Cancer treatment-related cardiovascular disease: Current status and future research priorities.

With the development of new drugs, such as molecular-targeted drugs, and multidisciplinary therapies, cancer treatment outcomes have improved, and the number of cancer survivors is increasing every year. However, some chemotherapeutic agents cause cardiovascular complications (cancer treatment-related cardiovascular disease, CTRCVD), which affect the life prognosis and quality of life (QOL) of cancer patients. Therefore, it is necessary to select treatment methods that take into account the prognosis and QOL of cancer patients, and to take measures against CTRCVD. The mechanism of cardiotoxicity of high-risk drugs, such as doxorubicin and HER2 inhibitors, are still unclear; genetic factors, and cardiovascular disease risk factors (e.g., hypertension, dyslipidemia, and diabetes) are associated with CTRCVD progression. The establishment of methods for prevention, early diagnosis, and treatment of CTRCVD and the generation of evidence for these methods are needed. It is also necessary to develop screening methods for chemotherapy cardiotoxicity. In this review, we discuss the current status of CTRCVD, its complications, and expected countermeasures.

Drugging the "Undruggable" MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers.

Effective treatment of pediatric solid tumors has been hampered by the predominance of currently "undruggable" driver transcription factors. Improving outcomes while decreasing the toxicity of treatment necessitates the development of novel agents that can directly inhibit or degrade these elusive targets. MYCN in pediatric neural-derived tumors, including neuroblastoma and medulloblastoma, is a paradigmatic example of this problem. Attempts to directly and specifically target MYCN have failed due to its similarity to MYC, the unstructured nature of MYC family proteins in their monomeric form, the lack of an understanding of MYCN-interacting proteins and ability to test their relevance in vivo, the inability to obtain structural information on MYCN protein complexes, and the challenges of using traditional small molecules to inhibit protein-protein or protein-DNA interactions. However, there is now promise for directly targeting MYCN based on scientific and technological advances on all of these fronts. Here, we discuss prior challenges and the reasons for renewed optimism in directly targeting this "undruggable" transcription factor, which we hope will lead to improved outcomes for patients with pediatric cancer and create a framework for targeting driver oncoproteins regulating gene transcription.

Cancer research using organoid technology.

Organoid technology has rapidly transformed basic biomedical research and contributed to significant discoveries in the last decade. With the application of protocols to generate organoids from cancer tissue, organoid technology has opened up new opportunities for cancer research and therapy. Using organoid cultures derived from healthy tissues, different aspects of tumour initiation and progression are widely studied including the role of pathogens or specific cancer genes. Cancer organoid cultures, on the other hand, are applied to generate biobanks, perform drug screens, and study mutational signatures. With the incorporation of cellular components of the tumour microenvironment such as immune cells into the organoid cultures, the technology is now also exploited in the rapidly advancing field of immuno-oncology. In this review, I discuss how organoid technology is currently being utilised in cancer research and what obstacles are still to be overcome for its broader use in anti-cancer therapy.

Role of Glutathione in Cancer: From Mechanisms to Therapies.

Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concentrations in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Molecular changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are associated with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects.

Targeting Glycosylation: A New Road for Cancer Drug Discovery.

Cancer is a deadly disease that encompasses numerous cellular modifications. Among them, alterations in glycosylation are a proven reliable hallmark of cancer, with most biomarkers used in the clinic detecting cancer-associated glycans. Despite their clear potential as therapy targets, glycans have been overlooked in drug discovery strategies. The complexity associated with the glycosylation process, and lack of specific methodologies to study it, have long hampered progress. However, recent advances in new methodologies, such as glycoengineering of cells and high-throughput screening (HTS), have opened new avenues of discovery. We envision that glycan-based targeting has the potential to start a new era of cancer therapy. In this article, we discuss the promise of cancer-associated glycosylation for the discovery of effective cancer drugs.

Update on in-vivo preclinical research models in adrenocortical carcinoma.

PURPOSE OF REVIEW: The aim of this review is to summarize recent advances on development of in vivo preclinical models of adrenocortical carcinoma (ACC). RECENT FINDINGS: Significant progress has been achieved in the underlying molecular mechanisms of adrenocortical tumorigenesis over the last decade, and recent comprehensive profiling analysis of ACC tumors identified several genetic and molecular drivers of this disease. Therapeutic breakthroughs, however, have been limited because of the lack of preclinical models recapitulating the molecular features and heterogeneity of the tumors. Recent publications on genetically engineered mouse models and development of patient-derived ACC xenografts in both nude mice and humanized mice now provide researchers with novel tools to explore therapeutic targets in the context of heterogeneity and tumor microenvironment in human ACC. SUMMARY: We review current in-vivo models of ACC and discuss potential therapeutic opportunities that have emerged from these studies.

Pancreatic Adenocarcinoma: Unconventional Approaches for an Unconventional Disease.

This review highlights current treatments, limitations, and pitfalls in the management of pancreatic cancer and discusses current research in novel targets and drug development to overcome these clinical challenges. We begin with a review of the clinical landscape of pancreatic cancer, including genetic and environmental risk factors, as well as limitations in disease diagnosis and prevention. We next discuss current treatment paradigms for pancreatic cancer and the shortcomings of targeted therapy in this disease. Targeting major driver mutations in pancreatic cancer, such as dysregulation in the KRAS and TGFß signaling pathways, have failed to improve survival outcomes compared with nontargeted chemotherapy; thus, we describe new advances in therapy such as Ras-binding pocket inhibitors. We then review next-generation approaches in nanomedicine and drug delivery, focusing on preclinical advancements in novel optical probes, antibodies, small-molecule agents, and nucleic acids to improve surgical outcomes in resectable disease, augment current therapies, expand druggable targets, and minimize morbidity. We conclude by summarizing progress in current research, identifying areas for future exploration in drug development and nanotechnology, and discussing future prospects for management of this disease.

Inmunoterapia y toxicidades inmunorrelacionadas: Experiencia clínica unicéntrica / No disponible

No disponible

Rapid screening of drug candidates against EGFR/HER2 signaling pathway using fluorescence assay.

Over the recent decade, the calcium-based assays have gained much popularity in order to discover new drugs. Since breast cancer is the second cause of death in the female population, rapid and effective methods are needed to screen drug compounds with fewer side effects. Human epidermal growth factor receptor 2 (HER2) increases intracellular free Ca2+ on its signaling pathways. In the present study, BT474 cell line, which overexpresses HER2 receptor, was selected and using fura-2-AM, intracellular Ca2+ release was investigated. The changes in the concentration of intracellular Ca2+ were evaluated by variation in the amount of fluorescence intensity. In the presence of epidermal growth factor (EGF), an increase in fluorescence intensity was observed so that after 20 min it raised to the maximum level. After treatment of BT474 cells by lapatinib, as a tyrosine kinase inhibitor (TKI), the signaling pathway of EGFR/HER2 heterodimer was significantly inhibited, which resulted in a decrease in Ca2+ entry into the cytoplasm and fluorescence emission decreased. The IC50 value for the effect of lapatinib on BT474 cells was 113.2 nmol/L. Our results suggest this method is a simple, efficient and specific approach and can potentially be useful for screening new drug candidates against EGFR/HER2 heterodimer signaling pathways. Graphical abstract ᅟ.

Preclinical progress and first translational steps for a liposomal chemotherapy protocol against adrenocortical carcinoma.

Systemic therapy of adrenocortical carcinoma (ACC) is limited by heterogeneous tumor response and adverse effects. Recently, we demonstrated anti-tumor activity of LEDP-M (etoposide, liposomal doxorubicin, liposomal cisplatin, mitotane), a liposomal variant of EDP-M (etoposide, doxorubicin, cisplatin, mitotane). To improve the therapeutic efficacy and off-target profiles of the clinical gold standard EDP-M, we investigated liposomal EDP-M regimens in different preclinical settings and in a small number of ACC patients with very advanced disease. Short- and long-term experiments were performed on two ACC models (SW-13 and SJ-ACC3) in vivo We evaluated the anti-tumoral effects and off-target profiles of EDP-M, LEDP-M and a novel regimen L(l)EDP-M including liposomal etoposide. Furthermore, the role of plasma microRNA-210 as a therapeutic biomarker and first clinical data were assessed. Classical and liposomal protocols revealed anti-proliferative efficacy against SW-13 (EDP-M P < 0.01; LEDP-M: P < 0.001; L(l)EDP-M: P < 0.001 vs controls), whereas in SJ-ACC3, only EDP-M (P < 0.05 vs controls) was slightly effective. Long-term experiments in SW-13 demonstrated anti-tumor efficacy for all treatment schemes (EDP-M: P < 0.01, LEDP-M: P < 0.05, L(l)EDP-M P < 0.001 vs controls). The analysis of pre-defined criteria leading to study termination revealed significant differences for control (P < 0.0001) and EDP-M (P = 0.003) compared to L(l)EDP-M treatment. Raising its potential for therapy monitoring, we detected elevated levels of circulating microRNA-210 in SW-13 after LEDP-M treatment (P < 0.05). In contrast, no comparable effects were detectable for SJ-ACC3. However, overall histological evaluation demonstrated improved off-target profiles following liposomal regimens. The first clinical data indicate improved tolerability of liposomal EDP-M, thus confirming our results. In summary, liposomal EDP-M regimens represent promising treatment options to improve clinical treatment of ACC.

Drug Discovery Goes Three-Dimensional: Goodbye to Flat High-Throughput Screening?

Immortalized cells, generated from two-dimensional cell culture techniques, are widely used in compound screening, lead optimization, and drug candidate selection. However, such cells lack many characteristics of cells in vivo. This could account for the high failure rates of lead candidates in clinical evaluation. New approaches from cell biology, materials science, and bioengineering are increasing the utility of three-dimensional (3D) culture. These approaches have become more compatible with automation and, thus, provide more physiologically relevant cells for high-throughput/high-content screening, notably in oncology drug discovery. Techniques range from simple 3D spheroids, comprising one or more cell types, to complex multitissue organoids cultured in extracellular matrix gels or microfabricated chips. Furthermore, each approach can be applied to stem cells, such as induced pluripotent stem cells, thereby providing additional phenotypic relevance and the exciting potential to enable screening in disease-specific cell types.

¿Qué ha cambiado en la epidemiología y el cribado del cáncer de próstata? / What has changed in the epidemiology and screening of prostate cancer?

OBJETIVO: El objetivo del presente estudio es examinar la evolución y los cambios en la epidemiología del cáncer de próstata y realizar un análisis del estado actual en el cribado del cáncer de próstata en base a los distintos estudios y de las recomendaciones de las sociedades científicas. MÉTODO: Se ha realizado una revisión bibliográfica de trabajos relevantes en relación con la epidemiología y el cribado del cáncer de próstata, con especial atención a los ensayos internacionales y multicéntricos sobre el screening poblacional. RESULTADOS: El número y perfil de los pacientes diagnosticados de cáncer de próstata en la actualidad ha cambiado de forma significativa desde los periodos pre-PSA a la actualidad. El diagnóstico precoz y las estrategias de cribado han hecho que haya aumentado su incidencia y que la mortalidad por cáncer haya disminuido en muchos países. CONCLUSIÓN: El despistaje sistemático parece, aunque existen inconsistencias en algunos estudios, poder mejorar la mortalidad específica por cáncer de próstata. La introducción de nuevos biomarcadores, técnicas de imagen como la mpRNM así como alternativas terapéuticas menos agresivas, posiblemente nos abren ventanas al futuro para un mejor diagnóstico y tratamiento de la enfermedad

OBJECTIVE: The objective of this study is to review the evolution and changes of prostate cancer epidemiology and to perform an analysis of the current status of prostate cancer screening based on the various studies and scientific societies recommendations. METHODS: We performed a bibliographic review of relevant papers in relation to prostate cancer epidemiology and screening, with special focus on international and multicentric trials on population screening. RESULTS: The current number and profile of patients being diagnosed of prostate cancer have changed significantly from the pre-PSA era to the present time. Early diagnosis and screening strategies have caused an increase in incidence and a decrease in cancer mortality in some countries. CONCLUSIONS: Systematic screening, despite inconsistencies in some studies, seems to improve prostate cancer specific mortality. The introduction of new biomarkers, imaging techniques such as mpMRI as well as less aggressive therapeutic alternatives, probably open windows to the future for a better diagnosis and treatment of the disease

Acridone-based antitumor agents: a mini-review.

In the past decades, tricyclic acridone ring system has become one of the major research interests of the medicinal chemists due to the biological significance of this moiety in drug design and drug discovery. Acridone scaffold has substantial bio-potential since it possess crucial activities such as antibacterial, antimalarial, antiviral and anti-neoplastic. The diverse biological activity of acridone and its prospective in reversal of multi-drug resistance has attracted attention of medicinal chemists to explore this scaffold especially to treat multi-drug resistance in cancer. Considering this potential in this review we have summarized the synthesis and the antitumor activities of different acridone derived compounds reported from 2000 to 2014.

Investigación en cribado de cáncer de mama: camino hacia estrategias personalizadas y decisiones compartidas / Research on breast cancer screening: toward personalized strategies and shared decision-making

La consolidación de los programas poblacionales de detección precoz de cáncer de mama y el debate sobre el balance entre el beneficio y el riesgo han juntado la oportunidad y la necesidad de investigación para mejorar la efectividad de los mismos. En España, en paralelo a otros países con programas poblacionales, la investigación en cribado ha evolucionado desde los primeros estudios descriptivos de participación hasta los estudios longitudinales sobre efectos adversos como falsos positivos y cáncer de intervalo, y estudios para conocer mejor el riesgo individual de presentar un cáncer de mama, aprovechando la información que ofrecen las cohortes de mujeres cribadas. Además, se han desarrollado nuevas metodologías de investigación que permiten evaluar nuevas estrategias de cribado, aún teóricas, basadas en el riesgo individual. Por último, se están empezando a desarrollar herramientas de ayuda a la toma de decisiones para facilitar el proceso de informar de forma individualizada a las mujeres (AU)

The consolidation of population-based screening programs for breast cancer and the debate on the risk-benefit balance have coincided with the opportunity and need for research to improve the effectiveness of these programs. In Spain, in parallel to other countries with population-based programs, research on screening has evolved from the early descriptive studies of participation to longitudinal studies of adverse effects, such as false-positives and interval cancers, and studies designed to better understand the individual risk of breast cancer. These studies have been able to take advantage of the information offered by the cohort of screened women. New research methodologies have been developed to allow the evaluation of new theoretical screening strategies based on individual risk. Finally, decision-making tools are being designed to facilitate the process of informing women individually, contributing to shared decision-making (AU)

Phenotypic screening in cancer drug discovery - past, present and future.

There has been a resurgence of interest in the use of phenotypic screens in drug discovery as an alternative to target-focused approaches. Given that oncology is currently the most active therapeutic area, and also one in which target-focused approaches have been particularly prominent in the past two decades, we investigated the contribution of phenotypic assays to oncology drug discovery by analysing the origins of all new small-molecule cancer drugs approved by the US Food and Drug Administration (FDA) over the past 15 years and those currently in clinical development. Although the majority of these drugs originated from target-based discovery, we identified a significant number whose discovery depended on phenotypic screening approaches. We postulate that the contribution of phenotypic screening to cancer drug discovery has been hampered by a reliance on 'classical' nonspecific drug effects such as cytotoxicity and mitotic arrest, exacerbated by a paucity of mechanistically defined cellular models for therapeutically translatable cancer phenotypes. However, technical and biological advances that enable such mechanistically informed phenotypic models have the potential to empower phenotypic drug discovery in oncology.

Better therapeutic trials in ovarian cancer.

The Ovarian Task Force of the Gynecologic Cancer Steering Committee convened a clinical trials planning meeting on October 28-29, 2011, with the goals to identify key tumor types, associated molecular pathways, and biomarkers for targeted drug intervention; review strategies to improve early-phase screening, therapeutic evaluation, and comparison of new agents; and optimize design of randomized trials in response to an evolving landscape of scientific, regulatory, and funding priorities. The meeting was attended by international clinical and translational investigators, pharmaceutical industry representatives, government regulators, and patient advocates. Panel discussions focused on disease types, early-phase trials, and randomized trials. A manuscript team summarized the discussions and assisted with formulating key recommendations. A more integrated and efficient approach for screening new agents using smaller selective randomized trials in specific disease-type settings was endorsed, together with collaborative funding models between industry and the evolving national clinical trials network, as well as efforts to enhance public awareness and study enrollment through advocacy.

Heat shock protein 90 inhibitors as therapeutic agents.

The molecular chaperone heat shock protein 90 (HSP90) is essential for the folding stability, intracellular disposition and proteolytic turnover of many of the key regulators of cell growth, differentiation and survival. These essential functions are used by the cells during the oncogenesis process to allow the tumor transformation and facilitate the rapid somatic evolution. Inhibition of HSP90 would provide combinatorial blockade of a range of oncogenic pathways, antagonizing many of the hallmark traits of cancer. Several HSP90 inhibitors are currently under clinical trial investigation for the treatment of cancer. This review summarizes the current state and progress achieved in the development of HSP90 inhibitors targeting the N-terminal ATP pocket, C-terminal domain, different compartmentalized isoforms, and protein (cochaperones and/or client proteins)/HSP90 interactions. In the context of drug discovery, the most relevant patents which appeared recently in the literature are discussed as well.