Perspectivas en oncología
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Perspectivas en oncología
- 1. TERAPIAS DIRIGIDAS EN ONCOLOGIA
- 20. EGFR Expression in Selected Human Tumors Percentage of Tumors Tumor Type Expressing EGFR References Colon 25% - 77% Salomon (1995); Goldstein (2001); Colon, refractory 72% Saltz (2001) Head and neck 95% - 100% Salomon (1995); Grandis (1996) Pancreatic 30% - 95% Salomon (1995); Uegaki (1997); Abbruzzese(2001) NSCLC 40% - 80% Salomon (1995); Fontanini (1998); Rusch (1997); NSCLC, refractory 88% Kim (2002) Renal carcinoma 50% - 90% Salomon (1995); Yoshida (1997) Breast 14% - 91% Klijn (1992); Beckman (1996); Bucci (1997); Walker (1999) Ovarian 35% - 70% Salomon (1995); Bartlett (1996); Fischer-Colbrie (1997) Glioma 40% - 63% Salomon (1995); Rieske (1998); Watanabe (1996) Bladder 31% - 48% Salomon (1995); Chow (1997)
- 21. Prognostic Significance of EGFR Expression in Selected Human Cancers Risk of Invasion/ Tumor Type Prognosis Survival Metastases References Colorectal Poor Mayer (1993) Poor Increased Hemming (1992) Head and Neck Decreased DFS Grandis (1998) Poor Decreased OS Maurizi (1996) Pancreatic Poor Dong (1998) Decreased OS Yamanak a (1993) NSCLC Decreased OS Volm (1998) Decreased OS Veale (1993) Poor Decreased OS Ohsaki (2000) Increased Pavelic 1993) Abbreviations: DFS, disease-free survival; OS, overall survival; NSCLC, non-small cell lung cancer. EGFR Expression Correlated With:
- 23. Selected Epidermal Growth Factor Receptor Inhibitors Abbreviations: MAb, monoclonal antibody; TKI, tyrosine kinase inhibitor. Compound Class Description Manufacturer Cetuximab IgG1 MAb EGFR-MAb ImClone Systems Incorporated/ Bristol-Myers Squibb Company EMD 72000 lgG1 MAb EGFR-MAb Merck KGaA Darmstadt, Germany ABX-EGF IgG2 MAb EGFR-MAb Abgenix/Amgen MDX447 MAb Bispecific MAb against EGFR and epitopes Medarex Erlotinib Quinazoline EGFR-TKI OSI Pharmaceuticals/Genentech Gefitinib Quinazoline EGFR-TKI AstraZeneca CI 1033 Quinazoline EGFR-TKI Pfizer PKI-166 Pyrrolopyrimidine EGFR-TKI Novartis
Notas del editor
- Existen múltiples vías de señalización sobrereguladas en las cél.cancerosas, que estimulan la proliferación celular promoviendo el paso de G1 a la fase S del ciclo celular. Señales del microambiente tumoral, entre ellos fibroblastos pueden también influir de manera positiva o negativa en la proliferación celular. La inhibición de estas vías de crecimiento por terapias dirigidas a alteraciones genéticas específicas ofrece un nuevo abordaje terapéutico, como son kinasas de abl y RFGE, estos y otros blancos están en azul. Un blanco potencial es Aurora A que tiene que ver en progresión mitótica. b; La Rt y Qt clásicas eliminan células cancerosas induciendo daño a DNA con apoptosis subsecuente. Vías de respuesta de daño al DNA las cuales emplean ATM y CHK promueven reparación y sobrevida. Defectos en la maquinaria apoptótica permiten que la célula con daño a DNA sobreviva. La inhibición de vías que reparan DNA o que ocasionan defectos en los mecanismos de apoptosis pueden tornar a las cél.cancerosas más susceptibles a los agentes que dañan al DNA y dar nuevas avenidas para el tratamiento del cáncer.
- The potential for EGFR-targeted therapies in cancer treatment has prompted the development of a variety of anti-EGFR agents, including: • Cetuximab, EMD 72000, ABX-EGF – monoclonal antibodies directed against the extracellular ligand binding domain, which prevents ligand binding. 58,59 • MDX447 – bispecific antibodies that target the extracellular ligand-binding domain of EGFR as well as epitopes on the surface of immune effector cells, such as macrophage-activated killer cells. 58 • Erlotinib, gefitinib, CI 1033 – small molecule EGFR tyrosine kinase inhibitors that target the intracellular tyrosine kinase domain of EGFR, inhibit ATP binding to the tyrosine kinase domain of the receptor, inhibiting tyrosine kinase activity and autophosphorylation, and subsequently, blocking signal transduction from the EGFR. 58 • PKI-166, in the chemical class pyrrolopyrimidine, is a selective inhibitor of tyrosine kinase activity of EGFR tyrosine kinase inhibitors. 58 Cetuximab, gefitinib, and erlotinib are the furthest developed of these agents. Preclinical data from these selected EGFR inhibitors support the rationale for using EGFR-targeted agents in cancer therapy, and their potential is being evaluated in clinical trials. 58
- Proposed mechanism of action for inhibition of EGFR function by tyrosine kinase inhibitors. • Tyrosine kinase inhibitors are small-molecule inhibitors designed to enter the cell and bind to the EGFR tyrosine kinase. The downstream signal transduction cascade is thus blocked, along with the growth-stimulating effects mediated by this pathway. 2 • Treatment with such inhibitors has been shown to inhibit the growth of EGFR-expressing tumor cells and induce apoptosis of tumor cells in vitro, and promote regression of tumors in animal xenograft models. 10,43.61,62,64 Preclinical studies have shown that the combination of a tyrosine kinase inhibitor with cytotoxic drugs may enhance apoptosis in tumor cell lines. 65 • Inhibition of the EGFR pathway may result in sensitization of tumor cells to radiation therapy. 2 • While certain tyrosine kinase inhibitors may have a high affinity toward the EGFR, many such inhibitors studied to date exhibit varying levels of selectivity for the EGFR tyrosine kinase. 2,43
- Proposed mechanism of action for inhibition of EGFR function by anti-EGFR monoclonal antibodies. • Anti-EGFR antibodies are designed to bind externally to the EGF cell surface receptor, to block binding of ligand (EGF, TGF- ) and subsequent signal transduction mediated via the receptor-associated tyrosine kinase, and prevent phosphorylation of the EGFR and other downstream proteins in the signal transduction cascade. 2,60,61 • Monoclonal antibodies are designed to be highly specific for the EGFR, to bind and inhibit the function of this receptor. 2 • The receptor-antibody complex is then internalized and degraded, resulting in receptor cell surface downregulation. 4 • Matrix metalloproteinases, which function in tumor cell invasion and metastasis, may also be downregulated. Preclinical studies have shown that monoclonal antibodies may exhibit inhibition of growth factor production and angiogenesis. 17,20,21 • Treatment with such antibodies has been shown to inhibit the growth of some EGFR-expressing tumor cells and human tumor xenografts. In vitro studies have shown this occurs by promoting apoptosis and cell cycle interruption. 62
- Las vías oncogénicas pueden ser múltiples a fin de desarrollar una neoplasia. De igual forma los manejos oncológicos deben de combinar la posibilidad de bloquear diferentes vías oncogénicas. Si solo una (B) o 2 (C) de las vías son bloqueadas puede no ser suficiente para elminar a la enfermedad neoplásica, requiriéndose el bloqueo en este ejemplo de las 3 vías de crecimiento celular.