Peptide and protein imaging mass spectrometry in cancer research

MALDI mass spectrometry is able to acquire protein profiles directly from tissue that can describe the levels of hundreds of distinct proteins. MALDI imaging MS can simultaneously reveal how each of these proteins varies in heterogeneous tissues. Numerous studies have now demonstrated how MALDI imaging MS can generate different protein profiles from the different cell types in a tumor, which can act as biomarker profiles or enable specific candidate protein biomarkers to be identified.     

A novel indium-111-labeled gonadotropin-releasing hormone peptide for human prostate cancer imaging

The purpose of this study was to evaluate the tumor targeting and imaging properties of a novel (111)In-labeled gonadotropin-releasing hormone (GnRH) peptide {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-Ahx-(D-Lys(6)-GnRH1)} for human prostate cancer. The biodistribution and tumor imaging properties of (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1) were determined in DU145 human prostate cancer-xenografted nude mice. (111)In-DOTA-Ahx-(d-Lys(6)-GnRH1) exhibited rapid tumor uptake (1.27 ± 0.40% ID/g at 0.5h post-injection) coupled with fast whole-body clearance through the urinary system. The DU145 human prostate cancer-xenografted tumor lesions were clearly visualized by single photon emission computed tomography (SPECT)/CT at 0.5h post-injection of (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1). The successful imaging of DU145 human prostate cancer-xenografted tumor lesions using (111)In-DOTA-Ahx-(d-Lys(6)-GnRH1) highlighted its potential as a novel imaging probe for human prostate cancer imaging.     

Ubiquitous cancer genes: multipurpose molecules for protein micro-arrays

Multipurpose genes in the human genome which are over-expressed in a large variety of different cancers have been identified. Forty-two of the 19,016 human genes annotated to date (0.2%) are ubiquitously over-expressed in half or more of the 36 investigated human cancers. Of these genes, 15 are involved in protein biosynthesis and folding, six of them in glycolysis. A group of 13 solid tumours over-express almost all (39-42 of 42) ubiquitous cancer genes, suggesting a common mechanism underlying these cancers. Others, such as endocrine cancers, have only a few over-expressed ubiquitous cancer genes. The proteins for which these genes code or the corresponding antibodies are candidates for small protein microarrays aiming at maximum information with only a limited number of proteins. Since the over-expression pattern varies from cancer to cancer, distinction between different cancer classes is possible using one single set of protein or antibody molecules.     

A curated census of autophagy-modulating proteins and small molecules: Candidate targets for cancer therapy

Autophagy, a programmed process in which cell contents are delivered to lysosomes for degradation, appears to have both tumor-suppressive and tumor-promoting functions; both stimulation and inhibition of autophagy have been reported to induce cancer cell death, and particular genes and proteins have been associated both positively and negatively with autophagy. To provide a basis for incisive analysis of those complexities and ambiguities and to guide development of new autophagy-targeted treatments for cancer, we have compiled a comprehensive, curated inventory of autophagy modulators by integrating information from published siRNA screens, multiple pathway analysis algorithms, and extensive, manually curated text-mining of the literature. The resulting inventory includes 739 proteins and 385 chemicals (including drugs, small molecules, and metabolites). Because autophagy is still at an early stage of investigation, we provide extensive analysis of our sources of information and their complex relationships with each other. We conclude with a discussion of novel strategies that could potentially be used to target autophagy for cancer therapy.     

Iron nanoparticles from animal blood for cellular imaging and targeted delivery for cancer treatment

Background

Iron nanoparticles (INPs) are usually prepared from inorganic sources, but we have prepared it from goat blood using incineration method. These INPs are then coated with chitosan (C) and coupled with folic acid (F) to form bionanocomposite for folate receptors.

Methods

The bionanocomposite was characterized for its physicochemical properties and cancer cell targeting studies using Fourier transform infrared spectroscopy, transmission electron microscopy, Zeta potential analysis, scanning electron microscopy–energy dispersive X-ray spectroscopy and magnetic resonance imaging analyses.

Results

The results have shown that the particle size of the INP-CF was found to be 80–300 nm and confirmed the presence of chitosan and folic acid in the bionanocomposite. Cancer and normal mouse embryonic cell line study confirmed the internalization of INP-CF and this phenomenon was also supported by physicochemical studies.

Conclusion

Thus, nanobiocomposite prepared using natural sources as a raw material will be beneficial compared to commercially available synthetic sources and can be used as receptor targeting agent for cancer treatment. This nanobiocomposite when coupled with substances such as monoclonal antibodies might act as a theranostic nanoagent for cancer therapy in the years to come.

General significance

The prepared novel nanobiocomposite containing INPs isolated from natural source may be used as multifunctional agent due its paramagnetic property apart from its drug delivery effect.     

Identifications small molecules inhibitor of p53-mortalin complex for cancer drug using virtual screening

Mortalin was over expressed in tumor cells and bind to p53 protein. This interaction was suggested to promote sequestration of p53 in the cytoplasm, thereby inhibiting its nuclear activity. The p53 is a tumor suppressor that is essential for the prevention of cancer development and loss of p53 function is one of the early events in immortalization of human cells. Therefore, abrogation p53-mortalin interaction using small molecule is guaranteed stop cancer cell grow. However study interaction of p53-mortalin, and its inhibition using small molecule is still challenging because specific site of mortalin that bind to p53, vice versa, is still debatable. This study has aims to analyze the p53-binding site of mortalin using molecular docking and to screen drug-like compounds that have potential as inhibitors of p53-mortalin interaction using virtual screening. The result showed that the lowest energy binding of p53-mortalin complex is -31.89 kcal/mol, and p53 protein bind to substrate binding domain of mortalin (THR433; VAL435; LEU436; LEU437; PRO442; ILE558; LYS555). Furthermore, the p53-binding domain of mortalin was used as receptor to screen 9000 drug-like compounds from ZINC database using molecular docking program Auto Dock Vina in PyRx 0.8 (Virtual Screening Tools). Here, we have identified three drug-like compounds that are ZINC01019934, ZINC00624418 and ZINC00664532 adequate to interrupt stability of p53-mortalin complex that warrant for anticancer agent.     

Tissue transglutaminase: An emerging target for therapy and imaging

Tissue transglutaminase (transglutaminase 2) is a multifunctional enzyme with many interesting properties resulting in versatile roles in both physiology and pathophysiology. Herein, the particular involvement of the enzyme in human diseases will be outlined with special emphasis on its role in cancer and in tissue interactions with biomaterials. Despite recent progress in unraveling the different cellular functions of transglutaminase 2, several questions remain. Transglutaminase 2 features in both confirmed and some still ambiguous roles within pathological conditions, raising interest in developing inhibitors and imaging probes which target this enzyme. One important prerequisite for identifying and characterizing such molecular tools are reliable assay methods to measure the enzymatic activity. This digest Letter will provide clarification about the various assay methods described to date, accompanied by a discussion of recent progress in the development of inhibitors and imaging probes targeting transglutaminase 2.     

Protein-protein interactions and cancer: small molecules going in for the kill

There has been much progress in the discovery of small, organic molecules that inhibit protein-protein interactions, particularly in the field of cancer. Tubulin polymerization represents a classic target whose function can be allosterically modulated by small molecules. Several protein-protein complexes that regulate apoptosis, or programmed cell death, appear to be particularly amenable to inhibition by small molecules, and recently described compounds have helped to characterize Bcl-2, MDM2 and XIAP as drug targets. Additionally, small-molecule antagonists have recently been described for several new targets, including Rac1-Tiam1, beta-catenin-T cell factor (Tcf), and Sur-2-ESX. Not only is the list of protein-protein inhibitors growing, but the inhibitors themselves are moving closer to treating disease.     

Seek & Destroy, use of targeting peptides for cancer detection and drug delivery

Accounting for 16 million new cases and 9 million deaths annually, cancer leaves a great number of patients helpless. It is a complex disease and still a major challenge for the scientific and medical communities. The efficacy of conventional chemotherapies is often poor and patients suffer from off-target effects. Each neoplasm exhibits molecular signatures – sometimes in a patient specific manner – that may completely differ from the organ of origin, may be expressed in markedly higher amounts and/or in different location compared to the normal tissue. Although adding layers of complexity in the understanding of cancer biology, this cancer-specific signature provides an opportunity to develop targeting agents for early detection, diagnosis, and therapeutics. Chimeric antibodies, recombinant proteins or synthetic polypeptides have emerged as excellent candidates for specific homing to peripheral and central nervous system cancers. Specifically, peptide ligands benefit from their small size, easy and affordable production, high specificity, and remarkable flexibility regarding their sequence and conjugation possibilities. Coupled to imaging agents, chemotherapies and/or nanocarriers they have shown to increase the on-site delivery, thus allowing better tumor mass contouring in imaging and increased efficacy of the chemotherapies associated with reduced adverse effects. Therefore, some of the peptides alone or in combination have been tested in clinical trials to treat patients. Peptides have been well-tolerated and shown absence of toxicity. This review aims to offer a view on tumor targeting peptides that are either derived from natural peptide ligands or identified using phage display screening. We also include examples of peptides targeting the high-grade malignant tumors of the central nervous system as an example of the complex therapeutic management due to the tumor’s location. Peptide vaccines are outside of the scope of this review.     

A simple but effective cancer vaccine consisting of an antigen and a cationic lipid

Developing a cancer vaccine with a potent adjuvant, which is safe for human use, remains to be an unmet need. In this study, we developed a simple, safe, yet efficient, peptide-based therapeutic cancer vaccine, DOTAP/E7 complex, which comprises only two molecules: a DOTAP cationic lipid and a peptide antigen derived from E7 oncoprotein of human papillomavirus (HPV) type 16. The anti-cancer activity of DOTAP/E7 against existing HPV positive TC-1 tumor was compared to that of our previous LPD/E7 formulation, which contains bacterial DNA CpG motifs. Tumor-bearing mice showed significant tumor inhibition following a single vaccination of either formulation at the optimal lipid dose, suggesting that DOTAP liposome alone can provide a potent adjuvant activity without plasmid DNA. E7 peptide formulated with DOTAP induced migration of activated dendritic cells (DC) to the draining lymph node (DLN) and efficiently generated functional antigen-specific CD8⁺ T lymphocyte responses. Accumulation of CD8⁺ tumor infiltrating T cells and apoptosis at tumor sites were observed after treatment with DOTAP/E7 complexes, which was also associated with a decreased amount of CD25⁺Foxp3⁺ regulatory T cells in treated animals. Reactive oxygen species (ROS) induced by DOTAP cationic lipid in DLN revealed a plausible mechanism of the initial interaction between DC and DOTAP. An adequate amount of ROS generation was apparently required for the initiation of the vaccine mechanism; however, an overdose of DOTAP induced massive ROS production and apoptosis of DC in DLN, which led to diminished anti-cancer immunity. Overall, these results indicate that cationic lipid DOTAP alone serves as an efficient vaccine adjuvant for the induction of a therapeutic, antigen-specific anti-cancer activity.     

Clinical relevance of novel imaging technologies for sentinel lymph node identification and staging

The sentinel lymph node (SLN) concept has become a standard of care for patients with breast cancer and melanoma, yet its clinical application to other cancer types has been somewhat limited. This is mainly due to the reduced accuracy of conventional SLN mapping techniques (using blue dye and/or radiocolloids as lymphatic tracers) in cancer types where lymphatic drainage is more complex, and SLNs are within close proximity to other nodes or the tumour site. In recent years, many novel techniques for SLN mapping have been developed including fluorescence, x-ray, and magnetic resonant detection. Whilst each technique has its own advantages/disadvantages, the role of targeted contrast agents (for enhanced retention in the SLN, or for immunostaging) is increasing, and may represent the new standard for mapping the SLN in many solid organ tumours. This review article discusses current limitations of conventional techniques, limiting factors of nanoparticulate based contrast agents, and efforts to circumvent these limitations with modern tracer architecture.     

Nanomaterials for cancer therapy and imaging

A variety of organic and inorganic nanomaterials with dimensions below several hundred nanometers are recently emerging as promising tools for cancer therapeutic and diagnostic applications due to their unique characteristics of passive tumor targeting. A wide range of nanomedicine platforms such as polymeric micelles, liposomes, dendrimers, and polymeric nanoparticles have been extensively explored for targeted delivery of anti-cancer agents, because they can accumulate in the solid tumor site via leaky tumor vascular structures, thereby selectively delivering therapeutic payloads into the desired tumor tissue. In recent years, nanoscale delivery vehicles for small interfering RNA (siRNA) have been also developed as effective therapeutic approaches to treat cancer. Furthermore, rationally designed multi-functional surface modification of these nanomaterials with cancer targeting moieties, protective polymers, and imaging agents can lead to fabrication versatile theragnostic nanosystems that allow simultaneous cancer therapy and diagnosis. This review highlights the current state and future prospects of diverse biomedical nanomaterials for cancer therapy and imaging.     

Synthesis and evaluation of 11C-labeled coumarin analog as an imaging probe for detecting monocarboxylate transporters expression

Upregulated monocarboxylate transporters (MCTs) in tumors are considered diagnostic imaging targets. Herein, we synthesized the positron emission tomography probe candidates coumarin analogs 2 and 3, and showed 55 times higher affinity of 2 for MCTs than a representative MCT inhibitor. Whereas [¹¹C]2 showed low tumor accumulation, probably due to adduct formation with plasma proteins, [¹¹C]2 showed high initial brain uptake, suggesting that the scaffold of 2 has properties that are preferable in imaging probes for the astrocyte–neuron lactate shuttle. Although further optimization of 2 is required, our findings can be used to inform the development of MCT-targeted imaging agents.     

Advances in ovarian cancer screening: health and medicine for women: a multidisciplinary, evidence-based review of mid-life health concerns

Early detection is imperative for improving survival from ovarian cancer, the leading cause of death from gynecological cancer in the United States. At the Health and Medicine for Women continuing medical education (CME) conference at Yale in September 2010, Dr. Gil Mor, a researcher in the Department of OB/GYN at Yale, presented recent advances on the pathophysiology of ovarian cancer. These advances, and particularly our growing understanding of cancer stem cells, may help overcome the limitations of current ovarian cancer detection and treatment methods.     

A snapshot of cancer in Chile: analytical frameworks for developing a cancer policy

Introduction

The South American country Chile now boasts a life expectancy of over 80 years. As a consequence, Chile now faces the increasing social and economic burden of cancer and must implement political policy to deliver equitable cancer care. Hindering the development of a national cancer policy is the lack of comprehensive analysis of cancer infrastructure and economic impact.

Objectives

Evaluate existing cancer policy, the extent of national investigation and the socio-economic impact of cancer to deliver guidelines for the framing of an equitable national cancer policy.

Methods

Burden, research and care-policy systems were assessed by triangulating objective system metrics – epidemiological, economic, etc. – with political and policy analysis. Analysis of the literature and governmental databases was performed. The oncology community was interviewed and surveyed.

Results

Chile utilizes 1% of its gross domestic product on cancer care and treatment. We estimate that the economic impact as measured in Disability Adjusted Life Years to be US$ 3.5 billion. Persistent inequalities still occur in cancer distribution and treatment. A high quality cancer research community is expanding, however, insufficient funding is directed towards disproportionally prevalent stomach, lung and gallbladder cancers.

Conclusions

Chile has a rapidly ageing population wherein 40% smoke, 67% are overweight and 18% abuse alcohol, and thus the corresponding burden of cancer will have a negative impact on an affordable health care system. We conclude that the Chilean government must develop a national cancer strategy, which the authors outline herein and believe is essential to permit equitable cancer care for the country.     

Statin use after esophageal cancer diagnosis and survival: A population based cohort study

BackgroundA recent epidemiological study of esophageal cancer patients concluded statin use post-diagnosis was associated with large (38%) and significant reductions in cancer-specific mortality. We investigated statin use and cancer-specific mortality in a large population-based cohort of esophageal cancer patients.MethodsNewly diagnosed [2009–2012] esophageal cancer patients were identified from the Scottish Cancer Registry and linked with the Prescribing Information System and Scotland Death Records (to January 2015). Time-dependent Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% confidence intervals (CIs) by post-diagnostic statin use (using a 6 month lag to reduce reverse causation) and to adjust these HRs for potential confounders.Results1921 esophageal cancer patients were included in the main analysis, of whom 651 (34%) used statins after diagnosis. There was little evidence of a reduction in esophageal cancer-specific mortality in statin users compared with non-users after diagnosis (adjusted HR = 0.93, 95% CI, 0.81, 1.07) and no dose response associations were seen. However, statin users compared with non-users in the year before diagnosis had a weak reduction in esophageal cancer-specific mortality (adjusted HR = 0.88, 95% CI, 0.79, 0.99).ConclusionsIn this large population-based esophageal cancer cohort, there was little evidence of a reduction in esophageal cancer-specific mortality with statin use after diagnosis.     

siRNAs and miRNAs: small RNA molecules for big tasks

Small RNAs have been recently discovered as important regulators of gene expression in Eukaryota. This review compares two categories of small RNAs existing in plants: short interfering RNAs (siRNAs) and microRNAs (miRNAs) and reveals similarities and differences between two intriguing processes: RNA degradation and translational repression directed by small RNAs. The disruption of miRNA-mediated regulation causes developmental abnormalities in plants, proving a fundamental role of miRNAs.     

Accuracy and completeness of the New Zealand Cancer Registry for staging of invasive breast cancer

PurposePopulation based cancer registries are an invaluable resource for monitoring incidence and mortality for many types of cancer. Research and healthcare decisions based on cancer registry data rely on the case completeness and accuracy of recorded data. This study was aimed at assessing completeness and accuracy of breast cancer staging data in the New Zealand Cancer Registry (NZCR) against a regional breast cancer register.MethodologyData from 2562 women diagnosed with invasive primary breast cancer between 1999 and 2011 included in the Waikato Breast Cancer Register (WBCR) were used to audit data held on the same individuals by the NZCR. WBCR data were treated as the benchmark.ResultsOf 2562 cancers, 315(12.3%) were unstaged in the NZCR. For cancers with a known stage in the NZCR, staging accuracy was 94.4%. Lower staging accuracies of 74% and 84% were noted for metastatic and locally invasive (involving skin or chest wall) cancers, respectively, compared with localized (97%) and lymph node positive (94%) cancers. Older age (>80 years), not undergoing therapeutic surgery and higher comorbidity score were significantly (p < 0.01) associated with unstaged cancer. The high proportion of unstaged cancer in the NZCR was noted to have led to an underestimation of the true incidence of metastatic breast cancer by 21%. Underestimation of metastatic cancer was greater for Māori (29.5%) than for NZ European (20.6%) women. Overall 5-year survival rate for unstaged cancer (NZCR) was 55.9%, which was worse than the 5-year survival rate for regional (77.3%), but better than metastatic (12.9%) disease.ConclusionsUnstaged cancer and accuracy of cancer staging in the NZCR are major sources of bias for the NZCR based research. Improving completeness and accuracy of staging data and increasing the rate of TNM cancer stage recording are identified as priorities for strengthening the usefulness of the NZCR.     

Synthesis and preclinical evaluation of 68Ga-PSMA-BCH for prostate cancer imaging

Prostate specific membrane antigen (PSMA) is a promising target for the diagnosis and therapy of prostate cancer. In this report, a NOTA-conjugated precursor, NOTA-PSMA (also named PSMA-BCH), was synthesized by peptide synthesizer with the chemical purity over 95%. ⁶⁸Ga-PSMA-BCH was obtained by radiolabeling NOTA-PSMA with ⁶⁸GaCl₃ with >99% radiochemical purity and 59–74?GBq/μmol specific activity. In vitro and in vivo study of ⁶⁸Ga-PSMA-BCH showed high stability, high uptake in PSMA-expressing cells and tumor, fast clearance and low non-target uptake. 22Rv1 tumors were clearly observed in micro-PET images of and showed good retention. Compared with ⁶⁸Ga-PSMA-617, ⁶⁸Ga-PSMA-BCH showed comparable tumor uptake and tumor-background ratios. Indicating ⁶⁸Ga-PSMA-BCH is a promising candidate for prostate cancer imaging and worthy of further clinical investigations.     

Nanostructure Initiator Mass Spectrometry for tissue imaging in metabolomics: future prospects and perspectives

Mass spectrometry-based metabolomics provides a new approach to interrogate mechanistic biochemistry related to natural processes such as health and disease. Physiological and pathological conditions, however, are characterized not only by the identities and concentrations of metabolites present, but also by the location of metabolites within a tissue. Unfortunately, most relevant MS platforms in metabolomics can only measure samples in solution, therefore metabolites are typically extracted by tissue homogenization. Recent developments of imaging-MS technologies, however, have allowed particular metabolites to be spatially localized within biological tissues. In this context, Nanostructure-Initiator Mass Spectrometry (NIMS), a matrix-free technique for surface-based analysis, has proven an alternative approach for tissue imaging of metabolites. Here we review the basic principles of NIMS for tissue imaging and show applications that can complement LC/MS and GC/MS-based metabolomic studies investigating the mechanisms of fundamental biological processes. In addition, the new surface modifications and nanostructured materials herein presented demonstrate the versatility of NIMS surface to expand the range of detectable metabolites.