Targeting the VEGF pathway: Antiangiogenic strategies in the treatment of non-small cell lung cancer

Aita, Marianna; Fasola, Gianpiero; Defferrari, Carlotta; Brianti, Annalisa; Bello, Maria Giovanna Dal; Follador, A.; Sinaccio, Graziella; Pronzato, P.; Grossi, Francesco

doi:10.1016/j.critrevonc.2008.05.002

Cited by 31 publications

(20 citation statements)

References 59 publications

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“…The observed better response rate and survival in adenocarcinoma compared to squamous-cell carcinoma recently reported with cisplatin and pemetrexed, as opposed to a better response and survival of squamous-cell carcinoma to cisplatin and gemcitabine, 4 and the proven benefit of adding bevacizumab to carboplatin and paclitaxel to improve the outcome of non-squamous cancer patients 5,6 indicate the clinical need to fine-tune the tailored approach in undifferentiated lung carcinomas. Owing to their rarity and also the recent subclassification (large-cell variants and sarcomatoid carcinoma variants), a molecular or immunochemical profiling would be very useful, in the absence of specific data about their clinical response to chemotherapy, to understand if at least part of LCCs is more closely related to adenocarcinoma or squamous-cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6] The recognition that some chemotherapeutic regimes were more effective in squamous-cell carcinomas, whereas other drug combinations were apparently better active in nonsquamous histological types (eg antifolate drugs), brought up the issue of accurately defining the histotypes in both preoperative and surgical materials. The responsiveness of large-cell lung cancers to new drugs apparently more selective for adenocarcinomas or squamous carcinomas is not fully understood, possibly due to the heterogeneous tumor types entered in this group along the years and by different pathologists.…”

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confidence: 99%

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Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

et al. 2009

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Lung cancer classification in small-cell and non-small-cell types was recently challenged by data on the differential efficacy of new cytotoxic agents in specific histotypes. An accurate histotype definition has therefore gained interest in both preoperative and surgical materials, but is a hard task especially in undifferentiated large-cell tumors lacking morphological signs of squamous or glandular differentiation. The responsiveness of these latter subtypes to new drugs apparently more selective for adenocarcinomas or squamous carcinomas is not fully understood, also due to the heterogeneity of diagnostic criteria for this tumor entity. Current immunohistochemical markers are not fully specific and new molecules are to be explored. On the basis of gene expression profiling data, reporting a remarkable differential expression of desmocollin-3 (a protein localized in desmosomal junctions of stratified epithelial) between adeno-and squamous cancers, we immunostained 62 cases of resected undifferentiated large-cell lung carcinomas for desmocollin-3 (and for TTF-1, p63 and mucin stain), to test its ability to identify a (residual) squamous phenotype, if present. Desmocollin-3 was expressed in almost half of the undifferentiated large-cell cancers and was mutually exclusive with TTF-1 (positive in 39%; the remaining 18 % of cases was double negative). Special large-cell carcinoma variants expressed desmocollin-3 in 6 of 6 basaloid, 7 of 12 clear-cell types, again mutually exclusive with TTF-1 expression. None of seven sarcomatoid carcinomas reacted for either marker. In 31 cytological samples diagnosed as 'non-small-cell lung carcinoma', desmocollin-3 was again mutually exclusive with TTF-1 and stained all squamous carcinomas, 1 of 19 adenocarcinoma only, and 50% of large-cell carcinoma (all histologically confirmed). This combined morphophenotypic approach may represent a valid adjunct (for both surgical and cytological samples) in the selection of patients with lung cancer to medical treatments tailored according to different efficacy in different lung carcinomas of the squamous, adeno-and large-cell types. Modern Pathology ( Keywords: large-cell carcinoma; squamous differentiation; desmocollin-3; diagnosis Lung cancer is subdivided into four histotypes, including small-cell carcinoma (SCLC) on the one side, and carcinomas of squamous-, adeno-and large-cell types on the other. These latter tumor groups have different pathological features, but have generally been treated so far according to similar strategies, so that a clear-cut distinction among these types (except for SCLC) was not considered clinically relevant. 1 Indeed, the WHO classifications of lung carcinoma have always kept the different histological types separate and proposed individual categories for squamous carcinoma, adenocarcinoma and large-cell (anaplastic) carcinoma (LCC). 2 The latter category underwent major changes in the last classification scheme, 3 having undifferentiated pleomorphic and/or sarcomatoid variants been moved to a new group o...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

et al. 2009

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“…VEGF plays a dominant role in tumor angiogenesis (18,19) and its inhibition has been implemented clinically, mostly in combination with chemotherapy, to treat cancers of intestine, liver (20), brain (21), colon (22), kidney (23)(24)(25), breast (26), and lung (27,28). However, in most cases the benefit to most patients from VEGF inhibition is modest at best (29, 30).…”

Section: Discussionmentioning

confidence: 99%

Chemical generation of bispecific antibodies

Doppalapudi

Huang

Liu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

115

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Bispecific antibodies (BsAbs) are regarded as promising therapeutic agents due to their ability to simultaneously bind two different antigens. Several bispecific modalities have been developed, but their utility is limited due to problems with stability and manufacturing complexity. Here we report a versatile technology, based on a scaffold antibody and pharmacophore peptide heterodimers, that enables rapid generation and chemical optimization of bispecific antibodies, which are termed bispecific CovX-Bodies. Two different peptides are joined together using a branched azetidinone linker and fused to the scaffold antibody under mild conditions in a site-specific manner. Whereas the pharmacophores are responsible for functional activities, the antibody scaffold imparts long half-life and Ig-like distribution. The pharmacophores can be chemically optimized or replaced with other pharmacophores to generate optimized or unique bispecific antibodies. As a prototype, we developed a bispecific antibody that binds both vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) simultaneously, inhibits their function, shows efficacy in tumor xenograft studies, and greatly augments the antitumor effects of standard chemotherapy. This unique antiangiogenic bispecific antibody is in phase-1 clinical trials.

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“…Expression of PC4 was evaluated by staining intensity and the percentage of positive cells in a specimen as described previously. 25,26 A total 'staining score' of 0-12 was calculated and graded as negative (score 0-1), weak (score 2-4), moderate (score [5][6][7][8] and strong (score 9-12).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…4 Thus, the early diagnosis and therapy of NSCLC is extremely necessary. As a promising approach for NSCLC treatment, molecular targeted therapy has been studied and several targeted agents have been explored recently, 5 including the antagonists of epidermal growth factor receptor 6 and vascular endothelial growth factor, 7 inhibitors of anaplastic lymphoma kinase 8 and others. 1 However, there is still a need to identify new specific and efficient targeting molecules to provide multipathways for future NSCLC therapy.…”

Section: Introductionmentioning

confidence: 99%

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

et al. 2012

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Transcriptional positive coactivator 4 (PC4) is a multifunctional nuclear protein that has important roles in DNA transcription, replication, repair and heterochromatinization. However, the role of PC4 in cancer remains to be clarified. Several studies propose that PC4 may act as a putative tumor suppressor. Here, we demonstrate for the first time that PC4 may represent a potential therapeutic target in non-small cell lung cancer (NSCLC). PC4 protein expression is significantly upregulated in NSCLC carcinoma tissues compared with their adjacent noncancerous counterparts as shown by immunohistochemical staining and western blotting in 104 pairs of formalin-fixed human NSCLC specimens and 6 fresh NSCLC samples. Knockdown of PC4 expression by sequence-specific small interfering RNA (siRNA) in human NSCLC cells (A549, H460 and H358) significantly inhibits the growth of cancer cells by the induction of cell cycle arrest and the increase of cell apoptosis in vitro. Interrupting the PC4 signaling pathway by injection of the PC4 siRNA liposome complex produced an effective regression of pre-established A549 cell xenografts in mice through growth inhibition and increased apoptosis. These results indicated that PC4 could be an attractive new therapeutic target for the treatment of NSCLC.

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Targeting the VEGF pathway: Antiangiogenic strategies in the treatment of non-small cell lung cancer

Cited by 31 publications

References 59 publications

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

Chemical generation of bispecific antibodies

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

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