[Biologic therapy: current and future applications in oncology]. / Bioterapia: aplicaciones actuales y futuras en oncología.

Nowadays, cancer is the first cause of death in the developed world, accounting for 94,000 yearly deaths in Spain. In recent years, advances in the field of molecular cancer biology and cancer therapy have identified a number of potential target molecules that play a critical role in the complex malignant cell transformation process. Since the approval of the first molecularly targeted drug imatinib in 2001, hundreds of novel agents are being investigated as monotherapy or in combination with chemotherapy and/or radiotherapy for the treatment of cancer of the breast, colon and rectum, lung, kidney, and head and neck, among others. Interestingly, molecularly targeted agents are becoming the new standard of care in some malignances such as renal-cell carcinoma and chronic myeloid leukemia. Future research on molecularly targeted therapies will focus on the identification of new drugs and drug targets, improved selection of tumors sensitive to these drugs, and the rational design and optimization of combination therapies.

Bioterapia: aplicaciones actuales y futuras en oncología / Biologic therapy: current and future applications in oncology

El cáncer representa hoy día la primera causa de mortalidad en el mundo desarrollado, con más de 94.000 fallecimientos anuales en Es paña. En los últimos años, los avances que han acontecido en el campo de la biología molecular del cáncer han permitido identificar toda una serie de moléculas susceptibles de ser dianas terapéuticas, dado su papel esencial en el proceso de transformación celular maligna. Desde la aprobación en 2001 del imatinib, el primer tratamiento mo lecular dirigido, hay cientos de componentes en desarrollo y algunos de ellos se han aprobado recientemente para el tratamiento del cáncer de mama, colorrectal, pulmón, renal y de cabeza y cuello, bien en monoterapia o combinados con quimioterapia y/o radioterapia. En algunos casos, como en el cáncer de células renales y en la leucemia mieloide crónica, la bioterapia ha sustituido al tratamiento estándar habitual. Ahora bien, la falta de biomarcadores y de modelos preclínicos óptimos dificulta el desarrollo de estos agentes. La investigación futura de los tratamientos moleculares deberá centrarse en la identificación de nuevos fármacos y dianas terapéuticas, en el perfeccionamiento de técnicas de selección de tumores sensibles a estos agentes y en el diseño racional y la optimización del tratamiento combinado

Nowadays, cancer is the first cause of death in the developed world, accounting for 94,000 yearly deaths in Spain. In recent years, advances in the field of molecular cancer biology and cancer therapy have identified a number of potential target molecules that play a critical role in the complex malignant cell transformation process. Since the approval of the first molecularly targeted drug imatinib in 2001, hundreds of novel agents are being investigated as monotherapy or in combination with chemotherapy and/or radiotherapy for the treatment of cancer of the breast, colon and rectum, lung, kidney, and head and neck, among others. Interestingly, molecularly targeted agents are becoming the new standard of care in some malignances such as renal-cell carcinoma and chronic myeloid leukemia. Future research on molecularly targeted therapies will focus on the identification of new drugs and drug targets, improved selection of tumors sensitive to these drugs, and the rational design and optimization of combination therapies

Inactivating mutations block the tumor necrosis factor-alpha-converting enzyme in the early secretory pathway.

The ectodomain of different transmembrane molecules is released by a proteolytic event known as shedding. The metalloprotease disintegrin proTNF-alpha converting enzyme (TACE) is responsible for the shedding of various proteins, including protransforming growth factor-alpha (proTGF-alpha) and amyloid-beta precursor protein (APP). Inactive TACE accumulates in the early secretory pathway of cell mutants (M1 and M2) defective in proTGF-alpha and APP shedding. Although previous evidences indicated that the component mutated in M1 and M2 cells is different from TACE, recent results show the existence of two heterozygous point mutations in TACE from M2 cells. Here, we show that wild-type TACE stably transfected in M2 cells is processed, transported to the cell surface, and rescues the proTGF-alpha and APP shedding-defective phenotype. Furthermore, M1 cells also express mutant TACE and transfection with wild-type TACE restores the wild-type phenotype. Therefore, different inactivating mutations result in the accumulation of TACE in the early secretory pathway, emphasizing the importance of the initial steps in the biosynthesis of TACE.

Impaired trafficking and activation of tumor necrosis factor-alpha-converting enzyme in cell mutants defective in protein ectodomain shedding.

Protein ectodomain shedding is a specialized type of regulated proteolysis that releases the extracellular domain of transmembrane proteins. The metalloprotease disintegrin tumor necrosis factor-alpha-converting enzyme (TACE) has been convincingly shown to play a central role in ectodomain shedding, but despite its broad interest, very little is known about the mechanisms that regulate its activity. An analysis of the biosynthesis of TACE in mutant cell lines that have a gross defect in ectodomain shedding (M1 and M2) shows a defective removal of the prodomain that keeps TACE in an inactive form. Using LoVo, a cell line that lacks of active furin, and alpha1-Antitrypsin Portland, a protein inhibitor of proprotein convertases, we show that TACE is normally processed by furin and other proprotein convertases. The defect in M1 and M2 cells is due to a blockade of the exit of TACE from the endoplasmic reticulum. The processing of other zinc-dependent metalloproteases, previously suggested to participate in activated ectodomain shedding is normal in the mutant cells, indicating that the component mutated is highly specific for TACE. In summary, the characterization of shedding-defective somatic cell mutants unveils the existence of a specific mechanism that directs the proteolytic activation of TACE through the control of its exit from the ER.

TACE is required for the activation of the EGFR by TGF-alpha in tumors.

The factors and mechanisms that transduce the intracellular signals sent upon activation of the receptor for the epidermal growth factor (EGFR) and related receptors are reasonably well understood and, in fact, are the targets of anti-tumor drugs. In contrast, less is known about the mechanisms implicated in sending the signals that activate these receptors. Here we show that when its proteolytic shedding is prevented, the transmembrane form of the transforming growth factor-alpha (proTGF-alpha) interacts with, but does not activate, the EGFR. Thus, shedding seems to control not only the availability of the soluble form of the growth factor (TGF-alpha) but also the activity of the transmembrane form. The activity of the protease responsible for the shedding of proTGF-alpha, tumor necrosis factor-alpha converting enzyme (TACE), is required for the activation of the EGFR in vivo and for the development of tumors in nude mice, indicating a crucial role of TACE in tumorigenesis. In agreement with this view, TACE is dramatically overexpressed in the majority of mammary tumors analyzed. Collectively, this evidence points to TACE as a promising target of anti-tumor therapy.