathway has just recently been studied. Although NRP genes share 44% homology, differences in their expression patterns, ligands specificities and signaling pathways were observed. Indeed, NRP2 may regulate tumor progression by several concurrent mechanisms, not only angiogenesis but lymphangiogenesis, epithelial-mesenchymal transition and metastasis. In view of their multiples functions in cancer promotion, NRPs fulfill all the criteria of a therapeutic target for innovative anti-tumor therapies. This review focuses on NRP-specific roles in tumor progression. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Review
Recent Advance in Biosensors for microRNAs Detection in Cancer
by Silvia Catuogno, Carla L. Esposito, Cristina Quintavalle, Laura Cerchia, Gerolama Condorelli and Vittorio De Franciscis
Cancers 2011, 3(2), 1877-1898; https://doi.org/10.3390/cancers3021877 - 8 Apr 2011
Cited by 84 | Viewed by 12376
Abstract
MicroRNAs (miRNAs) are short non-protein-coding RNA molecules that regulate the expression of a wide variety of genes. They act by sequence-specific base pairing in the 3’ untranslated region (3’UTR) of the target mRNA leading to mRNA degradation or translation inhibition. Recent studies have [...] Read more.
MicroRNAs (miRNAs) are short non-protein-coding RNA molecules that regulate the expression of a wide variety of genes. They act by sequence-specific base pairing in the 3’ untranslated region (3’UTR) of the target mRNA leading to mRNA degradation or translation inhibition. Recent studies have implicated miRNAs in a wide range of biological processes and diseases including development, metabolism and cancer, and revealed that expression levels of individual miRNAs may serve as reliable molecular biomarkers for cancer diagnosis and prognosis. Therefore, a major challenge is to develop innovative tools able to couple high sensitivity and specificity for rapid detection of miRNAs in a given cell or tissue. In this review, we focus on the latest innovative approaches proposed for miRNA profiling in cancer and discuss their advantages and disadvantages. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Review
The Potential Use of N-Myristoyltransferase as a Biomarker in the Early Diagnosis of Colon Cancer
by Sujeet Kumar, Jonathan R Dimmock and Rajendra K Sharma
Cancers 2011, 3(1), 1372-1382; https://doi.org/10.3390/cancers3011372 - 16 Mar 2011
Cited by 8 | Viewed by 8590
Abstract
Colon cancer is one of the most common malignant diseases and a major cause of mortality in the Western world. Metastasis to lymph nodes and other gastrointestinal organs, especially to the liver and lungs, is most common and occurs in up to 25% [...] Read more.
Colon cancer is one of the most common malignant diseases and a major cause of mortality in the Western world. Metastasis to lymph nodes and other gastrointestinal organs, especially to the liver and lungs, is most common and occurs in up to 25% of cancer patients when initially diagnosed. The majority of colon cancers develop from noncancerous adenomatous polyps on the lining of the colon which grow over the years to become cancerous. If detected early, the surgical resections of the growth, often in combination with chemotherapy, significantly increases life expectancy. We have shown that the enzyme N-myristoyltransferase (NMT) which carries out lipid modification of several proteins (including many of those involved in oncogenesis) is expressed at higher levels in cancerous tissues from the colon. We have also shown that in peripheral blood mononuclear cells (PBMC) and bone marrow (BM) cells collected from colon cancer patients and from azoxymethane-induced rats the expression and localization of NMT is altered. We have observed strong positivity for NMT in immunohistochemical analysis for PBMC from colon cancer patients as compared to control groups. Furthermore, in the bone marrow (BM) mononuclear cells, NMT was found to be confined to the nuclei whereas in control groups it was observed to be located in the cytoplasm. In conclusion, this strikingly differential localization offers the basis of a potential investigational tool for screening or diagnosis of individuals at risk for or suspected of having colon cancer. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Review
Genetic Alterations in Glioma
by Linda B. C. Bralten and Pim J. French
Cancers 2011, 3(1), 1129-1140; https://doi.org/10.3390/cancers3011129 - 7 Mar 2011
Cited by 24 | Viewed by 8877
Abstract
Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth [...] Read more.
Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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197 KiB  
Review
Protein Kinase A in Cancer
by Antonio Caretta and Carla Mucignat-Caretta
Cancers 2011, 3(1), 913-926; https://doi.org/10.3390/cancers3010913 - 28 Feb 2011
Cited by 73 | Viewed by 12262
Abstract
In the past, many chromosomal and genetic alterations have been examined as possible causes of cancer. However, some tumors do not display a clear molecular and/or genetic signature. Therefore, other cellular processes may be involved in carcinogenesis. Genetic alterations of proteins involved in [...] Read more.
In the past, many chromosomal and genetic alterations have been examined as possible causes of cancer. However, some tumors do not display a clear molecular and/or genetic signature. Therefore, other cellular processes may be involved in carcinogenesis. Genetic alterations of proteins involved in signal transduction have been extensively studied, for example oncogenes, while modifications in intracellular compartmentalization of these molecules, or changes in the expression of unmodified genes have received less attention. Yet, epigenetic modulation of second messenger systems can deeply modify cellular functioning and in the end may cause instability of many processes, including cell mitosis. It is important to understand the functional meaning of modifications in second messenger intracellular pathways and unravel the role of downstream proteins in the initiation and growth of tumors. Within this framework, the cAMP system has been examined. cAMP is a second messenger involved in regulation of a variety of cellular functions. It acts mainly through its binding to cAMP-activated protein kinases (PKA), that were suggested to participate in the onset and progression of various tumors. PKA may represent a biomarker for tumor detection, identification and staging, and may be a potential target for pharmacological treatment of tumors. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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530 KiB  
Review
NF-κB in T-cell Acute Lymphoblastic Leukemia: Oncogenic Functions in Leukemic and in Microenvironmental Cells
by Nuno R. Dos Santos, Marinella N. Ghezzo, Ricardo C. Da Silva and Mónica T. Fernandes
Cancers 2010, 2(4), 1838-1860; https://doi.org/10.3390/cancers2041838 - 5 Nov 2010
Cited by 17 | Viewed by 10872
Abstract
Two main NF-κB signaling pathways, canonical and noncanonical, performing distinct functions in organisms have been characterized. Identification of mutations in genes encoding components of these NF-κB signaling pathways in lymphoid malignancies confirmed their key role in leukemogenesis. T-cell acute lymphoblastic leukemia (T-ALL) is [...] Read more.
Two main NF-κB signaling pathways, canonical and noncanonical, performing distinct functions in organisms have been characterized. Identification of mutations in genes encoding components of these NF-κB signaling pathways in lymphoid malignancies confirmed their key role in leukemogenesis. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes that despite significant therapeutic advances can still be fatal. Although mutations in NF-κB genes have not been reported in T-ALL, NF-κB constitutive activation in human T-ALL and in acute T-cell leukemia mouse models has been observed. Although these studies revealed activation of members of both canonical and noncanonical NF-κB pathways in acute T-cell leukemia, only inhibition of canonical NF-κB signaling was shown to impair leukemic T cell growth. Besides playing an important pro-oncogenic role in leukemic T cells, NF-κB signaling also appears to modulate T-cell leukemogenesis through its action in microenvironmental stromal cells. This article reviews recent data on the role of these transcription factors in T-ALL and pinpoints further research crucial to determine the value of NF-κB inhibition as a means to treat T-ALL. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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