Special Targets for the Treatment and Prevention of Cancer: Angiogenesis, VEGF, COX-2

May 1, 2002

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.[1] 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).[2] This activity of a targeted agent against a solid tumor increases the interest in targeted therapy to an even greater degree.

Identification of targets in tumor cells vs normal cells (or at least adifferential in their expression) is certainly a promising method forapproaching the treatment and, indeed, the prevention of cancer. Presently,targeting of patient tumor cells has taken on even greater importance andinterest 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, butis not present in normal leucocytes.[1] The results with this agent targeted tothe p210 BCR-ABL tyrosine kinase are indeed spectacular. The agent is of evengreater interest in that it also works against some gastrointestinal stromalsarcomas with gain of function mutations in c-kit (CD117).[2] This activity of atargeted agent against a solid tumor increases the interest in targeted therapyto 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[3] hit a target that ispresent to a greater degree in tumor cells than in normal cells. More specifictargeting should give us significant new therapeutic and preventive agents.

This special issue of ONCOLOGY is devoted to a series of papers presented inpart at an educational satellite symposium held in conjunction with the AmericanSociety of Clinical Oncology 2001 Annual Meeting. The symposium was convened tospecifically examine vascular endothelial growth factor (VEGF) andcyclooxygenase (COX)-2 as potential new targets in cancer treatment andprevention. The presentations were outstanding, but I think the reader will findthese papers of even more interest.

More specifically, Drs. Anzick and Trent of the Cancer Genetics Branch of theNational Human Genome Research Institute, National Institutes of Health, give usan outstanding overview of the role of genomics in identifying new targets forcancer therapies. This extremely well-written article clearly presents thepotential for the use of genomics in the day-to-day care of the patient withcancer. In the article, they delineate the use of:

  • complementary DNA microarray to improve tumor classification and toprovide potential new targets (and clues as to the location of those targets inpathways critical to cell survival);

  • tissue arrays to determine how frequently a particular target is found ina particular tumor type and to determine the clinical significance of thatparticular target; and

  • single-nucleotide polymorphism analysis to predict either toxicity orresponse, or both, to a particular drug.

An overview of the role of angiogenesis in oncology, including inhibitors ofangiogenesis, is provided by Dr. Lee Ellis and colleagues of The University ofTexas M. D. Anderson Cancer Center. They give an outstanding review of VEGF as atarget associated with an aggressive phenotype in numerous solid malignancies.They also discuss the angiopoietins, COX-2, and numerous nonspecific angiogenicfactors. The tables and figures in this article give us an idea of the possibleredundancy in the process of angiogenesis and the challenges in targeting tumorangiogenesis.

Dr. Francis Giles of M. D. Anderson Cancer Center teaches us about theimportance of increased angiogenesis in the pathogenesis of hematologicmalignancies. In particular, Dr. Giles emphasizes VEGF as a proangiogenic factor(along with the other possible functions for VEGF in the pathogenesis ofhematologic malignancies) and discusses various methods being used to interveneto discover the effects of VEGF.

Drs. Dang, Shapiro, and Hudis from Memorial Sloan-Kettering and the JamesCancer Center cover COX-2 as a target for treatment and/or prevention of cancerand the use of selective COX-2 inhibitors to hit the target. They give anoverview of the role of prostaglandins and COX in carcinogenesis andtumorigenesis and review the epidemiologic evidence that inhibitors of COX-1 and-2 appear to reduce the incidence of various known cancers. Lastly, they brieflydiscuss the use of celecoxib (Celebrex) to reduce colon polyp burden in patientswith familial polyposis. The detailed rationale for an ongoing clinical trial ofcelecoxib plus trastuzumab (Herceptin) is also of considerable interest.

Finally, Drs. Stratton and Alberts of the Arizona Cancer Center give thereader an in-depth discussion of the use of selective COX-2 inhibitors in cancerprevention and treatment. They describe COX biochemistry and the importance ofCOX-2 as a target in colorectal neoplasia, nonmelanoma skin cancer, lung cancer,prostate cancer, breast cancer, gastric cancer, bladder cancer, esophagealcancer, and pancreatic cancer. This concluding article is an outstanding reviewand update on new advances.

In assembling this special issue of ONCOLOGY, I learned a great deal fromthese well-written manuscripts. I hope that the reader also benefits from thisspecial issue.

References:

1. Druker BJ, Sawyers CL, Kantarjian H, et al: Activity of a specificinhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloidleukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. NEngl J Med 344:1038-1042, 2001.

2. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al: Effect of the tyrosinekinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromaltumor. N Engl J Med 344:1052-1056, 2001.

3. Giovanella BC, Stehlin JS, Wall ME, et al: DNA topoisomerase I-targetedchemotherapy of human colon cancer in xenografts. Science 246:1046-1048, 1989.