RESUMO
BACKGROUND: This article describes and compares approved targeted therapies and the newer immunotherapy agents. MATERIALS AND METHODS: This article especially performs an in-depth review of currently available data for tivozanib, explaining its mechanism of action, its safety profile and its role as an efficacy drug in the management of renal cancer. RESULTS: Despite the fact that the treatment of advanced RCC has been dramatically modified in recent years, durable remissions are scarce and it remains a lethal disease. For first- and second-line therapy, there is now growing evidence to guide the selection of the appropriate treatment. CONCLUSIONS: Several TKIs are standard of care at different settings. Among those approved TKIs, tivozanib has similar efficacy than others with a better safety profile. The use of prognostic factors is critical to the selection of optimal therapy.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Ensaios Clínicos como Assunto , Consenso , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Metástase NeoplásicaRESUMO
INTRODUCTION: Kidney tumours are frequently characterised by hypoxic conditions due to a local imbalance between oxygen (O2) supply and consumption. Hif1-α regulates angiogenesis, tumour growth, tumour progression, metastatic spread, and glucose metabolism by acting as a transcription factor for relevant genes. Here, we describe an immunohistochemical study of Hif1-α, a comprehensive computational study of Hif1-α interacting proteins (HIPs), an analysis correlating expression levels of Hif1-α with upstream and downstream proteins, and an analysis of the utility of Hif1-α for prognosis in a cohort of patients with renal cell carcinoma. MATERIALS AND METHODS: The patient cohort included 80 patients. For immunohistochemistry evaluation, tissue microarrays were constructed. The IntAct, MINT, and BOND databases were used for the HIP approach. The Kruskal-Wallis test was used for comparing protein expression with pathology measurements. Correlation was expressed as the Pearson coefficient. RESULTS: Hif1-α expression correlates significantly with the "clear" histological subtype of renal cell carcinoma (p < 0.01). The samples with the worst prognoses related to the pathological variables analysed showed the highest levels of Hif1-α expression. Significant correlations were found with Bcl-2, CAIX, C-kit, EGFR, TGF-ß, proteins of the VEGF family, proteins related to differentiation (such as Notch1 and Notch3) and certain metabolic enzymes. Bioinformatic analysis suggested 45 evidence-based HIPs and 4 complexes involving protein Hif1-α. CONCLUSIONS: This work summarises the multifaceted role of Hif1-α in the pathology of renal cell carcinomas, and it identifies HIPs that could help provide mechanistic explanations for the different behaviours seen in tumours.
Assuntos
Carcinoma de Células Renais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , Mapeamento de Interação de Proteínas , Adulto , Idoso , Carcinoma de Células Renais/patologia , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Epidemiological studies provided the first evidence that COX may be involved in the pathogenesis of cancer. In the process of carcinogenesis and in the route of intracellular signalling during carcinogenesis, COX-2 expression may be a universal phenomenon. In general, COX-2 is up-regulated throughout the tumorigenic process, from early hyperplasia to metastatic disease. COX-2 has been reported to be constitutively overexpressed in a variety of malignancies and is frequently constitutively elevated in prostate carcinoma. COX-2 was consistently overexpressed in premalignant lesions such as prostatic intraepithelial neoplasia, and carcinoma. Cases are described with evolution of proliferative inflammatory atrophy of the prostate and prostate carcinoma. The increase of evidence implicating COX-2 in cancer has stimulated clinical trials to investigate the efficacy of selective COX-2 inhibitors in individuals at risk for human cancer. Regarding prostate carcinoma there is much direct or indirect evidence to support the use of COX-2 inhibitors in this disease. Trials using these drugs in familial adenomatous polyposis (FAP) and other patients with a high risk of colorectal carcinoma are ongoing.
Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Próstata/enzimologia , Humanos , Masculino , Transdução de SinaisRESUMO
The Hedgehog (Hh) family of intercellular signalling proteins have come to be recognised as key mediators in many fundamental processes in embryonic development. Their activities are central to the growth, patterning and morphogenesis of many different regions within the bodies of vertebrates. In some contexts, Hh signals act as morphogens in the dose-dependent induction of distinct cell fates within a target field, in others as mitogens in the regulation of cell proliferation or as inducing factors controlling the form of a developing organ. These diverse functions of Hh proteins raise many intriguing questions about their mode of action. Various studies have now demonstrated the function of Hh signalling in the control of cell proliferation, especially for stem cells and stem-like progenitors. Abnormal activation of the Hh pathway has been demonstrated in a variety of human tumours. Hh pathway activity in these tumours is required for cancer cell proliferation and tumour growth. Recent studies have uncovered the role for Hh signalling in advanced prostate cancer and demonstrated that autocrine signalling by tumour cells is required for proliferation, viability and invasive behaviour. Thus, Hh signalling represents a novel pathway in prostate cancer that offers opportunities for prognostic biomarker development, drug targeting and therapeutic response monitoring.
Assuntos
Proteínas Hedgehog/metabolismo , Neoplasias da Próstata/metabolismo , Transdução de Sinais , Animais , Células Epiteliais/metabolismo , Proteínas Hedgehog/genética , Humanos , Masculino , Mesoderma/metabolismo , Modelos Biológicos , Próstata/metabolismoRESUMO
Choroid plexus carcinomas are rare tumours, found chiefly during childhood. The commonest pattern of progression is via the neural axis. We present the case of a patient with unusual metastatic dissemination, affecting lungs and bones two years after diagnosis, and the approach adopted towards him.
Assuntos
Carcinoma/terapia , Neoplasias do Plexo Corióideo/terapia , Adulto , Neoplasias Ósseas/secundário , Carcinoma/secundário , Neoplasias do Plexo Corióideo/patologia , Humanos , Neoplasias Pulmonares/secundário , MasculinoRESUMO
The association of mediastinal germ-cell tumours (MGCTs) with haematologic neoplasms is a rare though well known circumstance, and few cases are found in the literature. Most of these refer to non-seminomatous tumours in young males. The diagnosis of the haematological condition is usually either synchronic or metachronic with that of the germ-cell tumour. From those cases that have been published, we know that the prognosis is poor and basically determined by the haematologic neoplasia. The case report we present is that of a young male with an initial diagnosis of both conditions. It was possible to apply specific treatment, initially in the case of the leukaemia, and later in the case of the germ-cell tumour. The approach adopted is a multidisciplinary one.
Assuntos
Leucemia Megacarioblástica Aguda , Neoplasias do Mediastino , Neoplasias Embrionárias de Células Germinativas , Neoplasias Primárias Múltiplas , Adulto , Humanos , Leucemia Megacarioblástica Aguda/diagnóstico , Leucemia Megacarioblástica Aguda/terapia , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/terapia , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/terapiaRESUMO
Stem cells, as classically defined, are cells with a capacity to self-renew and to generate daughter cells that can differentiate down several cell lineages to form all of the cell types that are found in the mature tissue. Stem cells and tumour cells have many similar features, including infinite lifespan, self-renewal, multidrug resistance, telomerase expression and, in the instance of the prostate, androgen independence. Evidence supports a role for stem cells in the etiology of many types of cancer. The evolution of androgen-independent prostate carcinoma may reflect the emergence of stemlike prostate tumour cells. Because cancer may be a disease of stem cell lineages and Shh-Gli signalling controls the behaviour of precursors and of cells with stem cell properties in the mammalian tissues, prostate cancer might derive from inappropriate expansion of prostatic epithelial stem cell lineages caused by abnormal Shh-Gli function. This review attempts to integrate these recent results.