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New approaches for improving cancer therapy
(C.Wiltschke, Vienna)

From an Oncology Workshop held in Vienna, Austria, in April '98

In the management of malignant tumors there are two main strategies in the research field that can lead to better treatment modalities and to an improvement of prognosis: better understanding of tumor development and trying to gain new insights into tumor progression, said Prof. Dr. C. Wiltschke, University Hospital, Vienna, referring to different approaches that are under investigation (table 1).

Different mechanisms at certain tumor stages

When looking at the tumor evolution one can define two major mechanisms that enable the development and the spreading of tumor cells. For example in breast cancer evolution there is a predominance of immunologic dysfunction in the early stage whereas in the stage of invasion and metastasis the number and importance of genetic defects are increasing. To investigate these genetic defects is one of the major research projects of the oncology department at Vienna university. As Wiltschke pointed out there is a variety of genetic defects being involved in tumor progression comprising dysfunction of tumor suppressor genes, cell cycle regulation and DNA repair genes. But genetic defects are also found on the level of tumor spreading. As to the current knowledge an over activation" of angiogenesis genes and a malfunction of metastasis inhibition genes play an important role. For some tumors it is already Possible to define an association between distinct gene mutations and the tumor stage (e.g. k-ras mutation in the early stage of colon adenoma) that could lead to improved therapeutic options in the future. Some promising data are also available for breast cancer, the mutation of BCRA 1 and 2 being the best known today. What makes this so important is the possibility to identify risk patients and thus enabling the detection of cancer at a very early stage. In the case of breast cancer identification of risk patients is also associated with therapeutic implications as the prevention study with tamoxifen has shown (Fisher 1998). But analysis of genetic defects is also a very helpful tool as far as prognosis of patients with breast cancer is concerned.

Therapy based on functional status of estrogen receptors

With regard to breast cancer the presence and functional status of estrogen receptors (ER) is one of the most important features from the therapeutic point of view. It is well known that the normal epithelium of the breast does not express ERs. In the early stages of tumor development (typical and atypical hyperplasia) one can consistently show the expression of ERs, whereas ERs can be missing at all stages after transformation into carcinoma cells (carcinoma in situ, invasive carcinoma, metastatic carcinoma). As Wiltschke pointed out it is not only the expression of ERs that is important but also the identification of subtypes that can provide important information concerning therapy. The so called variant type (domain E) is characterized by the fact that growth stimulation is possible with extremely small amounts of estrogens. Thus it seems unlikely that currently available anti-estrogens; will be effective in this subtype because one would have to cover all estrogen receptors in order to inhibit growth.

Future aspects

Another fascinating research area according to Wiltschke is the investigation of adhesion molecules which play an important role in the interaction between tumor cells and T-cells. And the reduced expression of adhesion molecules like ICAM-1 is believed to be one of the mechanisms by which tumors can escape the cells of the immune system.

When looking at the advances in clinical research there are also some promising approaches under investigation or already applied in the clinical setting. New drugs with an improved side effect profile like gemcitabine are regarded to be a major breakthrough, because this will have a tremendous impact on the quality of life, said Wiltschke. Finally it is noteworthy to mention that strategies to overcome drug resistance offer another aspect to improve treatment outcome in cancer patients in the near future.