Targeted Therapy Research Papers - Academia.edu (original) (raw)

Progressive tumor growth depends on angiogenesis to sustain metabolic needs of tumor cells, thus providing a potential target for cancer therapy. Malignant gliomas have retained their dismal prognosis despite aggressive multimodal... more

Progressive tumor growth depends on angiogenesis to sustain metabolic needs of tumor cells, thus providing a potential target for cancer therapy. Malignant gliomas have retained their dismal prognosis despite aggressive multimodal conventional therapeutic approaches, illustrating the need for novel therapeutic strategies. Gliomas are a suitable tumor type for probing angiogenesis inhibition as their proliferation is characterized by a prominent proliferative vascular component. In the present review, we discuss the current status and future directions of angiogenesis inhibition in gliomas. We focus on recently developed approaches inducing an antiangiogenic response such as targeted gene delivery, protein tyrosine kinase inhibitors and encapsulated producer cells. Although several of these modalities have shown promising results on their own, the true potential of these novel approaches lies in their combined use with radiotherapy or 'metronomically scheduled' chemotherapy. A combined approach potentially counteracts the selective pressure on hypoxia-resistant malignant tumor cells, circumvents endothelial resistance induced by local cytoprotective responses and enhances the delivery of cytotoxic agents by normalizing vascular physiology. Surrogate markers of angiogenesis currently under study may provide accurate assessment of response in individual patients. Future research on endothelial markers expressed on tumor-associated vasculature as well as endothelial responses to cytotoxic treatment will provide new avenues for molecularly targeted therapy in malignant gliomas. D

This is a literature review about large granular lymphocyte leukemia (LGLL), a rare and misdiagnosed oncohematological disease, characterized by a clonal expansion of T-cells (T-LGLL) or NK-cells (NK-LGLL) in the bone marrow and/or... more

This is a literature review about large granular lymphocyte leukemia (LGLL), a rare and misdiagnosed oncohematological disease, characterized by a clonal expansion of T-cells (T-LGLL) or NK-cells (NK-LGLL) in the bone marrow and/or peripheral blood. The clinical features of LGLL include cytopenias (anemia, neutropenia and thrombocytopenia), lymphocytosis (usually discrete), lymphadenopathy, hepatomegaly, splenomegaly, immune abnormalities and constitutional symptoms (fever, night sweats and weight loss). The diagnosis is based on the confirmation of the clonality of T-cells or NK-cells (polymerase chain reaction and Southern blot are the two methods most commonly used) and typical findings of the immunophenotypic analysis of peripheral blood lymphocytes (flow cytometry analyses for specific surface antigens). In contrast to the chronic and indolent course of T-LGLL, NK-LGLL has an acute presentation and poor clinical outcome. There are different current treatment options, depending on clinical presentation.

Aberrant activation of some members of human epidermal growth factor receptor (HER) family plays a key role in breast carcinogenesis. Lapatinib is an oral dual tyrosine kinase inhibitor selective for inhibition of epidermal growth factor... more

Aberrant activation of some members of human epidermal growth factor receptor (HER) family plays a key role in breast carcinogenesis. Lapatinib is an oral dual tyrosine kinase inhibitor selective for inhibition of epidermal growth factor receptor (EGFR/ErbB1) and HER2/ErbB2. Having more targets, probably its antitumor activity could be more efficient. Clinical data have shown that lapatinib is active in HER2-positive breast cancer as monotherapy, in combination with trastuzumab, and in trastuzumab-resistant patients. Phase I clinical trials have shown also that lapatinib is well tolerated, with mild diarrhea and skin rush as common toxic effects and low incidence of cardiotoxicity. Phase II and III clinical trials' data provide encouraging evidence of the clinical effectiveness of lapatinib in advanced or metastatic breast cancer and for its potential in patients with brain metastases. Interim results from the large, phase III trial in 392 patients showed that in combination with capecitabine lapatinib almost doubled time to progression when compared with capecitabine alone. Several clinical trials that explore the efficacy of lapatinib in combination with conventional chemotherapeutic agents [paclitaxel (Taxol), capecitabine and platinoids], hormonotherapy and other target therapies are ongoing in advanced breast cancer or in neo-adjuvant and adjuvant settings. Our improved understanding of the biology of breast cancer and the use of biomarkers for identification of specific subtypes are allowing us to bring patientspecific novel therapies such as lapatinib to the clinic.

Liver cancer accounts for 4.7% of all newly diagnosed cancers and 8.2% of cancer deaths annually. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. There are 2 curative strategies in HCC: resection and... more

Liver cancer accounts for 4.7% of all newly diagnosed cancers and 8.2% of cancer deaths annually. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. There are 2 curative strategies in HCC: resection and transplant. Unfortunately, 50% of patients who undergo resection will relapse in 2 years and many patients on transplant lists become ineligible for transplant due to disease progression. The majority of patients still require systemic therapies. Tyrosine kinase inhibitors have successfully extended the overall survival in patients with hepa-tocellular carcinoma. However, these treatments have been noted to cause severe side effects including liver toxicity, hypertension, gastrointestinal toxicity and cutaneous adverse effects. This article will focus on the adverse skin reactions seen during the treatment of hepatocellular carci-noma by various tyrosine kinase inhibitors. The focus will be symptomatology, management, and whether the development of cutaneous toxicities can be prognostic.

Metastatic renal cell carcinoma (mRCC) with sarcomatoid differentiation is an aggressive disease that is associated with poor outcomes to chemotherapy or immunotherapy. The utility of vascular endothelial growth factor (VEGF)-targeted... more

Metastatic renal cell carcinoma (mRCC) with sarcomatoid differentiation is an aggressive disease that is associated with poor outcomes to chemotherapy or immunotherapy. The utility of vascular endothelial growth factor (VEGF)-targeted therapy in patients with this disease is unknown.

The concept of sound symbolism proposes that even the tiniest sounds comprising a word may suggest the qualities of the object which that word represents. Cancer-related medication names, which are likely to be charged with emotional... more

The concept of sound symbolism proposes that even the tiniest sounds comprising a word may suggest the qualities of the object which that word represents. Cancer-related medication names, which are likely to be charged with emotional meaning for patients, might be expected to contain such sound-symbolic associations. We analyzed the sounds in the names of 60 frequently-used cancer-related medications, focusing on the medications' trade names as well as the names (trade or generic) commonly used in the clinic. We assessed the frequency of common voiced consonants (/b/, /d/, /g/, /v/, /z/; thought to be associated with slowness and heaviness) and voiceless consonants (/p/, /t/, /k/, /f/, /s/; thought to be associated with fastness and lightness), and compared them to what would be expected in standard American English using a reference dataset. A Fisher's exact test for independence showed the chemotherapy consonantal frequencies to be significantly different from standard English (p=0.009 for trade; p<0.001 for "common usage"). For the trade names, the majority of the voiceless consonants were significantly increased compared to standard English; this effect was more pronounced with the "common usage" names (for the group, O/E=1.62; 95% CI [1.37, 1.89]). Hormonal and targeted therapy trade names showed the greatest frequency of voiceless consonants (for the group, O/E=1.76; 95% CI [1.20, 2.49]). Our results suggest that taken together, the names of chemotherapy medications contain an increased frequency of certain sounds associated with lightness, smallness and fastness. This finding raises important questions about the possible role of the names of medications in the experiences of cancer patients and providers.

Bleomycin has been used as a carrier for several radioisotopes; however, its potential for clinical use has been limited either by the in vivo stability of the complexes or the half-life of the isotope used. The chemical, biological, and... more

Bleomycin has been used as a carrier for several radioisotopes; however, its potential for clinical use has been limited either by the in vivo stability of the complexes or the half-life of the isotope used. The chemical, biological, and radiological properties of 105 Rhodium appear to make it an ideal choice for targeted radiotherapy. The synthesis and purification of a hereto unreported 105 Rhodium-bleomycin ( 105 Rh-BLM) complex is described. The stability of this complex in plasma is sufficient to allow targeted delivery of the radioisotope.

Adalimumab is a fully human monoclonal antibody that binds tumor necrosis factor (TNF)-␣. Its efficacy as maintenance therapy for patients with ulcerative colitis has not been studied in a controlled, double-blind trial. METHODS:... more

Adalimumab is a fully human monoclonal antibody that binds tumor necrosis factor (TNF)-␣. Its efficacy as maintenance therapy for patients with ulcerative colitis has not been studied in a controlled, double-blind trial. METHODS: Ulcerative colitis long-term remission and maintenance with adalimumab 2 (ULTRA 2) was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of adalimumab in induction and maintenance of clinical remission in 494 patients with moderateto-severe ulcerative colitis who received concurrent treatment with oral corticosteroids or immunosuppressants. Patients were stratified based on prior exposure to TNF-␣ antagonists (either had or had not been previously treated with anti-TNF-␣) and randomly assigned to groups given adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every other week or placebo. Primary end points were remission at weeks 8 and 52. RESULTS: Overall rates of clinical remission at week 8 were 16.5% on adalimumab and 9.3% on placebo (P ϭ .019); corresponding values for week 52 were 17.3% and 8.5% (P ϭ .004). Among anti-TNF-␣ naïve patients, rates of remission at week 8 were 21.3% on adalimumab and 11% on placebo (P ϭ .017); corresponding values for week 52 were 22% and 12.4% (P ϭ .029). Among patients who had previously received anti-TNF agents, rates of remission at week 8 were 9.2% on adalimumab and 6.9% on placebo (P ϭ .559); corresponding values for week 52 were 10.2% and 3% (P ϭ .039). Serious adverse events occurred in 12% of patients given adalimumab or placebo. Serious infections developed in 1.6% of patients given adalimumab and 1.9% given placebo. In the group given adalimumab, 1 patient developed squamous cell carcinoma and 1 developed gastric cancer. CONCLUSIONS: Adalimumab was safe and more effective than placebo in inducing and maintaining clinical remission in patients with moderate-to-severe ulcerative colitis who did not have an adequate response to conventional therapy with steroids or immunosuppressants.

An increased understanding of the molecular etiology of cancer has enabled the development of novel therapies that are collectively referred to as molecular targeted agents. Unlike the drugs used in conventional chemotherapy, these agents... more

An increased understanding of the molecular etiology of cancer has enabled the development of novel therapies that are collectively referred to as molecular targeted agents. Unlike the drugs used in conventional chemotherapy, these agents are designed to specifically interfere with key molecular events that are responsible for the malignant phenotype. They hold great promise for widening the therapeutic window, which would provide more effective treatment options as compared with cytotoxic therapies. In addition, the targeted approach that is characteristic of these drugs provides unique opportunities for combination therapies with other anticancer agents that have non-overlapping toxicities. Targeted agents are therefore primed to become invaluable therapeutic tools in the multimodal treatment of cancer. The challenges associated with these novel targeted therapies are distinct from those faced in conventional chemotherapy. These unique challenges include the need to select appropr...

A major goal of palliative medicine is to control symptoms that interfere with quality of life. Identification of symptoms that occur together (cluster) may aid in symptom management, resulting in greater therapeutic benefit to the... more

A major goal of palliative medicine is to control symptoms that interfere with quality of life. Identification of symptoms that occur together (cluster) may aid in symptom management, resulting in greater therapeutic benefit to the patient. An analysis of 25 symptoms from 922 patients with advanced cancer was undertaken to determine if symptom clusters could be identified. Cluster analysis was done using an agglomerative hierarchical method with average linkage; the absolute value of the correlation between pairs of symptoms was used as the measure of similarity. A correlation of ≥0.68 was used to define the final clusters. Seven clusters were identified: (1) fatigue: anorexia-cachexia; (2) neuropsychological; (3) upper gastrointestinal; (4) nausea and vomiting; (5) aerodigestive; (6) debility; (7) pain. Recognition of symptom clusters should help understand symptom pathophysiology and target therapies that perhaps can be used to relieve multiple symptoms in that cluster. This could result in improved quality of life for patients with advanced cancer and perhaps reduce polypharmacy, lessen drug side effects, and have pharmacoeconomic benefits.

Nanotechnology has already started to significantly impact many industries and scientific fields including biotechnology, pharmaceutics, food technology and semiconductors. Nanotechnology-based tools and devices, including high-resolution... more

Nanotechnology has already started to significantly impact many industries and scientific fields including biotechnology, pharmaceutics, food technology and semiconductors. Nanotechnology-based tools and devices, including high-resolution imaging techniques, enable characterization and manipulation of materials at the nanolevel and further elucidate nanoscale phenomena and equip us with the ability to fabricate novel materials and structures. One of the most promising impacts of nanotechnology is in the area of nanotherapy. Employing nanosystems such as dendrimers, nanoliposomes, niosomes, nanotubes, emulsions and quantum dots, nanotherapy leads toward the concept of personalized medicine and the potential for early diagnoses coupled with efficient targeted therapy. The development of smart targeted nanocarriers that can deliver bioactives at a controlled rate directly to the designated cells and tissues will provide better efficacy and reduced side effects. Nanocarriers improve the solubility of bioactives and allow for the delivery of not only small-molecule drugs but also the delivery of nucleic acids and proteins. This review will focus on nanoscale bioactive delivery and targeting mechanisms and the role of high-resolution imaging techniques in the evaluation and development of nanocarriers. #

Nephritis is the most frequent severe manifestation of anti-neutrophil cytoplasm antibody associated (ANCA) systemic vasculitis (AASV) and systemic lupus erythematosus (SLE) and carries substantial morbidity. Although immunosuppressive... more

Nephritis is the most frequent severe manifestation of anti-neutrophil cytoplasm antibody associated (ANCA) systemic vasculitis (AASV) and systemic lupus erythematosus (SLE) and carries substantial morbidity. Although immunosuppressive medications and glucocorticoids are effective at inducing remission, patients still suffer from high relapse rates and experience significant treatment-related toxicity. Rituximab (RTX), a chimeric antibody directed against CD20, found on B lymphocytes, shows potential as a treatment for both AASV and SLE. Although direct comparisons with standard therapies are currently unavailable, patients in several studies of refractory and relapsing disease have achieved a remission despite the failure of standard therapies. These reports are supported by several lines of experimental evidence that underlie the rationale for using targeted B-cell therapies and have improved our understanding of the pathogenesis of these complex diseases. Future randomized control trials and long-term follow-up studies are required to confirm the role of RTX and other B-cell targeting therapies in AASV and SLE.

The landscape of cancer treatment has dramatically changed over the last four decades. The age when surgery and radiotherapy were the only effective way to fight tumour growth has ended. A complex scenario where the molecular features of... more

The landscape of cancer treatment has dramatically changed over the last four decades. The age when surgery and radiotherapy were the only effective way to fight tumour growth has ended. A complex scenario where the molecular features of tumours seem to be the cornerstone of any therapy is now emerging. Here we provide an overview on the different approaches to cancer treatment. This review will help the reader to acknowledge the pivotal role of some classic cancer therapies, including surgery, radiation, chemotherapy and endocrine therapy, now better understood in the mechanims underpinning their efficacy. Following, we focus on the understanding of the value of systemic treatment and on an up-date on the novel, up-coming therapies of the current targeted therapy age, including new antibodies, small molecules, antiangiogenics and viral therapy. We briefly elaborate, finally, on new biomarkers development and how it should rule and determine the future of therapeutic research in cancer.

Seventy-four hemiplegic patients (31 female and 43 male) participated in this study. The average (AEstandard deviation) age, mass and height of the participants were as follows: 55.6 AE 9.4 and 58.9 AE 9.3 years, 69.6 AE 11.6 and 78.7 AE... more

Seventy-four hemiplegic patients (31 female and 43 male) participated in this study. The average (AEstandard deviation) age, mass and height of the participants were as follows: 55.6 AE 9.4 and 58.9 AE 9.3 years, 69.6 AE 11.6 and 78.7 AE 9.9 kg, 162 AE 5 and 173.8 AE 5.2 cm (females and males, respectively). Fifty-five were diagnosed with ischemic stroke, 20 with hemorrhagic stroke. The inclusion criteria were: age 40-70 years, first incident of hemorrhagic or ischemic stroke within the past six months, capable of walking independently using no aids, with no other disorders of an orthopedic, rheumatologic, etc., nature that could affect gait kinematics and no cognitive disorders. Participants and their physicians and physiotherapists provided consent for their participation in this study. The sample size, 74, consisted of all patients treated by the host institution in 2005-2007 who met these inclusion criteria.

Overall survival from childhood malignancies has dramatically improved, with survival rates now reaching over 70%. Nevertheless, some types of childhood cancer remain a difficult challenge, and for those who survive the burden of... more

Overall survival from childhood malignancies has dramatically improved, with survival rates now reaching over 70%. Nevertheless, some types of childhood cancer remain a difficult challenge, and for those who survive the burden of treatment can be considerable. The current paradigm for new cancer therapies is to increase our knowledge of the molecular basis of carcinogenesis, followed by the development of cancer-cell specific therapies. Historically, drug development was focused on adult cancers, and the potential efficacy in childhood malignancies was not considered. Recently, a European academic consortium was established, namely 'innovative therapies for children with cancer' (ITCC), to address this unmet need. This initiative is focused on the evaluation of novel agents in pediatric cancer pre-clinical models, and early clinical development of promising new drugs. The number of pediatric patients eligible to participate in such trials is limited, and accurate pre-clinical evaluation may provide evidence-based prioritization for clinical development. Until recently, clinical development of new drugs in childhood cancer was restricted by the limited accessibility of such agents. Recent changes in EU legislation oblige pharmaceutical companies to provide pediatric clinical data for all new drugs relevant to children, including anti-cancer drugs. Pediatric consortiums like ITCC have established networks of expertise with the specific aim of evaluating new drugs for the treatment of childhood cancers. Through proper evaluation in collaborative clinical trials we will learn how best to use these new therapeutic approaches and improve the survival rates and reduce toxicity for children with cancer.

Full collaboration in supply chains is an ideal that the participant firms should try to achieve. However, a number of factors hamper real progress in this direction. Therefore, there is a need for forecasting demand by the participants... more

Full collaboration in supply chains is an ideal that the participant firms should try to achieve. However, a number of factors hamper real progress in this direction. Therefore, there is a need for forecasting demand by the participants in the absence of full information about other participants' demand. In this paper we investigate the applicability of advanced machine learning techniques, including neural networks, recurrent neural networks, and support vector machines, to forecasting distorted demand at the end of a supply chain (bullwhip effect). We compare these methods with other, more traditional ones, including naïve forecasting, trend, moving average, and linear regression. We use two data sets for our experiments: one obtained from the simulated supply chain, and another one from actual Canadian Foundries orders. Our findings suggest that while recurrent neural networks and support vector machines show the best performance, their forecasting accuracy was not statistically significantly better than that of the regression model.

Survival rates for metastatic colorectal cancer (CRC) have increased considerably over the years largely because of the application of optimized chemotherapy regimens. More recently, the addition of the targeted agents bevacizumab,... more

Survival rates for metastatic colorectal cancer (CRC) have increased considerably over the years largely because of the application of optimized chemotherapy regimens. More recently, the addition of the targeted agents bevacizumab, cetuximab, and panitumumab in advanced disease has also demonstrated clinical benefit. Adjuvant chemotherapy is the standard of care in patients with early-stage CRC who are at high risk of recurrence. One challenge is how to apply targeted agents in early-stage CRC. Initial results from the NSABP-08 trial in CRC, the first report of bevacizumab in the adjuvant treatment of solid cancers, are disappointing. Nevertheless, the results of several important phase III trials of targeted adjuvant therapy are awaited. Until then, the use of targeted agents in early-stage CRC cannot be recommended. The identification of biomarkers to select patients who might derive clinical benefit is crucial in determining the full potential of targeted agents in the adjuvant s...

Targeted therapies affecting specific molecular target, expressed preferentially by neoplastic cells, block cancer growth. Current targets are represented by cell-surface trans-membrane proteins, intracellular proteins, and by growth... more

Targeted therapies affecting specific molecular target, expressed preferentially by neoplastic cells, block cancer growth. Current targets are represented by cell-surface trans-membrane proteins, intracellular proteins, and by growth factors. Today a targeted therapy exists for most commonly diagnosed types of human cancer often combined with chemotherapy or sometimes as monotherapy option. The epidermal growth factor receptors (EGFR) and vascular endothelial growth factors (VEGF) are known as the two main control key intracellular pathways, governing fundamental processes in cancer cells. The concept of using anti-EGFR and anti-VEGF strategies, as cancer treatment, has been soon developed and exploited extensively. We review targeted drugs currently available for routine treatment of lung, breast, colorectal and renal cell cancers, summarizing the history of identification and molecular characterization of targets or signaling pathways responsible for abnormal cell growth. We also focus on new targeted strategies, still under investigation, able to affect simultaneously tightly interconnected biological pathways or directed against new molecular targets.

The identification of markers that are associated with tumour but not normal tissue has allowed the development of highly-specific targeted therapies. Monoclonal antibodies, either alone or linked to radioisotopes or toxins, have provided... more

The identification of markers that are associated with tumour but not normal tissue has allowed the development of highly-specific targeted therapies. Monoclonal antibodies, either alone or linked to radioisotopes or toxins, have provided a powerful tool for research, as well as the basis for promising therapeutic agents with less side effects than standard radiotherapy or chemotherapy. A new class of drugs, the tyrosine kinase inhibitors, which interfere with the function of key molecules in cancer-promoting pathways, have had a dramatic effect in haematological malignancy and are being trialled in solid tumours, including glioma. Although the problem of achieving specific, high-level delivery of these various agents to tumours in the brain remains a major issue, encouraging early results with some targeted agents support the attractive theoretical principles of this new paradigm. Further work to identify new molecular targets and to develop agents exploiting them, is needed, as well as confirmation of their safety and efficacy by clinical trials. ª

In this review on current therapy in non-small cell lung cancer (NSCLC), the current status of immune therapy is presented. This therapeutic area is dominated by the biological therapeutics, or “biologics”. Firstly, the immune checkpoint... more

In this review on current therapy in non-small cell lung cancer (NSCLC), the current status of immune therapy is presented. This therapeutic area is dominated by the biological therapeutics, or “biologics”. Firstly, the immune checkpoint inhibitors include antibodies to PD-1, e.g., nivolumab (BMS-936558) and pembrolizumab (MK-3475), and anti- bodies to PD-L1, i.e., BMS-936559, MPDL-3280A and MEDI-4736. Secondly, the vaccines include the EGF vaccine (CIMAvax-EGF®), astuprotimut-R (Zumagev, MAGE-A3), belagenpumatucel-L (Lucanix®), tecemotide (L-BLP-25, Stimuvax®), tergenpumatucel-L, TG-4010, tertomotide (GV-1001), INGN-225, MVA-5T4 (TroVax®) and CV-9202. Thirdly, there are now some developments in adoptive cell transfer in NSCLC, with ongoing clinical trials involving carcinoembry- onic antigen and NY-ESO-1 as targets for “designer” T cells. Finally, new areas of immune therapy are discussed, including chimeric anti- gen receptors and peptides as immune vaccines. A number of new clin- ical trials are ongoing in immune therapy in NSCLC and these are summarized.

In recent years, discovery of the in vitro and in vivo dierentiation of APL blasts by all-trans retinoic acid (ATRA) has modi®ed the therapeutic approach of APL and lead to important advances in understanding the biology of APL. Since it... more

In recent years, discovery of the in vitro and in vivo dierentiation of APL blasts by all-trans retinoic acid (ATRA) has modi®ed the therapeutic approach of APL and lead to important advances in understanding the biology of APL. Since it became apparent that dierentiation therapy of APL with ATRA was indeed a true model of targetted therapy, evidencing the molecular targets of retinoic acid ecacy became crucial. These molecular targets are closely related to the biological features of APL cells, some of which are well-known and have contributed to the morphological and cytogenetic de®nition of the leukemia, others have just been de®ned or re-discovered in the light of a better understanding of molecular controls of cell growth and dierentiation. The aims of characterizing the biological features of APL cells should allow a better management of APL therapy and the identi®cation of potential markers for dierentiation therapies in other leukemias or solid tumors. Oncogene (2001) 20, 7154 ± 7160.

Over the past decade, molecular-targeted therapies have been added to cytotoxic and anti-endocrine drugs in the treatment of cancer, with the aim to target the molecular pathways that underlie the carcinogenic process and maintain the... more

Over the past decade, molecular-targeted therapies have been added to cytotoxic and anti-endocrine drugs in the treatment of cancer, with the aim to target the molecular pathways that underlie the carcinogenic process and maintain the cancer phenotype. Success with some of these agents has suggested that identification and validation of the drug target is the starting point for the route of development of active, safe and effective drugs. Main molecular targets used to the development of anticancer drugs are cell surface receptors, signal transduction pathways, gene transcription targets, ubiquitin-proteasome/heat shock proteins and tumour microenvironment components (especially antiangiogenic agents). Here, we review the development of the main molecular targeted non-cytotoxic agents studied in cancer, highlighting lessons derived from the development of these novel drugs and proposing new horizons for the clinical development of molecular-targeted therapies.

Much effort is currently being spent on developing anticancer drugs targeted at cellular signal transduction mechanisms, and several signal inhibitors have also been introduced into clinical practice. The rationale for such therapy is the... more

Much effort is currently being spent on developing anticancer drugs targeted at cellular signal transduction mechanisms, and several signal inhibitors have also been introduced into clinical practice. The rationale for such therapy is the realization that, in general, oncogenes and tumour suppressor genes encode proteins that are mutated or dysregulated forms of key components in major regulatory pathways. However, while we have witnessed striking clinical effects in certain malignancies, as in the treatment of chronic myelogeneous leukemia, the results in many other cancers have been rather disappointing, and this has raised the question of whether major advances can realistically be expected by the use of signal-targeted therapies on a broad scale. Here we briefly review the cellular and molecular basis for treatment with pharmacological signal inhibitors and the clinical experience with their use in different malignancies. We also discuss general strategies to improve the treatment, including approaches to the problem of resistance development. Clinical results vary greatly, from little or no treatment success in some cancers to an increasing number of examples of very promising responses. Progress has primarily been achieved in those malignancies and subsets of patients where the underlying molecular mechanisms have been explored in detail and the targets have been well defined. In conclusion, it is likely that novel signal-directed approaches will lead to further important advances in cancer therapy, but this will require continued efforts to identify targets that are oncogenic determinants, and systematic work to select patients for more individualized therapies.

Cancer is primarily a disease of old age, and that life style plays a major role in the development of most cancers is now well recognized. While plant-based formulations have been used to treat cancer for centuries, current treatments... more

Cancer is primarily a disease of old age, and that life style plays a major role in the development of most cancers is now well recognized. While plant-based formulations have been used to treat cancer for centuries, current treatments usually involve poisonous mustard gas, chemotherapy, radiation, and targeted therapies. While traditional plant-derived medicines are safe, what are the active principles in them and how do they mediate their effects against cancer is perhaps best illustrated by curcumin, a derivative of turmeric used for centuries to treat a wide variety of inflammatory conditions. Curcumin is a diferuloylmethane derived from the Indian spice, turmeric (popularly called ''curry powder") that has been shown to interfere with multiple cell signaling pathways, including cell cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF-jB, TNF, IL-6, IL-1, COX-2, and 5-LOX). The activity of curcumin reported against leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reflects its ability to affect multiple targets. Thus an ''old-age" disease such as cancer requires an ''age-old" treatment.

Background: Ovarian cancer ascites fluid (OCAF), contains malignant cells, is usually present in women with an advanced stage disease and currently has no effective therapy. Hence, we developed a new therapy strategy to target the... more

Background: Ovarian cancer ascites fluid (OCAF), contains malignant cells, is usually present in women with an advanced stage disease and currently has no effective therapy. Hence, we developed a new therapy strategy to target the expression of diphtheria toxin gene under the control of H19 regulatory sequences in ovarian tumor cells. H19 RNA is present at high levels in human cancer tissues (including ovarian cancer), while existing at a nearly undetectable level in the surrounding normal tissue. Methods: H19 gene expression was tested in cells from OCAF by the in-situ hybridization technique (ISH) using an H19 RNA probe. The therapeutic potential of the toxin vector DTA-H19 was tested in ovarian carcinoma cell lines and in a heterotopic animal model for ovarian cancer. Results: H19 RNA was detected in 90% of patients with OCAF as determined by ISH. Intratumoral injection of DTA-H19 into ectopically developed tumors caused 40% inhibition of tumor growth. Conclusion: These observations may be the first step towards a major breakthrough in the treatment of human OCAF, while the effect in solid tumors required further investigation. It should enable us to identify likely non-responders in advance, and to treat patients who are resistant to all known therapies, thereby avoiding treatment failure.

Tumor tissue biomarkers are the basis for targeted therapy in non small-cell lung cancer (NSCLC). These biomarkers either reflect the target of the specific drug or some factor that might abrogate the effect of the drug. These targeted... more

Tumor tissue biomarkers are the basis for targeted therapy in non small-cell lung cancer (NSCLC). These biomarkers either reflect the target of the specific drug or some factor that might abrogate the effect of the drug. These targeted drugs are small-molecule inhibitors of a specific tyrosine kinase or a monoclonal antibody against a specific recep- tor. In this review, tissue biomarkers in NSCLC and com- panion diagnostics will be described, followed by an overview of targeted therapy to EGF/EGFR, HER2, VEGF/VEGFR, ALK, KRAS, BRAF, MEK and MET and some of the newer potential targets. Recent initiatives include the Lung Cancer Matrix Network, the BATTLE trials and the Lung Cancer Mutation Consortium. There are a number of key clinical trials in targeted therapy in NSCLC which will be reporting during the next year.

Abstract Over the course of the last three decades, a large body of evidence has shown that polyphenols, the secondary metabolites occurring in plant foods and beverages, exert protective effects due to their antioxidant activity mediated... more

Abstract
Over the course of the last three decades, a large body of evidence has shown that polyphenols, the
secondary metabolites occurring in plant foods and beverages, exert protective effects due to their
antioxidant activity mediated through different mechanisms ranging from direct radical scavenging and
metal chelating activities, to the capacity to inhibit pro-oxidant enzymes and to target specific cellsignalling
pathways. In the last decade, dietary components, and polyphenols in particular have gained
considerable attention as chemopreventive agents against different types of cancer. The signal
transducers and activators of transcription (STAT) family is a group of cytoplasmic transcription
factors which interact with specific sequences of DNA, inducing the expression of specific genes
which in turn give rise to adaptive and highly specific biological responses. Growing evidence suggests
that, of the seven STAT members identified, STAT3 is over-expressed in many human tumors (i.e. solid
tumors and hematological malignancies) promoting the onset and development of cancer in humans by
inhibiting apoptosis or by inducing cell proliferation, angiogenesis, invasion, and metastasis. This
review article aims to assess the most recent studies on the role of STATs, with focus on STAT3, in
oncogenesis, and the promising effects of some polyphenols on STAT expression. Moreover, the
mechanisms behind the anti-inflammatory and antioxidant activities of polyphenols which have an
influence on STAT expression are discussed, with a focus on their ability to target specific cellsignalling
pathways.
Keywords: Anti-inflammatory response; Antioxidant defense; Cell-signalling pathways; signal
transducers and activators of transcription (STAT); Polyphenols

A series of radiolabeled peptides have been designed and optimized for tumor-targeted peptide receptor radionuclide therapy (PRRT). Pre-clinical and clinical applications of PRRT have shown promising results on tumor response, overall... more

A series of radiolabeled peptides have been designed and optimized for tumor-targeted peptide receptor radionuclide therapy (PRRT). Pre-clinical and clinical applications of PRRT have shown promising results on tumor response, overall survival, and quality of life in patients with several kinds of tumors. 90Y-DOTA-TOC and 177Lu-DOTA-TATE are two of the most common radiopharmaceuticals with symptomatic improvements and complete clinical data. In addition to somatostatin analogs, radiolabeled peptides have been developed to target the relative receptors overexpressed in the tumors, such as integrin α vβ 3, gastrin-releasing peptide receptor (GRPR), melanocortin-1 receptor (MC1-R), cholecystokinin (CCK) receptor, and glucagon-like peptide-1 receptor (GLP-1R). Several strategies have been designed to improve the therapeutic efficacy of PRRT. For instance, radiolabeled peptides could be optimized by the amino acid modification and radionuclide selection. Healthy tissue protective agents and multi-cycle procedures could effectively decrease the side effects of PRRT. Furthermore, combination treatments, including PRRT combined with surgery, chemotherapeutic agents, or radiosensitizing agents could be applied to increase the effectiveness of PRRT. In this review, the current progress of peptide-based radiopharmaceuticals for tumor-targeted PRRT was summarized. Radiopharmaceuticals currently under clinical investigation were also described.

The thesis of this study is that the convergence of genetics, genomics and proteomics spurs new technological paradigms in medicine, which are generating a R&D corporate change: division of scientific labour of the drug discovery process... more

The thesis of this study is that the convergence of genetics, genomics and proteomics spurs new technological paradigms in medicine, which are generating a R&D corporate change: division of scientific labour of the drug discovery process by strategic alliances among firms in order to reinforce the integrative capabilities in different biomedical research fields and collective and cumulative learning between in-house R&D and external sources of innovation. This study shows, by key a case study of pharmaceutical companies, as scientific and technological paradigms in medicine are main drivers of industrial and R&D corporate change to enhance and accelerate the discovery process of ground-breaking drugs for more and more personalised healthcare.

Cancer patients are at risk for adverse events involving bone. Metastasis of cancer to bone and primary bone tumors can compromise the integrity of bone. Various cancer therapies cause long-term skeletal disorders, particularly bone loss,... more

Cancer patients are at risk for adverse events involving bone. Metastasis of cancer to bone and primary bone tumors can compromise the integrity of bone. Various cancer therapies cause long-term skeletal disorders, particularly bone loss, osteomalacia, and avascular necrosis. Cancer therapies that include chemotherapy, glucocorticoids, hormonal agents, and newer targeted therapies can affect bone in several ways. With the improved effectiveness of cancer treatment, more cancer patients are surviving longer and may experience fractures as a long-term complication of bone loss. Prevention of bone loss through early detection and appropriate use of anti-osteoporosis treatment may decrease bone loss and fractures. This article reviews causative risk factors, mechanisms, and prevention and treatment strategies for cancer therapy-related bone loss in hematologic and specific solid malignancies.

In the last few decades there has been a shift in the paradigm of rectal cancer treatment. Surgery, historically the only weapon against rectal malignances, has found valuable allies in other treatment modalities, extending the range of... more

In the last few decades there has been a shift in the paradigm of rectal cancer treatment. Surgery, historically the only weapon against rectal malignances, has found valuable allies in other treatment modalities, extending the range of cure to previously untreatable stages of disease. Perioperative protocols have led to a dramatic improvement in local control of locally advanced disease. The integration of targeted therapies with more effective cytotoxic protocols and refined surgical strategies has expanded the treatment of metastatic disease, resulting in improved survival. Advances in risk stratification will allow us to identify patients who may benefit from conservative surgical approaches in the future. This manuscript reviews the accepted standard of care protocols and highlights areas currently under debate.

In the last ten years, the development of several novel targeted drugs and the refinement of state of the art technologies such as the genomics and proteomics and their introduction to clinical practice have revolutionized the management... more

In the last ten years, the development of several novel targeted drugs and the refinement of state of the art technologies such as the genomics and proteomics and their introduction to clinical practice have revolutionized the management of patients affected by cancer.

Targeted therapies for hematological malignancies have come of age since the advent of all trans retinoic acid (ATRA) for treating APL and STI571/Imatinib Mesylate/Gleevec for CML. There are good molecular targets for other malignancies... more

Targeted therapies for hematological malignancies have come of age since the advent of all trans retinoic acid (ATRA) for treating APL and STI571/Imatinib Mesylate/Gleevec for CML. There are good molecular targets for other malignancies and several new drugs are in clinical trials. In this review, we will concentrate on individual abnormalities that exist in the myelodysplastic syndromes (MDS) and myeloid leukemias that are targets for small molecule therapies (summarised in ). We will cover fusion proteins that are produced as a result of translocations, including BCR-ABL, the FLT3 tyrosine kinase receptor and RAS. Progression of diseases such as MDS to secondary AML occur as a result of changes in the balance between cell proliferation and apoptosis and we will review targets in both these areas, including reversal of epigenetic silencing of genes such as p15 INK4B .

This article aims at highlighting the most recent and promising research trends, the open challenges and the possible routes to follow in the field of targeted therapy. A highly interdisciplinary viewpoint has been used, trying to... more

This article aims at highlighting the most recent and promising research trends, the open challenges and the possible routes to follow in the field of targeted therapy. A highly interdisciplinary viewpoint has been used, trying to evidence and discuss the different opportunities deriving from recent evolutions of nanotechnology, polymer science, robotics and biotechnology. The most used vectors for nanomedicine applications are described, together with the different action strategies reported in the literature, such as passive targeting, site-directed targeting and remotely triggerable drug delivery. Special emphasis is given to magnetically triggered systems and ultrasound-responsive materials, identified as the most promising paradigms. Key competences and system integration strategies derived from robotics are also introduced, focusing the attention on the crucial issue of achieving high controllability of the vector at the micro- and nano-scale. Finally, biocomponents are described, highlighting their potential as functional sensing elements or smart mechanisms to be integrated on board of advanced micro-nano therapeutic devices. The conclusion aims at depicting the importance of novel and improved targeted therapy strategies, to be coupled with the emerging world of predicting and personalized medicine. To this aim, a real merging of skills and approaches, derived from the aforementioned research fields, is recognized as highly desirable and rich of opportunities.

In the version of this article initially published, in several instances "guanidine" should have read "guanine", "uridine" should have read "uracil", and "adenine" should have read adenosine; in two instances; "tetratrispolin" should have... more

In the version of this article initially published, in several instances "guanidine" should have read "guanine", "uridine" should have read "uracil", and "adenine" should have read adenosine; in two instances; "tetratrispolin" should have read "tristetraprolin"; and ,d should have illustrated the structure from PDB record 1M8Y. These errors have been corrected in the HTML and PDF versions of the article. e r r ata a n D co r r i g e n Da

This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the... more

This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like 211 At, 223 Ra, 225 Ac/ 213 Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments.

Background: Treatment options for patients with metastatic breast cancer (MBC) include a rapidly expanding repertoire of medical, surgical and supportive care measures. Design: To provide timely and evidence-based recommendations for the... more

Background: Treatment options for patients with metastatic breast cancer (MBC) include a rapidly expanding repertoire of medical, surgical and supportive care measures. Design: To provide timely and evidence-based recommendations for the diagnostic workup and treatment of patients with MBC, an international expert panel reviewed and discussed the evidence available from clinical trials regarding diagnostic, therapeutic and supportive measures with emphasis on their impact on the quality of life and overall survival of patients with MBC. Results: Evidence-based recommendations for the diagnostic workup, endocrine therapy, chemotherapy, use of targeted therapies and bisphosphonates, surgical treatment and supportive care measures in the management of patients with MBC were formulated.

Approximately 10% of the pheochromocytomas and 20% of the paragangliomas are malignant with poor survival. As the biological behaviour of these tumours cannot be predicted with certainty from pathology the diagnosis of malignancy is... more

Approximately 10% of the pheochromocytomas and 20% of the paragangliomas are malignant with poor survival. As the biological behaviour of these tumours cannot be predicted with certainty from pathology the diagnosis of malignancy is difficult. Genetic testing is gaining impact as mutations in the tumour suppressor gene Von Hippel-Lindau and the mitochondrial succinate dehydrogenase enzyme complex subunit B (SDHB) are associated with malignancy. Excess release of catecholamines is characteristic for pheochromocytomas. High levels of chromogranin A, that is co-stored and co-secreted with catecholamines, may indicate tumour mass and malignancy and can be used to monitor response and relapse. The secretory and non-secretory tumours can be visualised with functional (specific and non-specific) imaging as SPECT and PET using ¹²³I-MIBG, somatostatin analogues, ¹⁸F-DOPA, and ¹⁸F-FDG. These modalities are recommended in patients with extra-adrenal and suspected metastatic/malignant disease, in case of distorted post-operative anatomy, and when suspected recurrence. The sensitivities of ¹²³I-MIBG scintigraphy or ¹⁸F-DOPA PET are relatively low in SDHB mutated tumours, but high using ¹⁸F-FDG. Specific PET imaging with somatostatin analogues generally has high sensitivity in malignant disease. There are no curative therapeutic options for malignant, metastatic pheochromocytomas/paragangliomas, wherefore consolidation of quality of life is essential. Adjuvant radionuclide treatment with beta-emitting isotopes coupled to MIBG or somatostatin analogues have shown response in approximately 30%. Chemotherapy is restricted to patients not accessible for surgery and resistant to radionuclide therapy. Novel targeted therapies, which mainly through a cytostatic effect interfere with specific targeted molecules needed for carcinogenesis and tumour growth show encouraging results.

The advent of targeted anticancer therapies over the past few decades has reinvigorated the field of cancer therapeutics, with the promise of increased cancer cure rates accompanied by decreased toxicity. But, has that promise been... more

The advent of targeted anticancer therapies over the past few decades has reinvigorated the field of cancer therapeutics, with the promise of increased cancer cure rates accompanied by decreased toxicity. But, has that promise been fulfilled? The short answer is definitely 'no', both because of disappointing tumor responses and unexpectedly high toxicity, as well as the extremely high financial cost of these agents. However, failing to completely fulfill initial promise does not mean that targeted therapies should be abandoned. Increased progression-free survival might ultimately lead to increased overall survival, and targeted therapies have changed the course of cancers such as breast, lung and renal. Therefore, we would argue that despite some disappointments, targeted therapies have a vital role in future cancer treatment. This Review will discuss the positives and negatives of targeted agents, and propose a way to optimize their use and development to ensure proper pers...

The phosphoinositide-3 kinase (PI3K) pathway plays a critical role in cancer cell growth and survival. PI3K is activated in human cancers by elevated receptor tyrosine kinase activity, RAS mutation, as well as by mutation, amplification,... more

The phosphoinositide-3 kinase (PI3K) pathway plays a critical role in cancer cell growth and survival. PI3K is activated in human cancers by elevated receptor tyrosine kinase activity, RAS mutation, as well as by mutation, amplification, and deletion of genes encoding components of the pathway. Additionally, PI3K pathway activation plays an important role in acquired resistance to both chemotherapy and targeted agents. The essential role of PI3K in human cancer has led to the development of PI3K pathway inhibitors that have shown promise in preclinical models and have entered phase 1 clinical trials. This article reviews preclinical and clinical data on members of this novel drug class, as well as data justifying the combination of PI3K inhibitors with other anticancer agents.

Please cite this article in press as: Colombo M, et al. HER2 targeting as a two-sided strategy for breast cancer diagnosis and treatment: Outlook and recent implications in nanomedical approaches. Pharmacol Res (2010), a b s t r a c t At... more

Please cite this article in press as: Colombo M, et al. HER2 targeting as a two-sided strategy for breast cancer diagnosis and treatment: Outlook and recent implications in nanomedical approaches. Pharmacol Res (2010), a b s t r a c t At present, mammary carcinoma is the second most common type of malignant tumor in adult women after lung cancer, as more than one million women are diagnosed with breast cancer every year. Despite advances in diagnosis and treatment, which have resulted in a decrease in mortality in recent decades, breast cancer remains a major public health problem. One of the most significant unresolved clinical and scientific problems is the occurrence of resistance to clinical treatments and their toxicity (and how to predict, prevent and overcome them). However, the heterogeneity of human breast cancer in terms of genetic features, molecular profiles and clinical behavior represents a constraint obstructing the discovery of a solution to the disease. It is currently considered that the chances of success of therapy may increase if the tumor cells are selectively removed before they can evolve to their mature stages up to metastases production. Therefore, novel and more sensitive diagnostic tools are being developed, with the aim of improving the early and noninvasive detection of rising malignancies and the accuracy of tumor tissue localization. Meanwhile, there is an emerging use of targeted therapies in oncology, depending on the expression of specific proteins or genes present in tumor cells. Among the molecular targets considered for the treatment of breast cancer cells so far, we chose to focus on examples involving overexpression and/or gene amplification of "Human Epidermal growth factor Receptor 2" (HER2) protein. In current studies, various types of nanoparticles conjugated with the anti-HER2 monoclonal antibody, the so-called "trastuzumab", are investigated extensively due to promising results in biological and preclinical applications aimed at improving the treatment of breast cancer. In this paper, we present a critical review of the preparation and use of different kinds of trastuzumab-functionalized nanoparticles, with an emphasis on the therapeutic and diagnostic (theranostic) potential of this generation of hybrid nanoparticles, exploiting the multifaceted mechanisms of action of trastuzumab against malignant cells.

Imatinib mesylate (IM) is used in the targeted therapy of chronic myelogenous leukemia and gastrointestinal stromal tumors. It is well tolerated and leads to no higher incidence of hemorrhagic events than other therapies. Of 87 patients... more

Imatinib mesylate (IM) is used in the targeted therapy of chronic myelogenous leukemia and gastrointestinal stromal tumors. It is well tolerated and leads to no higher incidence of hemorrhagic events than other therapies. Of 87 patients we treated with IM for a minimum of 3 months, 10 patients (11%) developed unilateral or bilateral conjunctival hemorrhage (CH). No other hemorrhagic events were observed during follow-up, except for CH recurrence in 6 cases (7%). Because there was no other obvious reason for such a high incidence of CH, we hypothesize drug hypersensitivity or ocular irritation induced by IM treatment.

Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis,... more

Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis, relevant to preneoplastic lesions progression to full malignancy in rodent models, and evaluation of these changes in human hepatocellular carcinomas (HCCs). Activation of ERB receptor family, MAPK, JAK-STAT, -Catenin cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine decarboxylase, Cyclins and CDKs occurs in human and rodent hepatocarcinogenesis. This is associated with downregulation of the cell cycle inhibitors p16 INK4A and p53 and TGF-/SMAD signaling. Oncosuppressor genes, including p16 INK4A , E-CAD, and DLC-1 are often hypermethylated in humans and rodents. Moreover, protection of cell cycle from p16 INK4A inhibition by upregulation of CDC37, HSP90, and CRM1 correlates to HCC progression. A body of evidence indicates that inhibition of key genes of aforementioned signaling pathways by antisense or siRNA approaches or specific inhibitors restraints growth of in vitro cultured or in vivo xenografted HCCs. Efforts are currently dedicated to improve transduction efficiency. HCC cells may escape gene therapy by various mechanisms. Attempts to overcome this difficulty include discovery of new therapeutic targets, gene therapy directed to different molecular targets essential for tumor cell survival and specifically directed to HCC subtypes.