Human Studies And Human Cancer

Human studies

Dr. J. M. Folkman presented an excellent example how, based on animal observations, one could predict and proceed to similar principles in human cancer. The angiogenesis inhibitors, angiostatin and endostatin, were discovered in an animal model in which a primary tumor suppresses its metastases. A different strategy was developed to discover endogenous inhibitors of angiogenesis generated by human tumors. An equal number of tumor cells was infected into each flank of a mouse and if one tumor grew and suppressed the opposite tumor, he searched for an inhibitor of angiogenesis in the circulation and in conditional medium from cultures of the tumor cells. A cleaved fragment of antithrombin 3 was generated by a human small cell lung cancer and by a human pancreatic cancer. This fragment is a specific endothelial inhibitor and a potent angiogenesis inhibitor, and does not bind thrombin.

When this finding is taken together with angiostatin, an internal fragment of plasminogen, it suggests a molecular linkage between the homeostatic system and regulators of angiogenesis.

Dr. W. G. Kaelin pointed out that the human von Hippel-Lindau (vHL) tumor suppressor protein may have an effect on the increasingly important proteasome degradation machinery. Inactivation of the vHL tumor suppressor gene in humans gives rise to a hereditary cancer syndrome characterized by central nervous system and retinal hemangioblastomas. The vHL protein (pvHL) plays an important role in the inhibition of hypoxia-inducible genes under well-oxygenated conditions. This activity has been linked to the ability of pvHL, once bound to elongin C and cul2, to target HIF1α and HIF2α for degradation.

The acquisition of cell immortality is an important step in tumor progression often conferred by the expression of the telomerase enzyme. Dr. R. A. Weinberg showed that the inactivation of the enzyme through use of a dominant negative telomerase results in crisis and death of telomerase-positive human tumor cells. Introduction of the telomerase gene together with the SV40 large T and ras oncogenes results in the transformation to tumorigenicity of normal human cells, resulting in turn in the creation of human tumor cells of defined genetic constitution.

A glimpse of a final outlook came from Dr. A. J. Levine, who showed that new technologies could widen insight into the natural history of human cancer without, however, abolishing the need for the experimental model, which will provide conceptual progress for the biology of cancer. He examined human colon cancers and matched normal colon tissue for their transcription profile using Affymetrix DNA chips. A cluster analysis of the patterns of gene expression was able to separate cancer tissue, normal tissue and colon cancer cell lines. Genes that were coordinately regulated (e.g., genes for ribosomal proteins) clustered and were different in their expression pattern in normal and cancer tissue.

Does one always have to go and can one always go via the animal model to insights on the natural history of human cancer?

Dr. E. A. Sausville's introduction not only set the tone for the meeting but raised the key question about the relevance of animal models both for understanding human cancer and for drug development. The empirical model of cancer drug discovery and development is based on the antiproliferative activity of agents in murine xenografts of human tumor cells. Retrospective comparison of activity in Phase II clinical trials with preclinical activity leads to the conclusion that there is a poor correlation in the histology with a drug's activity in preclinical models and subsequent clinical performance in the same histology. If anything, there is a correlation in the number of different models and the magnitude of response with subsequent demonstration of activity in some human tumor. These results encourage efforts to define drug leads by their performance in rationally and molecularly defined models. Development and optimization occurs in relation to continued ability of the lead structure to affect the molecular target. In vivo models would serve this goal by allowing a clear-cut read-out of the drug's effect on its molecular target in the milieu of an intact animal host.

Dr. B. A. Chabner pointed out that often animal models are difficult to come by when one wants to evaluate details in a drug that happened to be effective in humans. He presented the story of the identification, preclinical evaluation and early clinical evaluation of a new cytotoxic molecule (ETF 43), a DNA minor groove-binding molecule that has shown activity in human sarcomas, melanoma and mesotheliomas. Cell line screening detected antitumor activity accurately, but no validated mouse models exist for predicting activity in humans. The genetic diversity of human tumors, the complexity of genetic changes in human tumors and the diversity of host handling of drugs all complicate the development of predictive models. The speaker suggested that human leukemias, with specific characteristic translocations, might be easier to model than human epithelial tumors with highly complex sequential genetic mutations.