Cancer chemotherapy failure: a synthetic view

Cancer is a highly prevalent and fatal disease, being one of the main causes of death in Brazil and in the world. In the last decades, a great advance has been reached in fight against cancer, with some translation in curability. However, these advances are still insufficient, and the prognosis of the cancer patient is usually unfavorable. Indeed, there are still many gaps in our knowledge about this complex and heterogeneous disease. Several treatments approaches against cancer are available to clinical practice - and some others are being developed - one of which is chemotherapy, both traditional and targeted therapy (TT), used - above all - as primary treatment for metastatic or secondary treatment in local or locally advanced disease. Several factors can act through many mechanisms to determine the failure of chemotherapy treatment. These factors are distributed across the various biological scales, from the molecular to the socioeconomic level, making the holistic view of treatment a great challenge and impairing the awareness of what can go wrong. The purpose of this paper is to be a comprehensive - but not superficial - picture of the many factors that influence the success of chemotherapy. In this way, the result of this work was this discussion on chemotherapy failure, were it was exposed recent advances, challenges to be overcome and new paths to be explored on this field.O Câncer é uma doença de alta prevalência e letalidade, sendo uma das principais causas de morte no Brasil e no mundo. Nas últimas décadas, grandes avanços foram alcançados na luta contra o câncer, com alguma tradução em curabilidade. Contudo, esses avanços ainda não são suficientes, de modo que o prognóstico do paciente com câncer ainda é, geralmente, desfavorável. De fato, há ainda diversas lacunas em nosso conhecimento a respeito dessa complexa e heterogênea doença. Diversos tratamentos contra o câncer já estão disponíveis à prática clínica - e outros ainda estão sendo desenvolvidos - uma delas a quimioterapia, tanto a tradicional quando a alvo dirigida, utilizada, sobretudo, como tratamento primário contra doença metastática ou secundário contra doença local ou localmente avançada. Diversos fatores podem atuar, através de vários mecanismos, de modo a determinar a falha do tratamento quimioterápico. Esses fatores estão distribuídos ao longo de diversas escalas biológicas, do nível molecular ao socioeconômico, tornando uma visão holística do tratamento um grande desafio, prejudicando a compreensão acerca do que pode dar errado. O objetivo deste trabalho é ser uma leitura compreensiva - mas não superficial - dos muitos fatores que influenciam o sucesso de quimioterapia. Deste modo, o resultado foi a presente discussão, na qual foram expostos avanços recentes, desafios a serem superados e novos caminhos a serem explorados na área

Tumors as complex organs: are cancers manageable through the modification of their microenvironment?

FAPESP (Center for Cell-based Therapy Research), Instituto Nacional de Ciência e Tecnologia- Redoxoma and UICC-Yamagiwa Yoshida Grant

Resistance Mechanisms Influencing Oncolytic Virotherapy, a Systematic Analysis:a Systematic Analysis

Resistance to therapy is a frequently observed phenomenon in the treatment of cancer, and as with other cancer therapeutics, therapies based on oncolytic viruses also face the challenges of resistance, such as humoral and cellular antiviral responses, and tumor-associated interferon-mediated resistance. In order to identify additional mechanisms of resistance that may contribute to therapeutic failure, we developed a systematic search strategy for studies published in PubMed. We analyzed 6143 articles on oncolytic virotherapy and found that approximately 8% of these articles use resistance terms in the abstract and/or title. Of these 439 articles, 87 were original research. Most of the findings reported pertain to resistance mediated by tumor-cell-dependent interferon signaling. Yet, mechanisms such as epigenetic modifications, hypoxia-mediated inhibition, APOBEC-mediated resistance, virus entry barriers, and spatiotemporal restriction to viral spread, although not frequently assessed, were demonstrated to play a major role in resistance. Similarly, our results suggest that the stromal compartment consisting of, but not limited to, myeloid cells, fibroblasts, and epithelial cells requires more study in relation to therapy resistance using oncolytic viruses. Thus, our findings emphasize the need to assess the stromal compartment and to identify novel mechanisms that play an important role in conferring resistance to oncolytic virotherapy

An Antibody to De-N-Acetyl Sialic Acid Containing-Polysialic Acid Identifies an Intracellular Antigen and Induces Apoptosis in Human Cancer Cell Lines

Polysialic acid (PSA), an α2,8-linked homopolymer of N-acetylneuraminic acid (Neu5Ac), is developmentally regulated and its expression is thought to be restricted to a few tissues in adults. Recently, we showed that two human pathogens expressed a derivative of PSA containing de-N-acetyl sialic acid residues (NeuPSA). Here we show that an epitope identified by the anti-NeuPSA monoclonal antibody, SEAM 3 (SEAM 3-reactive antigen or S3RA), is expressed in human melanomas, and also intracellularly in a human melanoma cell line (SK-MEL-28), a human T cell leukemia cell line (Jurkat), and two neuroblastoma cell lines (CHP-134 and SH-SY5Y). SEAM 3 binding induced apoptosis in the four cell lines tested. The unusual intracellular distribution of S3RA was similar to that described for the PSA polysialyltransferases, STX and PST, which are also expressed in the four cell lines used here. Interestingly, suppression of PST mRNA expression by transfection of SK-MEL-28 cells with PST-specific short interfering RNA (siRNA) resulted in decreased SEAM 3 binding. The results suggest further studies of the utility of antibodies such as SEAM 3 as therapeutic agents for certain malignancies

Cancer and the tumor microenvironment

Antes tido como um conjunto de células alteradas em proliferação, hoje o câncer é mais bem entendido como um microambiente, em que as interações entre os elementos celulares e moleculares que o compõem são determinantes na progressão tumoral. Como resultado, a compreensão do evento neoplásico ganha complexidade crescente. A dinâmica das células tumorais passa a ser avaliada como parte de um verdadeiro tecido tumoral, sujeita a condições de vascularização, de oxigenação, de pressão intersticial e de necrose tecidual, que influenciam na cinética tumoral. Estão sendo identificados novos componentes deste nicho tumoral e as suas respectivas atuações. Entre esses integrantes, encontram-se os elementos da imunidade, cuja modulação tem sido demonstrada por uma série de pesquisas aqui revisadas, tanto no sentido da vigilância imunológica, como pressão seletiva negativa, quanto no favorecimento da progressão tumoral. Esta revisão analisará a neoplasia do ponto de vista de um microambiente tumoral, focando na participação imunológica e na cinética tumoral, expondo as principais idéias e descobertas que criaram e estão aperfeiçoando o conceito de câncerFormerly referred to as a group of altered cells in proliferation, today cancer is better understood as a microenvironment, in which the interactions between the cellular and molecular elements are determinative in tumor progression. As a result, the comprehension of a neoplasic event gains increasing complexity. The dynamics of the tumor cells are now analyzed as part of a true tumoral tissue, subject to conditions of vascularization, oxygenation, interstitial pressure and tissue necrosis, which influence tumor kinetics. New components of this tumoral niche and their respective actions are being identified. Among these constituents are the elements of the immune system which, as a series of experiments have shown, are involved in the aspect of immunosurveillance, as negative selective pressure, as well as in mechanisms of tumor progression. This review will analyze neoplasia as a tumor microenvironment, focusing on immunological participation and on tumor kinetics, and exposing the main ideas and discoveries that created and are improving the concept of cance

A systematic analysis on the clinical safety and efficacy of onco-virotherapy

Several onco-virotherapy candidates have been developed and clinically evaluated for the treatment of cancer, and several are approved for clinical use. In this systematic review we explored the clinical impact of onco-virotherapy compared to other cancer therapies by analyzing factors such as trial design, patient background, therapy design, delivery strategies, and study outcomes. For this purpose, we retrieved clinical studies from three platforms: ClinicalTrials.gov, PubMed, and EMBASE. We found that most studies were performed in patients with advanced and metastatic tumors, using a broad range of genetically engineered vectors and mainly administered intratumorally. Therapeutic safety was the most frequently assessed outcome, while relatively few studies focused on immunological antitumor responses. Moreover, only 59 out of 896 clinical studies were randomized controlled trials reporting comparative data. This systemic review thus reveals the need of more, and better controlled, clinical studies to increase our understanding on the application of onco-virotherapy either as a single treatment or in combination with other cancer immunotherapies

Role of Immune System in Kidney Cancer

Almost all kidney cancers are associated to immune dysfunction. Among these, renal cell carcinoma (RCC) represents approximately 2% of malignancies that affect adults and for 90–95% of all kidney cancers. Recent evidences have collaborated to elucidate the mechanisms involved in the development of this disease. In this view, dysfunctional neutrophil migration, as well as T lymphocyte-DC (dendritic cell) cross talk, DC maturation, immune cell metabolism, and reactivity and abnormal expression of cytokines and chemokines and their receptors have been highlighted in RCC and stroma cells. A rational development of novel therapies to recover antitumor activity of immune system is closely related to the understanding of the complex interactions between immune system and tumor. Some insights have been reached and immunomodulatory molecules, such as interleukin-2 (IL-2) and IFN-α, immune checkpoint inhibitors, and chemokines antagonists have shown clinical efficacy. In this chapter, we overview the essential role of innate and adaptive immune response in RCC and discuss drugs approved or in development for its treatment

Platelet activating factor receptor antagonists improve the efficacy of experimental chemo- and radiotherapy

Platelet activating factor is a lipid mediator of inflammation, and in recent decades, it has emerged as an important factor in tumor outcomes. Platelet activating factor acts by specific binding to its receptor, which is present in both tumor cells and cells that infiltrate tumors. Pro-tumorigenic effects of platelet activating factor receptor in tumors includes promotion of tumor cell proliferation, production of survival signals, migration of vascular cells and formation of new vessels and stimulation of dendritic cells and macrophages suppressor phenotype. In experimental models, blocking of platelet activating factor receptor reduced tumor growth and increased animal survival. During chemotherapy and radiotherapy, tumor cells that survive treatment undergo accelerated proliferation, a phenomenon known as tumor cell repopulation. Work from our group and others showed that these treatments induce overproduction of platelet activating factor-like molecules and increase expression of its receptor in tumor cells. In this scenario, antagonists of platelet activating factor markedly reduced tumor repopulation. Here, we note that combining chemo- and radiotherapy with platelet activating factor antagonists could be a promising strategy for cancer treatment