RESUMO
Over the past two decades, progresses in colorectal cancer treatment have significantly improved patient survival and quality of life. However, unresectable metastatic colorectal cancer remains virtually incurable, making the search for new effective therapeutics mandatory. An important limitation to the development of new agents has been the difficulty to exploit mutated tumor suppressors or "undruggable" oncogenes as a target. Recently, evidence that mutations in tumor suppressors, such as BRCA1/2, make cancer cells highly susceptible to inhibitors of a compensatory DNA repair pathway [poly-(ADP-ribose) polymerase 1 (PARP1)] has broadened the range of possible therapeutic targets by extending it to gene products that are in a "synthetic lethal" relationship with oncogenes and tumor suppressors. Inhibition of such targets blocks specific buffer-mechanisms that are required for survival in the presence of defined oncogenic mutations, but not in their absence. As a consequence, selective elimination of mutation-bearing cells results. This approach has led to identify compounds that are highly active in the presence of different types of mutated tumor suppressors and oncogenes, including DNA repair genes, RAS, and Myc. In addition, ongoing studies promise to identify new mechanisms which, when pharmacologically interfered with, will selectively eradicate mutated cancer cells. Here, we revise and discuss these new aspects of cancer biology and highlight their potential applications in colorectal cancer treatment.
Assuntos
Adenoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adenoma/genética , Adenoma/prevenção & controle , Animais , Proteína BRCA1/antagonistas & inibidores , Proteína BRCA1/genética , Proteína BRCA2/antagonistas & inibidores , Proteína BRCA2/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/prevenção & controle , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Reparo de Erro de Pareamento de DNA/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Camundongos , Mutação , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Poli(ADP-Ribose) Polimerases , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras) , Resultado do Tratamento , Proteína Supressora de Tumor p53/agonistas , Proteína Supressora de Tumor p53/genética , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética , Proteínas ras/antagonistas & inibidores , Proteínas ras/genéticaRESUMO
Novel anti-vasculature strategies that are emerging for the treatment of cancer and for the inhibition of angiogenesis may be a promising new tool for the adjuvant therapy of malignant tumours. Over the last fifteen years, several reports have been published concerning the relationship between tumour progression and angiogenesis in experimental models of neuroblastoma in vitro and in vivo. Moreover, a high vascular index in neuroblastoma correlates with poor prognosis, suggesting dependence of aggressive tumour growth on active angiogenesis. Here, we present an overview of the most recent advances in anti-vasculature therapy of neuroblastoma, and describe some preclinical results as well as future perspectives.