Identification of targets in tumor cells vs normal cells (or at least a
differential in their expression) is certainly a promising method for
approaching the treatment and, indeed, the prevention of cancer. Presently,
targeting of patient tumor cells has taken on even greater importance and
interest with the discovery of the new agent imatinib mesylate (STI571, Gleevec),
which is targeted to a kinase present in chronic myeloid leukemia (CML) cells
(p210 BCR-ABL abnormal cells), which is required for CML cells to survive, but
is not present in normal leucocytes. The results with this agent targeted to
the p210 BCR-ABL tyrosine kinase are indeed spectacular. The agent is of even
greater interest in that it also works against some gastrointestinal stromal
sarcomas with gain of function mutations in c-kit (CD117). This activity of a
targeted agent against a solid tumor increases the interest in targeted therapy
to an even greater degree.
Of course, there are multiple other examples of targeted (or semi-targeted)
therapies, such as monoclonal antibodies (to CD20, CD33, CD52 or HER2/neu),
aromatase inhibitors, antiestrogens, and many others.
Even agents such as inhibitors of topoisomerase I hit a target that is
present to a greater degree in tumor cells than in normal cells. More specific
targeting should give us significant new therapeutic and preventive agents.
This special issue of ONCOLOGY is devoted to a series of papers presented in
part at an educational satellite symposium held in conjunction with the American
Society of Clinical Oncology 2001 Annual Meeting. The symposium was convened to
specifically examine vascular endothelial growth factor (VEGF) and
cyclooxygenase (COX)-2 as potential new targets in cancer treatment and
prevention. The presentations were outstanding, but I think the reader will find
these papers of even more interest.
More specifically, Drs. Anzick and Trent of the Cancer Genetics Branch of the
National Human Genome Research Institute, National Institutes of Health, give us
an outstanding overview of the role of genomics in identifying new targets for
cancer therapies. This extremely well-written article clearly presents the
potential for the use of genomics in the day-to-day care of the patient with
cancer. In the article, they delineate the use of:
- complementary DNA microarray to improve tumor classification and to
provide potential new targets (and clues as to the location of those targets in
pathways critical to cell survival);
- tissue arrays to determine how frequently a particular target is found in
a particular tumor type and to determine the clinical significance of that
particular target; and
- single-nucleotide polymorphism analysis to predict either toxicity or
response, or both, to a particular drug.
An overview of the role of angiogenesis in oncology, including inhibitors of
angiogenesis, is provided by Dr. Lee Ellis and colleagues of The University of
Texas M. D. Anderson Cancer Center. They give an outstanding review of VEGF as a
target associated with an aggressive phenotype in numerous solid malignancies.
They also discuss the angiopoietins, COX-2, and numerous nonspecific angiogenic
factors. The tables and figures in this article give us an idea of the possible
redundancy in the process of angiogenesis and the challenges in targeting tumor
Dr. Francis Giles of M. D. Anderson Cancer Center teaches us about the
importance of increased angiogenesis in the pathogenesis of hematologic
malignancies. In particular, Dr. Giles emphasizes VEGF as a proangiogenic factor
(along with the other possible functions for VEGF in the pathogenesis of
hematologic malignancies) and discusses various methods being used to intervene
to discover the effects of VEGF.
1. Druker BJ, Sawyers CL, Kantarjian H, et al: Activity of a specific
inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid
leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N
Engl J Med 344:1038-1042, 2001.
2. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al: Effect of the tyrosine
kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal
tumor. N Engl J Med 344:1052-1056, 2001.
3. Giovanella BC, Stehlin JS, Wall ME, et al: DNA topoisomerase I-targeted
chemotherapy of human colon cancer in xenografts. Science 246:1046-1048, 1989.