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PubMedDate not supplied

Developing new anti-cancer drugs: novel targets and methodological problems.

The identification of molecular events relevant in the biology of cancer cells and the possibility of defining the molecular profile of cancer cell lines have radically changed the process of cancer-drug development. Cancer drug discovery relies now mainly on the National Cancer Institute cell line screening program; this screening system allows the selection of compounds with well-defined molecular mechanisms of action by screening them on cell lines characterised at the molecular level and by comparing their cytotoxicity through a computer-based analysis of the response profile. Biologically targeted drugs, which should hit specific molecular or biochemical targets, can be classified by a specific target, such as farnesyltransferase inhibitors, or by general mechanism of action. The clinical development of these new anti-cancer agents presents a significant challenge because clinical studies should comply with the molecular premises and be devised in order to provide the "proof of principle", that is the ability of the drug to interact with and activate or block the molecular target. After a summary of the main features and problems faced in the clinical development of biologically targeted anti-cancer therapies, the pre-clinical and clinical data available for some cell-cycle modulators, signal transduction inhibitors, drugs acting on the mitochondria and proteasome inhibitors will be reviewed.

Antineoplastic Agents↗

PubMed1997

Glutamate, excitotoxicity and amyotrophic lateral sclerosis.

The "glutamate hypothesis" is one of three major pathophysiological mechanisms of motor neurone injury towards which current research effort into amyotrophic lateral sclerosis (ALS) is directed. There is great structural and functional diversity in the glutamate receptor family which results from combinations of 14 known gene products and their splice variants, with or without additional RNA editing. It is possible that motor neurones express a unique molecular profile of glutamate receptors. Abnormal activation of glutamate receptors is one of five main candidates as a final common pathway to neuronal death. In classical acute excitotoxicity, there is influx of Na+ and CI-, and destabilisation of intracellular Ca2+ homeostasis, which activates a cascade of harmful biochemical events. The concept of secondary excitotoxicity, where cellular injury by glutamate is triggered by disturbances in neuronal energy status, may be particularly relevant to a chronic neurodegenerative disease such as ALS. Data are now beginning to emerge on the fine molecular structure of the glutamate receptors present on human motor neurones, which have a distinct profile of AMPA receptors. Two important molecular features of motor neurones have been identified that may contribute to their vulnerability to neurodegeneration. The low expression of calcium binding proteins and the low expression of the GluR2 AMPA receptor subunit by vulnerable motor neurone groups may render them unduly susceptible to calcium-mediated toxic events following glutamate receptor activation. Eight lines of evidence that indicate a disturbance of glutamatergic neurotransmission in ALS patients are reviewed. The links between abnormal activation of glutamate receptors and other potential mechanisms of neuronal injury, including activation of calcium-mediated second messenger systems and free radical mechanisms, are emphasised. Riluzole, which modulates the glutamate neurotransmitter system, has been shown to prolong survival in patients with ALS. Further research may allow the development of subunit-specific therapeutic targeting of glutamate receptors and modulation of "downstream" events within motor neurones, aimed at protecting vulnerable molecular targets in specific populations of ALS patients.

Amyotrophic Lateral Sclerosis↗

PubMed2006

Molecular prognostic markers in resectable colorectal liver metastases: a systematic review.

BACKGROUND: Determination of prognosis in patients with resectable colorectal liver metastases (CLM) is desirable in order to improve case selection for surgery and tailor adjuvant treatment according to individual recurrence risk. Conventional clinicopathological factors lack the sensitivity to accurately achieve this goal. Consideration of tumour biology and the identification of molecular prognostic markers may allow more accurate risk stratification. METHOD: This systematic review examines evidence from published manuscripts looking at molecular markers in resectable colorectal liver metastases and their correlation with disease recurrence and survival following hepatectomy. RESULTS: Studies have yielded promising results in the search for prognostic molecular markers of CLM. Molecular biomarkers from varied aspects of tumour biology have been examined and a number of these, including proliferation indices, telomerase, thymidylate synthase, microvessel density and thrombospondin-1 appear to have prognostic utility in this context. Validation of other markers, notably p53, has been limited by a failure of methodologies to account for their biological complexity. CONCLUSIONS: A biomarker-based approach may yield significant benefits through informed treatment of resectable metastatic colorectal malignancy. Standardised retrospective analyses are necessary to confirm preliminary findings and identify existing and novel markers for inclusion into prospective studies. Assessment and verification of multiple molecular markers in this manner may allow molecular profiling of metastases and tailoring of therapy according to the biological aggressiveness of individual tumours. The advent of genomic- and proteomic-based technologies will allow the simultaneous analysis of multiple molecular markers and the derivation of disease profiles associated with disease recurrence and poor survival.

Apoptosis↗

PubMed2001

Personalized medicine: revolutionizing drug discovery and patient care.

Advances in human genome research are opening the door to a new paradigm for practising medicine that promises to transform healthcare. Personalized medicine, the use of marker-assisted diagnosis and targeted therapies derived from an individual's molecular profile, will impact the way drugs are developed and medicine is practiced. Knowledge of the molecular basis of disease will lead to novel target identification, toxicogenomic markers to screen compounds and improved selection of clinical trial patients, which will fundamentally change the pharmaceutical industry. The traditional linear process of drug discovery and development will be replaced by an integrated and heuristic approach. In addition, patient care will be revolutionized through the use of novel molecular predisposition, screening, diagnostic, prognostic, pharmacogenomic and monitoring markers. Although numerous challenges will need to be met to make personalized medicine a reality, with time, this approach will replace the traditional trial-and-error practice of medicine.

Drug Design↗

PubMed2005

Overlap between neurodegenerative disorders.

Neurodegenerative disorders are characterized by the formation of distinct pathological changes in the brain, including extracellular protein deposits, cellular inclusions, and changes in cell morphology. Since the earliest published descriptions of these disorders, diagnosis has been based on clinicopathological features, namely, the coexistence of a specific clinical profile together with the presence or absence of particular types of lesion. In addition, the molecular profile of lesions has become an increasingly important feature both in the diagnosis of existing disorders and in the description of new disease entities. Recent studies, however, have reported considerable overlap between the clinicopathological features of many disorders leading to difficulties in the diagnosis of individual cases and to calls for a new classification of neurodegenerative disease. This article discusses: (i) the nature and degree of the overlap between different neurodegenerative disorders and includes a discussion of Alzheimer's disease, dementia with Lewy bodies, the fronto-temporal dementias, and prion disease; (ii) the factors that contribute to disease overlap, including historical factors, the presence of disease heterogeneity, age-related changes, the problem of apolipoprotein genotype, and the co-occurrence of common diseases; and (iii) whether the current nosological status of disorders should be reconsidered.

Brain↗

PubMed2004

Clinical impact of gene expression profiling on oncology diagnosis, prognosis, and treatment.

Genomics has enabled the examination of the totality of disease at the transcriptome level. Dependent upon a myriad of genetic aberrations for its pathogenesis, cancer has been the focus of gene expression profiling studies that have highlighted the potential clinical applications of this technology. This type of molecular profiling has the potential to enhance the ability of pathologists and oncologists to correctly classify tumors, not just into existing subgroups which may or may not have clear prognostic implications, but into new groups which carry predictable correlations with outcomes. Ultimately, these outcome predictions can be tied to specific treatment regimens, allowing clinicians to predict at the time of diagnosis to which therapy a given patient may best respond. Although this ultimate goal of personalized therapy remains in the future, the numerous studies to date have clearly demonstrated the overall feasibility of this approach. This review will showcase a few of these studies in several key tumor types with the goal of demonstrating which type of studies have been conducted and what types of results are currently possible.

Breast Neoplasms↗

PubMed2004

Molecular characterization of the transition to malignancy in a genetically engineered mouse-based model of ductal carcinoma in situ.

A transplantable model of human ductal carcinoma in situ that progresses to invasive carcinoma was developed from a genetically engineered mouse (GEM). Additional lines were established using early mammary premalignant lesions from transgenic MMTV-PyV-mT mice. These lines were verified to be premalignant and transplanted repeatedly to establish stable and predictable properties. Here, we report the first in-depth molecular analysis of neoplastic progression occurring in one premalignant transplantable GEM-derived line. Oligonucleotide microarrays showed that many genes are differentially expressed between the quiescent and prelactating mammary gland and the premalignant GEM outgrowth. In contrast, a small but consistent group of genes was associated with the transformation from premalignancy to tumor. This suggests that the majority of gene expression changes occur during the premalignant transition from normal to premalignancy, whereas many fewer changes occur during the malignant transition from premalignancy to invasive carcinoma. The premalignant transition is associated with several cell cycle-related genes and the up-regulation of oncogenes is associated with various cancers (Ccnd11, Cdk4, Myb, and Ect2). The changes identified in the malignant transition included genes previously associated with human breast cancer progression. Misregulation of the insulin-like growth factor and transforming growth factor-beta signaling pathways and the stromal-epithelial interaction were implicated. Our results suggest that this transplantable GEM-based model recapitulates human ductal carcinoma in situ at both histologic and molecular levels. With consistent tumor latency and molecular profiles, this model provides an experimental platform that can be used to assess functional genomics and molecular pharmacology and to test promising chemoprevention strategies.

Animals↗

PubMed2001

Gene expression profiling in the post-mortem human brain--no cause for dismay.

Global expression profiling techniques such as microarray technology promise to revolutionize biology. Soon it will be possible to investigate alterations at the transcript level of the entire human genome. There is great hope that these techniques will at last shed light on the pathological processes involved in complex neuropsychiatric disorders such as schizophrenia. These scientific advances in turn have re-kindled a great interest and demand for post-mortem brain tissue. Good quality post-mortem tissue undoubtedly is the fundamental prerequisite to investigate complex brain disorders with molecular profiling techniques. In this review we show that post-mortem brain tissue can yield good quality mRNA and intact protein antigens which allow the successful application of traditional molecular biology methods as well as novel profiling techniques. We also consider the use of laser-capture microdissection on post-mortem tissue. This recently developed technique allows the experimenter to explore the molecular basis of cellular function at the single cell level. The combination of laser-capture microdissection with high throughput profiling techniques offers opportunities to obtain precise genetic fingerprints of individual neurons allowing comparisons of normal and pathological states.

Autopsy↗

PubMed2004

Expression profiling of non-small cell lung carcinoma identifies metastatic genotypes based on lymph node tumor burden.

OBJECTIVE: This study hypothesized that non-small cell lung carcinoma cells from primary tumors isolated by laser capture microdissection would exhibit gene expression profiles associated with graded lymph node metastatic cell burden. METHODS: Non-small cell lung carcinoma tumors (n = 15) were classified on the basis of nodal metastatic cell burden by 2 methods, obtaining 3 groups: no metastasis, micrometastasis, and overt metastasis. We then performed microarray analysis on microdissected primary tumor cells and identified gene expression profiles associated with graded nodal tumor burden using a correlation-based selection algorithm coupled with cross-validation analysis. Hierarchical clustering showed the regrouping of tumor specimens; the classification inference was assessed with Fisher's exact test. We verified data for certain genes by using another independent assay. RESULTS: The 15 specimens clustered into 3 groups: cluster A predominated in specimens with overt nodal metastasis; cluster B had more specimens with nodal micrometastases; and cluster C included only specimens without nodal metastases. Cluster assignment was based on a validated 75-gene discriminatory subset. Notably, genes not previously associated with positive non-small cell lung carcinoma lymph node status were encountered in the profiling analysis. CONCLUSIONS: Microdissection, combined with microarray analysis, is a potentially powerful method to characterize the molecular profile of tumor cells. The 75-gene expression profiles representative of clusters A and B may define genotypes prone to metastasize. Overall, the 3 groups of tumor specimens clustered separately, suggesting that this approach may identify graded metastatic propensity. Further, genes singled out in clustering may yield insights into underlying metastatic mechanisms and may represent new therapeutic targets.

Carcinoma, Non-Small-Cell Lung↗

PubMed2006

[Current opinions on the treatment of androgen-independent prostate cancer].

Prostate cancer is a most common malignant neoplasm in males. In recent years, its incidence has been rising dramatically in China. Patients with recurrent prostate cancer may be treated with androgen deprivation strategies, but most cases will eventually develop into androgen-independent prostate cancer (AIPC). Until recently, chemotherapy has been shown to be effective in palliating the symptoms of the disease but not in improving survival. Current strategies for the treatment of AIPC have shown significant palliation, but no definitive increase in survival. Molecular mechanisms underlying the development of androgen-independent prostate cancer (AIPC) are poorly understood. However, there is growing evidence that different molecular profiles may result in the development of AIPC. In this paper, we not only review the molecular mechanism of AIPC, but also present some of the promising management principles and systemic chemotherapy options against AIPC.

Androgens↗

PubMed2003

Gene expression profiling detects gene amplification and differentiates tumor types in breast cancer.

Global gene expression analysis using microarrays has been used to characterize the molecular profile of tumors. Gene expression variability at the mRNA level can be caused by a number of different events, including novel signaling, downstream activation of transcription enhancers or silencers, somatic mutation, and genetic amplification or deletion. Genomic amplifications are commonly observed in cancer and often include known oncogenes. The tyrosine kinase-type cell surface receptor, ERBB2, is an oncogene located on chromosome 17q21.1 that is amplified in 10-40% of breast tumors. We report for the first time that phenylethanolamine N-methyltransferase (PNMT), proteasome subunit, beta type 3 (PSMB3), ribosomal protein L19 (RPL19), and nuclear receptor subfamily 1, group D, member 1 (NR1D1) are coexpressed with ERBB2 in 34 breast cancer biopsies and also mapped within the same chromosomal location as the ERBB2 gene. Consistent with previous reports, we also observed that the steroidogenic acute regulatory protein-related gene, MLN64, and growth factor receptor bound protein 7 were coexpressed with ERBB2. Coexpression and colocalization of PNMT and MLN64 with ERBB2 suggested that the amplification of ERBB2 includes the chromosomal region harboring these genes. This hypothesis was validated in a subset of 12 biopsies. Gene amplification of ERBB2, PNMT, and MLN64 significantly correlated with increased mRNA gene expression (P < 0.05). These results suggest that gene expression profiling of breast biopsies may become a valuable method for adequately characterizing and choosing treatment modality for patients with breast cancer.

Breast Neoplasms↗

PubMed2002

Impact of integrating clinical and genetic information.

To assess the relevance of molecular markers it is required to combine clinical and genetic information. For reliable assessment of parameters relevant to diagnostics and therapy large patient collectives must be characterized both with respect to phenotype and genotype. Matching of genetic data like gene expression profiles, molecular genetics and cytogenetics with clinical data like follow-up, morphological findings and diagnoses involves integration of complex databases. In the context of a nationwide leukemia research network in Germany we designed an integrated database covering both genetic and clinical data of patients. The system contains follow-up data and relevant laboratory modalities, i. e. cytomorphology, cytogenetics, molecular genetics, FISH, immunophenotyping and gene expression profiling. So far 13,541 cases from 7,746 patients treated by 1,225 physicians are documented. The data structure consists of up to 888 variables per case. From our experience, integration of clinical and genetic information requires significant efforts - including data protection issues -, but is feasible and improves data quality leading to faster and more reliable research results for the benefit of the patients.

Computer Systems↗

PubMed2002

Integrating cytogenetics and gene expression profiling in the molecular analysis of multiple myeloma.

Multiple Myeloma (MM), is a currently incurable malignancy of a terminally differentiated antibody secreting plasma cell (PC) that can be controlled with high dose therapy and stem cell support. Conventional cytogenetic analysis has revealed a genomic instability that sets MM apart from the other blood cell cancers. In spite of this "genomic chaos" recurrent structural rearrangements and ploidy changes have aided the identification of important molecular mechanisms of disease etiology and that have also proved to be useful clinical landmarks. Yet, abnormal cytogenetics, present in only 30% of cases, combined with other clinical parameters, only account for 20% of the variability in clinical outcome, which can range from 2 months to > 10 years. Thus, the genomic chaos may mask a unifying chromosome abnormality, e.g. Philadelphia chromosome in CML, or may indicate that MM is a broad descriptor of constellation of many distinct clinical and molecular entities. The advent of microarray profiling of global gene expression patterns is providing evidence that both of these possibilities may be true. We will discuss how the integration of conventional and molecular cytogenetics with gene expression profiling has confirmed past observations and, yet fundamentally changed the way we view the disease.

Chromosome Aberrations↗

PubMed2026

RAS Pathway Activation and Microenvironmental Adaptation as Hallmarks of Myeloid Sarcoma.

UNLABELLED: Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in approximately 20% of patients and remains strikingly understudied in large-scale genomic and multiomic investigations. The key drivers of its tumor evolution are largely unknown; timely detection in asymptomatic patients poses a clinical challenge, and effective treatment options are limited, as patients are often excluded from clinical trials, rendering it a largely neglected disease entity. In this study, we demonstrate that myeloid sarcoma evolves from medullary AML but exhibits distinct site-specific clonal evolution. This is supported by unique transcriptional signatures of myeloid sarcoma, reflecting adaptation to the extramedullary microenvironment. We establish a proof of concept that circulating tumor DNA (ctDNA) sequencing captures the molecular composition of myeloid sarcoma, offering a potential noninvasive approach for molecular profiling of extramedullary AML. Our findings highlight marked differences between medullary AML and myeloid sarcoma, including universal molecular evolution and RAS pathway activation as disease hallmarks. SIGNIFICANCE: We provide a comprehensive multiomic characterization of myeloid sarcoma, identifying key molecular pathways that contribute to its development, and suggest ctDNA as a noninvasive method of detection. We identify RAS pathway activation and transcriptional adaptation to the solid tissue microenvironment as cardinal features of myeloid sarcoma, suggesting novel therapeutic avenues.

Sarcoma, Myeloid↗

PubMed2026

Cellular transcriptomic signatures underpinning the heterogeneity of depression in Alzheimer's disease.

INTRODUCTION: Late-onset Alzheimer's disease (LOAD) and major depressive disorder (MDD) share genetic etiologies. Here, we investigated brain transcriptomic landscapes to gain insights into shared and divergent molecular and biological etiologies across LOAD and MDD. METHODS: Brain single-nucleus RNA sequencing (snRNA-seq) datasets from cognitively normal older and young individuals and LOAD patients stratified by comorbid MDD were analyzed to identify differential expressed genes (DEGs). Using cell type-specific DEGs we performed biological pathway and intercellular-communication networks analyses. We investigated shared DEGs across MDD and LOAD cohorts and sex-specific DEGs. Results were validated by comparison with four transcriptomic and proteomic studies of MDD and depression. RESULTS: MDD-associated dysregulated genes and pathways were shared between LOAD and cognitive-normal individuals, including JUNB and DUSP1 in glutamatergic neurons, and PRAM1 and SNX9 in microglia. DEGs shared between the MDD and LOAD cohorts included HSPA1A and NDUFB7 in glutamatergic neurons. Sex interaction analysis identified numerous new DEGs in the MDD cohorts, whereas there were ≈5 to 10 times more DEGs in female than in male individuals. LOAD and MDD common microglial pathways included neuronal injury, stress, peroxisome proliferator-activated receptor (PPAR) signaling and interferon alpha/beta signaling. DISCUSSION: LOAD and MDD exhibited common molecular profiles, dysregulated pathways, and cellular communication changes. MDD develops earlier in life, thus, our findings provide a window into early molecular and biological processes preceding LOAD-onset.

Humans↗

PubMed2002

HER-2 profiling and targeting in prostate carcinoma.

BACKGROUND: The clinical effects of targeting HER-2 in prostate carcinoma are not known. This study explored the feasibility of molecular profiling to determine the correlation between HER-2 expression, hormonal sensitivity, and the antitumor effects of trastuzumab and paclitaxel in patients with prostate carcinoma. METHODS: Patients with progressive androgen dependent (AD) and androgen independent (AI) prostate carcinoma were eligible to participate in the study. HER-2 expression was assessed on pretreatment tissue specimens, and patients were then assigned to one of four treatment groups: AD HER-2 positive, AD HER-2 negative, AI HER-2 positive, and AI HER-2 negative. They were treated with weekly trastuzumab at a dose of 2 mg/kg (after a 4 mg/kg loading dose) until they experienced disease progression, when weekly paclitaxel at 100 mg/m(2) was added. RESULTS: The authors screened 130 patients for HER-2 expression. In total, 23 patients were treated. Six eligible patients had HER-2 positive disease; therefore, only the AI HER-2 negative arm accrued to completion. All patients (100%) experienced disease progression on trastuzumab alone at or before the first 12 weeks of treatment. Fifteen patients received combined therapy: Seven patients (47%) experienced disease progression, 5 patients (33%) had stable disease, and 3 patients (20%) had a decline > or = 50% in prostate specific antigen PSA level or in soft tissue disease. HER-2 overexpression was found in significant proportions only in AI metastatic tissue samples (42% HER-2 positive; 95% confidence interval, 14-60%). In three of nine matched pairs, the AD prostate biopsy was HER-2 negative, and the AI metastatic sample was HER-2 positive. CONCLUSIONS: Trastuzumab is not effective as a single agent for the treatment of patients with AI HER-2 negative tumors. HER-2 expression varies by clinical state in patients with prostate carcinoma: Accurate HER-2 profiling requires sampling metastatic tissue in patients with metastatic disease. Further development of trastuzumab for the treatment of patients with metastatic prostate carcinoma is not feasible until more reliable and practical methods of sampling metastatic disease are developed to identify patients with HER-2 positive tumors.

Aged↗

PubMed2004

Applications of tissue microarray technology in immunohistochemistry: a study on c-kit expression in small cell lung cancer.

Tissue microarray technology allows the immediate evaluation of molecular profiles of numerous different tissues, with savings of money and time. It was created for rapid, large-scale molecular studies, and the main concern regarding its possible broad acceptance is that the analysis of tissue microarrays instead of whole tissue sections may lead to false negative or positive results because of tissue heterogeneity. In the present study, we analyzed in 54 small cell lung cancers, by immunohistochemistry, the expression of the antigen c-kit, which seems to be important in these neoplasms' tumorigenesis, and compared the staining obtained on whole sections with that of the corresponding tissue microarrays. Although c-kit expression of the whole sections agreed with that of the corresponding biopsies in many cases, the correlation between whole sections and all the companion nonlost single cores or their mean value turned out to be highly significant only if the 36 double negatives (ie, both whole sections and companion tissue microarrays negative) were included (P <0.0001). In fact, if only cases positive to at least 1 of the tests (i.e. whole sections or corresponding tissue microarrays positive) were considered, the correlation was not significant (P=0.055). Tissue microarrays showed a good specificity (94.2% for all single cores and 92.3% for their mean value) but a rather poor sensitivity (respectively, 69.4% and 71.4%). Moreover, a high percentage (13.4%) of cores was lost, and this loss was not random. To sum up, in our experience, tissue microarray technology cannot be a substitute for whole sections in clinical diagnosis of individual cases.

Adult↗

PubMedDate not supplied

Current molecular aspects of the carcinogenesis of the uterine endometrium.

Carcinogenesis in many tissues is a multistep process accompanied by a variety of morphologic, biochemical, and genetic changes in each step. It is well known that endometrial cancers arise through a series of precursor lesions, simple, complex, and atypical hyperplasia, by unopposed and prolonged estrogen stimulation. It is also accepted that there is an estrogen-independent type in which the precursor lesions are not identified. Recent molecular-based evidence has revealed three possible pathways for endometrial carcinogenesis, namely hyperplasia, metaplasia, and de novo pathways. The pathways each have their own features in both histopathology and molecular biology. Such understanding of the molecular profile of endometrial carcinoma prompted us to revise the classic criteria in histopathology regarding endometrial carcinogenesis. The recent molecular-based studies have provided a concept of endometrial intraepithelial lesions: endometrial intraepithelial neoplasia (EIN) as the precursor lesions of endometrial carcinomas. The new terminology might improve cancer screening protocols and treatment modalities.

Endometrial Hyperplasia↗