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Speakers and participants at the 12th Symposium on Medicinal Chemistry in Eastern England, held April 26, 2001, in Hatfield, U.K., considered a wide spectrum of therapeutic targets. From the talks and discussions, two important common themes were evident: the validation of targets and models and the integration of a range of disciplines early in the medicinal chemistry process.
Over the last decade, the concept of dialysis adequacy has evolved to become a component of the optimal dialysis that includes quantitative and qualitative aspects. Current method used to assess dialysis efficacy in ESRD patients relies on a targeting approach using several vital indicators. Dialysis quality is a complex and evolutionary concept that has to be viewed in a quality assurance process to improve outcomes of ESRD patients. To simplify this assessment we propose a quantitative approach including several steps: the first step consists of selecting pertinent indicators (targets) tracking specific uremia metabolic abnormalities and defining suitable range values (target values); the second step consists of defining a method checking that targeted values are achieved on a regular basis; the third step consists of validating that targeted values offer the best survival to ESRD patients; the fourth step consists of correcting treatment prescription (treatment schedule) and implementation (effective treatment delivered) to improve treatment delivery and performances. Based on this approach, it is then possible to assess the efficacy of dialysis therapy both at the individual and at the dialysis unit level, that can be easily implemented in a computerized automatic control system.
The potential of therapeutic targeting of tumor cell surface epidermal growth factor receptors (EGFRs) by modified ligands or specific antibodies has been limited by the normal tissue distribution of the receptor. The identification and characterization of a variant of this receptor, EGFRvIII, which is not expressed in normal tissues but has been described in gliomas, non-small cell lung carcinomas, and breast carcinomas, has provided a highly specific, internalizing target for antibody-mediated approaches. To determine the feasibility of immunotargeting EGFRvIII, we have assessed the qualitative distribution and quantitative expression at both the population and cellular levels of EGFRvIII in 21 biopsy samples of human gliomas by indirect analytical and quantitative flow cytometry and by immunohistochemical assay of frozen and formalin-fixed tissue. Consistent with previous reports, 50% of gliomas tested (1 of 2 anaplastic astrocytomas, 7 of 12 glioblastoma multiforme, and 2 of 6 oligodendrogliomas) expressed EGFRvIII, as determined by a minimum of 2 separate assays. Minimum estimates of the proportion of positive tumor cells in these populations ranged from 37-86%; in four of five cases in which quantitation of the EGFRvIII density/cell was performed, values of 2.7-6.8 x 10(5) were obtained with monoclonal antibody (mAb) L8A4 (EGFRvIII specific), levels consistent with successful in vivo immunotargeting. Confocal microscopic analysis confirmed that the subcellular localization of EGFRvIII was identical to that described for EGFR: predominant cell membrane expression, with some perinuclear distribution suggestive of localization to the Golgi region. Neither EGFR nor EGFRvIII was found within the nucleus. This study establishes for the first time that approximately 50% of human glioma biopsies contain cell populations expressing a sufficient number of membrane-expressed EGFRvIIIs to mediate specific anti-EGFRvIII mAb localization. Coupled with previous demonstrations of the rapid internalization of specific mAb-EGFRvIII complexes and the susceptibility of the targeted cells to isotope or toxin-mediated cytotoxicity, this study establishes the validity of targeting EGFRvIII for therapy of mutant receptor-positive gliomas, breast carcinomas, and non-small cell lung carcinomas.
OBJECTIVES: To describe the recruitment, enrollment, and retention of women participating in the Women on the Move study, a physical activity validation study targeting urban minority women aged 40 to 70 years. DESIGN: The intensive 15-day validation protocol included ingestion of doubly labeled water (2H2 18O), collection of 9 urine samples, completion of multiple physical activity surveys, including selected questions from the BRFSS and NHANES III, wearing an accelerometer, and completing a detailed diary of physical activity for 7 days. The follow-up interview included completion of more questionnaires, followed by measurement of resting metabolic rate. In planning for recruitment, enrollment, and retention of participants, investigators consulted with a community advisory board and conducted focus groups with members of the target communities and with key community leaders. METHODS: Recruitment methods included print, television, and radio advertisements and presentations at community health fairs, churches, and health clinics. RESULTS: Of the 656 women who expressed interest in the study, 386 (59%) met eligibility criteria, and 260 were enrolled (130 Latina, 130 African-American). To retain participants in the study, investigators had intensive telephone contact with the participants, scheduled meetings at times and locations convenient for the participants, used bilingual and bicultural staff, and offered participants staged monetary payments. Of the women enrolled, the retention for the meetings that could happen at more convenient locations was 98.8% and for the required meeting at a central location it was 85.4%. CONCLUSION: Experience from the Women on the Move study suggests that by working with community members, Latina and African-American women can be successfully recruited and, through extensive contact, retained, even in research studies with demanding protocols.
RNA interference (RNAi) is widely used to specifically silence the expression of any gene to study its function and to identify and validate therapeutic targets. Despite the popularity of this technology, recent studies have shown that RNAi may also silence non-targeted genes. Here we demonstrate the utility of a quick, efficient and robust approach to directly validate the specificity of RNAi as an alternative to indirect validation of RNAi through gene expression profiling. Our approach involves reversing (complementing) the RNAi-induced phenotype by introducing a synthetic version of the target gene that is designed to escape silencing. This synthetic gene complementation approach can also be used for mutational analysis of the target gene, or to provide a functional version of a defective protein after silencing the defective gene by RNAi. Using this approach we demonstrate that the loss of systemic acquired resistance, a form of innate immunity in plants, is indeed due to the silencing of salicylic acid-binding protein 2 rather than to off-target effects.
Initially linked to the pathogenesis of inflammatory and hematologic diseases, integrins have become validated drug targets with the approval of five drugs. Moreover, there are several promising drug candidates in preclinical and clinical stages of development for multiple clinical indications. Integrins are attractive drug targets as their antagonism can block several steps in disease progression or maintenance. Integrin inhibitors can block the proliferation, migration, or tissue localization of inflammatory, angiogenic, and tumor cells, as well as signaling and gene expression contributing to disease. There has been a rapid increase in the elucidation of integrin structure, their allosteric mechanisms of bidirectional signaling, and the structure of complexes with drugs. This information brings greater focus to how integrins support various cellular functions and how they have been and may be targeted to develop novel drugs. Here we review conformational switches, including an internal ligand, which allosterically regulate the transition from low- to high-affinity ligand binding. We address some of the successes, disappointments, and challenges in targeting competitive or allosteric sites to develop therapeutics. We also discuss new opportunities, including a structure-based approach to discover novel drugs to treat inflammatory and other diseases. This approach targets structural relatives of the von Willebrand factor A-domain present in integrins and many functionally diverse proteins.
With almost 40 million people infected with human immunodeficiency virus (HIV), it is one of the most devastating diseases with no cure in sight. Over the past two decades, significant progress has been made to identify and validate drug targets for HIV. However, most of the 20 FDA approved drugs are targeted to two enzymes; reverse transcriptase and protease. Other drug targets derived from HIV and host factors are being validated, and novel compounds are being developed to overcome drug resistance. Recent data indicate that low and residual virus found in tissues of the lymphoid and central nervous system (CNS) is likely due to insufficient drug levels. Thus, improvement in the delivery of anti-HIV drugs to these tissues with limited drug penetration or accumulation, is equally important to maximally suppress viral replication. Novel lipid associated drugs (i.e. indinavir) targeted to the lymphoid tissue have been shown to overcome limited drug exposure in the lymph nodes and to further reduce residual virus in tissue. This review discusses viral and cellular targets that could interrupt viral replication, as well as novel and proven strategies to enhance the delivery of anti-HIV drugs to the lymphoid, CNS, and cells where low viral replication and limited drug levels exist.
Protein phosphorylation is a key mechanism of cell regulation in normal and cancer cells. Various new cancer drugs and drug candidates are aimed at protein kinase targets. However, selecting patients likely to respond to these treatments, even among individuals with tumors expressing validated kinase targets remains a major challenge. There exists a need for biomarkers to facilitate the monitoring of modulation of drug-targeted kinase pathways. Phospho-proteomics involves the enrichment of phosphorylated proteins from tissue, and the application of technologies such as mass spectrometry (MS) for the identification and quantification of protein phosphorylation sites. It has potential to provide pharmacodynamic readouts of disease states and cellular drug responses in tumor samples, but technical hurdles and bioinformatics challenges will need to be addressed.
The failure of matrix metalloproteinase (MMP) inhibitor drug clinical trials in cancer was partly due to the inadvertent inhibition of MMP antitargets that counterbalanced the benefits of MMP target inhibition. We explore how MMP inhibitor drugs might be developed to achieve potent selectivity for validated MMP targets yet therapeutically spare MMP antitargets that are critical in host protection.
MOTIVATION: Cancer remains a leading cause of mortality globally. Recent improvements in survival have been facilitated by the development of targeted and less toxic immunotherapies, such as chimeric antigen receptor (CAR)-T cells and antibody-drug conjugates (ADCs). These therapies, effective in treating both pediatric and adult patients with solid and hematological malignancies, rely on the identification of cancer-specific surface protein targets. While technologies like RNA sequencing and proteomics exist to survey these targets, identifying optimal targets for immunotherapies remains a challenge in the field. RESULTS: To address this challenge, we developed ImmunoTar, a novel computational tool designed to systematically prioritize candidate immunotherapeutic targets. ImmunoTar integrates user-provided RNA-sequencing or proteomics data with quantitative features from multiple public databases, selected based on predefined criteria, to generate a score representing the gene's suitability as an immunotherapeutic target. We validated ImmunoTar using three distinct cancer datasets, demonstrating its effectiveness in identifying both known and novel targets across various cancer phenotypes. By compiling diverse data into a unified platform, ImmunoTar enables comprehensive evaluation of surface proteins, streamlining target identification and empowering researchers to efficiently allocate resources, thereby accelerating the development of effective cancer immunotherapies. AVAILABILITY AND IMPLEMENTATION: Code and data to run and test ImmunoTar are available at https://github.com/sacanlab/immunotar.
Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and/or survival. Hsp90 client proteins include telomerase, mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2), mutated B-Raf, mutated EGF receptor, and HIF-1alpha. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause inactivation, destabilization and eventual degradation of Hsp90 client proteins, and they have shown promising anti-tumor activity in various preclinical tumor models. One Hsp90 inhibitor, 17-AAG, is currently in Phase II clinical trial and other inhibitors will shortly be entering the clinic. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways on which cancer cells depend for growth and survival. Identification of benzoquinone ansamycins as the first Hsp90 inhibitors allowed investigators to determine the biologic effects, at first in vitro and then in vivo, of pharmacologic inhibition of Hsp90. These studies rapidly enhanced our understanding of Hsp90 function and led to the identification of radicicol as a structurally distinct Hsp90 inhibitor. Additional target-based screening uncovered novobiocin as a third structurally distinct small molecule with Hsp90 inhibitory properties. Use of novobiocin, in turn, led to identification of a previously uncharacterized C-terminal ATP binding site in the chaperone. Small molecule inhibitors of Hsp90 have been very useful in understanding Hsp90 biology and in validating this protein as a molecular target for anti-cancer drug development.
In a previous meta-analysis of intracoronary brachytherapy (ICBT) studies, we identified the target tissue at 0.6 to 0.7 mm tissue depth and we developed two models, describing the relationship between dose and ICBT effectiveness. The purpose of the present study was to validate the identified target tissue depth and the developed dose models, using the results of 1) two prospective animal studies with ICBT, 2) a retrospective analysis of animal studies with external beam irradiation and 3) results of recent clinical ICBT trials. ICBT effectiveness in the porcine restenosis studies was quantified as inhibition of neointima proliferation. The results of these studies were correlated with the developed dose-effectiveness model. Finally, the agreement of the restenosis rates of the recent clinical trials with the developed dose-restenosis model was tested. The porcine restenosis studies demonstrated a dose-related inhibition of neointima proliferation. The radiation effectiveness of both prospective studies and the effectiveness of the studies with external beam irradiation demonstrated the best agreement with the developed dose model at a tissue depth of 0.6 mm. Furthermore, the restenosis rates of the recent clinical ICBT studies were in concordance with the developed dose-restenosis model. In conclusion, the current study validated the localization of the target tissue for ICBT at a tissue depth of 0.6 to 0.7 mm as well as the relationship between dose and ICBT effectiveness at this depth. The data provide a rationale for setting a common dose prescription point at 0.6 to 0.7 mm tissue depth.
The specific binding of aminoglycoside antibiotics to the bacterial ribosomal decoding site (A-site) has inspired the study of RNA-small molecules interactions and the search for novel RNA binders. Among the numerous RNA targets studied so far, the A-site holds a unique place. It is among the few truly validated RNA targets for which naturally occurring ligands have been discovered as "cognate" binders. In addition, due to its encapsulating architecture, the A-site is a more discriminating RNA target when compared to other RNA sequences. Previous observations and current challenges for the designers of potent and specific RNA binders are discussed.
The pharmaceutical industry has come under increasing pressure due to regulatory restrictions on the marketing and pricing of drugs, competition, and the escalating costs of developing new drugs. These forces can be addressed by the identification of novel targets, reductions in the development time of new drugs, and increased productivity. Emphasis has been placed on identifying and validating new targets and on lead generation: the response from industry has been very evident in genomics and high throughput screening, where new technologies have been applied, usually coupled with a high degree of automation. The combination of numerous new potential biological targets and the ability to screen large numbers of compounds against many of these targets has generated the need for large diverse compound collections. To address this requirement, high-throughput chemistry has become an integral part of the drug discovery process.
Effective T cell-based immunotherapies require functional receptors that can be engineered and redeployed to recognize tumor-restricted antigens. Noncanonical peptides arising from transcription outside annotated protein-coding regions expand the antigenic landscape of cancer; however, systematic strategies to biologically prioritize and functionally validate such targets remain underdeveloped. Here, we integrated de novo transcript analysis, exon-resolved quantification, RNA in situ hybridization, and immunopeptidomics to identify melanoma-associated noncanonical transcripts and advance candidates through receptor-level validation. Among three recurrent melanoma-associated transcripts, EVA003 emerged as a lead target based on its distinct repeat-enriched genomic architecture, consistent tumor-enriched exon-level expression across independent datasets, and a genomically unique immunogenic core sequence. We demonstrate endogenous presentation of EVA003-derived peptides on HLA-A*03:01 and detect specific reactivity in patient-derived tumor-infiltrating lymphocytes. Single-cell transcriptomic profiling identified a dominant peptide-reactive clonotype, enabling isolation of a naturally occurring T cell receptor. Transfer of this receptor into healthy donor T cells conferred antigen-dependent activation and cytotoxicity against both peptide-pulsed targets and melanoma cells expressing EVA003 endogenously. Together, these findings establish a biologically informed strategy for prioritizing noncanonical tumor antigens and demonstrate that genomically unique, tumor-enriched noncanonical peptides can be presented to molecularly defined receptors capable of mediating cancer cell killing. These findings support the integration of prioritized noncanonical antigens into engineered T cell therapeutic strategies.
In radiation therapy with hadron beams, conformal irradiation to a tumour can be achieved by using the properties of incident ions such as the high dose concentration around the Bragg peak. For the effective utilization of such properties, it is necessary to evaluate the volume irradiated with hadron beams and the deposited dose distribution in a patient's body. Several methods have been proposed for this purpose, one of which uses the positron emitters generated through fragmentation reactions between incident ions and target nuclei. In the previous paper, we showed that the maximum likelihood estimation (MLE) method could be applicable to the estimation of beam end-point from the measured positron emitting activity distribution for mono-energetic beam irradiations. In a practical treatment, a spread-out Bragg peak (SOBP) beam is used to achieve a uniform biological dose distribution in the whole target volume. Therefore, in the present paper, we proposed to extend the MLE method to estimations of the position of the distal and proximal edges of the SOBP from the detected annihilation gamma ray distribution. We confirmed the effectiveness of the method by means of simulations. Although polyethylene was adopted as a substitute for a soft tissue target in validating the method, the proposed method is equally applicable to general cases, provided that the reaction cross sections between the incident ions and the target nuclei are known. The relative advantage of incident beam species to determine the position of the distal and the proximal edges was compared. Furthermore, we ascertained the validity of applying the MLE method to determinations of the position of the distal and the proximal edges of an SOBP by simulations and we gave a physical explanation of the distal and the proximal information.
Ischemic cardiac injury is a complication of atherosclerosis, which remains a major contributor to morbidity and mortality throughout much of the world. Previous studies have documented apoptotic cardiomyocyte death in this setting; however, its functional contribution remains incompletely defined. We briefly review general mechanisms of apoptosis and then present evidence from interventional studies that suggests apoptotic cell death may indeed play an important role in the pathogenesis of ischemic injury. In some instances, the signaling pathways controlling both cardiomyocyte survival and function appear to converge, suggesting these pathways may represent particularly attractive targets for therapeutic intervention in ischemic heart disease. In this context, gene transfer provides both a powerful experimental tool for validating such targets for intervention, as well as an approach to therapy.
We examined the influence of auditory spatial cues on the processing of subsequently presented lateralized auditory target stimuli. In three experiments, effects of the position of the cue on event-related potentials (ERPs) and reaction times (RTs) to the target, which could occur at the same or at a different position to the cue, were examined. In Experiments I and II, stimulus-pairs were delivered via loudspeakers 13 degrees to the right or left of fixation. The cue was task-irrelevant in the sense that it never required a response, whereas the target was task-relevant. In Experiment I, the cue was not informative about the position of the succeeding target, that is, the target was presented at the same or at a different position to the cue with equal probability. In Experiment II, the cue predicted a target with high validity, occurring at the position opposite to the cue. In both experiments, the ERPs to targets presented at the same position as the preceding cue were negatively modulated compared with the ERPs to targets presented at a different position. This negative difference (Nd) between the ERPs to same and different position stimuli occurring between 200-300 ms relative to target onset was also obtained in situations where no overt behavior was required. Effects of cue position on RTs to the target were only observed in Experiment II, being shorter for validly predicted targets. These Nd effects either reflect refractoriness of location-specific exogeneous ERP components or involuntary attentional selection. In order to decide between these alternatives, a third experiment was performed, in which stimulus-pairs were presented via headphones to the left and right ear in attend and ignore condition. An Nd effect was obtained in the attend condition only. The absence of Nd effects in the ignore condition suggests that the Nd obtained in attend condition cannot completely be explained by refractoriness of exogeneous ERP components and thus reflects attentional processes.