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The role of angiogenesis inhibition in the treatment of primary and metastatic cancers is an area of exciting and intense research. Tumors produce factors that elicit or inhibit the formation of new blood vessels, which are crucial for the growth of the tumor and its metastases. Another area of active research involves the development of screening tests, with one aim being stopping tumor growth before full-blown tumor angiogenesis begins. Fundamental principals of cell biology are being exploited in the development of new screening tests for various types of cancer. Monday's (September 13) session was devoted to recent advances in these two areas.
Angiogenesis refers to the generation of new blood vessels and is an absolute requirement for cancer cell growth and dissemination. Whereas the nutritional requirements of small tumors can be satisfied by the simple diffusion of nutrients from the immediate vicinity, larger tumors require the formation of new blood vessels within the tumor masses to survive. In addition, dissemination of malignant cells through intratumoral blood vessels is the first step in the process of cancer metastasis. The genesis of blood vessels is a complex pathological phenomenon: cancer cells and surrounding stromal cells produce and secrete a variety of molecules known as angiogenesis growth factors which, on binding to specific receptors in the membrane of endothelial cells, induce cell proliferation and blood vessel formation. Some of these factors, such as vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF), can be measured in the serum and urine of patients with various types of cancer. In general, the levels of these factors correlate with disease prognosis. New and interesting data were presented in this session that pertain to several areas of angiogenesis research and its application to cancer diagnosis, prognostic risk assessment, and therapy.
Angiogenesis Inhibition: Growth Factors Are Attractive Targets
VEGF, also known as vascular permeability factor, induces the growth and permeability of endothelial cells and is one of the most relevant and well-characterized angiogenesis growth factors. Considering the important role of VEGF in the process of tumor angiogenesis and tumor progression, this molecule is an attractive target for treatment. There are several potential ways to therapeutically interfere with VEGF. The two modalities that have been more consistently explored to date are the inhibition of VEGF production by antisense oligonucleotides and the blocking of activation of the VEGF receptor on endothelial cells by specific tyrosine kinase inhibitors. At this session, further work was presented on the use of an antisense oligonucleotide and a monoclonal antibody that block VEGF production.
Halting VEGF Production
Investigators from the Universities of Naples Federico II, University of Pisa (Italy), and University of Texas MD Anderson Cancer Center in Houston, Texas, in collaboration with Hybridon Inc, Cambridge, Mass, presented data on the inhibition of VEGF production in a colon cancer cell line by HYB 676, a novel VEGF antisense oligonucleotide.[1] In addition, administration of this agent to mice bearing colon cancer xenografts resulted in the reduction of VEGF production and blood vessel formation and tumor growth inhibition.
Of interest, the same effects on VEGF production were observed after treating malignant cancer cell lines with Mab C225, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR) and which is currently undergoing clinical evaluation in patients with malignant diseases. Furthermore, treatment of the mice with the two agents in combination resulted in increased inhibition of VEGF production and tumor growth inhibition.
These data indicate that the in vivo effects of the EGFR monoclonal antibody could at least partly be related to VEGF inhibition and that the addition of other VEGF inhibitors could result in better therapeutic results. This study suggests that the combination of both agents could result in improved therapeutic activities, and warrants the conduction of clinical trials.
Plasma D-dimer: A Prognostic Marker?
Patients with cancer frequently have alterations of blood coagulation processes, which are thought to be associated with higher angiogenesis potential and worse prognosis. Dirix and colleagues from Sint-Augustinus, Wilrijk, Belgium, measured the level of plasma D-dimer, a marker of coagulation activation and fibrinolysis, in three cohorts of patients with either local, inflammatory, or metastatic breast cancer to determine whether the level correlates with tumor stage, tumor growth ratio, and aggressiveness.[2] Overall, the plasma levels of D-dimer increased with tumor stage and were higher in cancer patients than in normal individuals. In patients with local, operable breast cancer, high levels of D-dimer correlated with lymph node metastasis, which is the major prognostic factor in localized breast cancer. In patients with advanced breast cancer, the plasma levels of D-dimer did not correlate with such characteristics as age, tumor type, estrogen receptor status, and time to treatment failure, but did have a significant relation to tumor doubling time. In addition, the levels of plasma D-dimer decreased in patients with metastatic disease that responded to chemotherapy.
These data suggest that the plasma levels of D-dimer could have prognostic implications in patients with breast cancer. These results are preliminary, however, and should be considered with caution. The validation of a molecular marker such as D-dimer as a prognostic factor requires larger studies than the one presented here. More important, the evaluation of molecular markers such as D-dimers as prognostic factors requires multivariate statistical analysis, the results of which were not available at the time of the presentation.
Detection of Genomic Instability May Be an Early Screening Test
Over the past few years, the field of cancer cell biology has been the subject of intense research efforts, with results increasingly being applied to clinical cancer care. One of the most relevant characteristics of malignant cells is their genomic instability. Whereas normal cells have mechanisms that guarantee the integrity and fidelity of their genetic information, the loss of these mechanisms characterize cancer cells. The genetic instability of cancer cells has two principal manifestations that can be detected with appropriate technology: loss of heterozygosity (LOH) and microsatellite alterations (MA). In fact, the inability to maintain genome integrity is probably one of the earliest alterations in cancer cells and may occur in the very early stage of tumor development. Therefore, the detection of genomic instability could possibly be used as a screening test for early cancer detection.
Field and coworkers from the Roy Castle International Center for Lung Cancer Research and the University of Liverpool, Liverpool, United Kingdom, evaluated the potential use of genomic instability detection for lung cancer screening.[3] The authors analyzed microsatellite markers in 90 specimens from bronchial lavage in individuals with suspected lung cancer. Thirty-five percent of patients found to have lung cancer by cytological and radiological techniques had genomic instability. Unfortunately, genomic instability was also detected in 23% of patients without either cytological or radiological evidence of lung cancer. In patients subsequently found to have lung cancer, the genomic instability predominantly resulted from LOH, whereas the genomic instability in individuals without lung cancer was mostly caused by MA.
Unfortunately, with current cytological and radiological techniques, the diagnosis of lung cancer usually occurs late, when the disease is beyond the possibility of being cured. This study represents an innovative approach to lung cancer diagnosis and applies current knowledge in cell cancer biology to a clinical endpoint. However, the results of the study were negative. For a screening test to be useful, it must have a high positive and a high negative predictive value, which the test evaluated by Field and colleagues does not have. In their study, the diagnosis of lung cancer based on genomic instability in bronchial lavage had a high rate of false negative results (65%) as well as false positive results (72%). Whether these negative results are the consequence of technical deficiencies is currently unknown, but this approach requires further refinement before it can be applied to clinical practice.
Summary: Implications for Clinical Practice
- Blocking of the EGFR by monoclonal antibodies results in downregulation of VEGF. Inhibition of VEGF expression by antisense oligonucleotides results in tumor growth inhibition. Combination of both therapeutic modalities results in additive antitumor effects. The implications of these findings deserve exploration in clinical trials.
- The plasma levels of D-dimer may correlate with breast cancer aggressiveness and prognosis. This hypothesis should, however, be confirmed by large multivariate analysis studies.
- Screening for lung cancer by analysis of genomic instability in microsatellite markers isolated from bronchial fluid specimen does not appear to be effective.
References
- Ciardiello F, Bianco R, Damiano V, et al. Antiangiogenic and antitumor effect of VEGF antisense oligonucleotide in combination with anti-EGFR C225 monoclonal antibody in human colon cancer. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 357.
- Dirix L, Weytjens R, Salgado R, et al. Plasma D-dimer levels, serum VEGF, b-FGF and IL-6 in metastatic breast cancer (MBC): Correlation with tumour load and response to therapy. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 359.
- Field JK, Lioglou T, Xinarianos G, et al. Genomic instability in bronchial lavage specimens from individuals with no evidence of lung cancer: An early detection marker? Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 361.
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