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Start of funding 01.07.2002

Modulation of stroma cells by tumor derived cytokines: Setting the groundwork for stroma targeted cancer therapies

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Novel cancer therapies are targeting the interaction of cancer cells with stromal cells (fibroblasts, endothelial cells). Currently running protocols (e.g. rofecoxib, pioglitazone, trofosfamid in a Phase II in Regensburg) exhibit promising therapeutic responses in an unprecedented wide range of human malignancies, but the molecular basis of this empirical approach is not yet understood. In this BaCaTec financed cooperation of the Dept. of Dermatology, University of Regensburg, Germany, and the Sidney Kimmel Cancer Center, San Diego, USA, tissues from metastases responding or not-responding to this therapy are analysed with a special focus on tumor-expressed genes (cytokines, receptor tyrosine kinase ligands etc.) known to modulate fibroblast and endothelial cell functions by a fluorescence-based oligonucleotide array. The aim is to set the ground-work for understanding and further improving the current protocols or to enable a pre-therapeutic selection of patients that could benefit from this kind of first and second line therapy of metastatic cancer.

Final report:
The primary goal of the project was to provide platforms for fluorescence based oligonucleotide array technologies in order to develop tumor-stroma targeted therapies of chemorefractory cancers.

The BaCaTec grant was primarily spent for „knowledge transfer“ from the partner institute SKCC San Diego, i.e., the money was spent to cover traveling costs.

Supported by the profound experiences of our partner institute in the USA, we succeeded in establishing our array facility, which is already documented by some publications (1). Both commercial high density arrays and „on site“ developed low density arrays that sample selected families of genes are applied. Both instruments are currently used for the analysis of melanoma tissues. 35 tumors and metastases have been included. This is an ongoing project. Problems arose from the fact that only a fraction of the material sampled is suitable for array analysis, which expands the time frame significantly.

However, this project does bear a chance to generate data to identify suitable targets in the tumor itself or in the stroma, which could be used for small molecule therapeuticals such as kinase inhibitors, Cox-2-, PPAR-targeting drugs and others. Higher numbers of included patients could be used to define subsets of patients with an increased chance to profit from the use of such drugs.

Particularly the newly developed low density arrays have given new insights and new potential targets are emerging, which have not been previously investigated in melanoma, for instance the DDR2 receptor. In addition, this tool has attracted the interest of other researchers. Most remarkably we could start a further cooperation using our array for the analysis of a colon cancer model together with Dr. Richard Bates PhD, Harvard Medical School, Boston, USA. In this system we got very consistent an novel data concerning the differential regulation of Eph-receptors and ephrins in colo-rectal cancer progression. Furthermore, the low density arrays were also applicable to gain new insights in wound healing processes in the intestine, which documents the “pluripotence” of the established tools very well (1).

The described developments go hand-in-hand with the development of clinical protocols that employ stroma targeting, which is also documented by a recent series of papers (2).

1) References that documet the successful knowledge transfer and “cristalization” of innovative technology: Array-based analysis

Becker B, Stolz W, Landthaler M, Vogt T. LPC-microdissection combined with microarray analysis identifies genes discriminating melanocytic nevi and malignant melanomas. J Invest Dermatol, 122:361-368, 2004

Hafner C, Meyer S, Hagen I, Becker B, Rösch A, Landthaler M, Vogt T. Ephrin-B reverse signaling induces expression of wound healing associated genes in IEC6 intestinal epithelial cells. W J Gastroenterol 11:4511-8, 2005

2) References that document the concomitant progress in the clinical development of stroma-targeting therapies:

Reichle A, Vogt T, Kunz-Schunghart L, Bachthaler M, Bretschneider T, Bross K, Freund S, Napiralski S, Berand A, Andreesen R. Anti-inflammatory and angiostatic therapy in chemorefractory multisystem Langerhans cell histiocytosis of adults. Br J Hematol 128,730-736, 2005

Coras B, Hafner C, Reichle A, Hohenleutner U, Szeimies RM, Landthaler M, Vogt T. Antiangiogenic therapy with pioglitazone, rofecoxib and trofosfamide in a patient with endemic Kaposi’s sarcoma. Arch Dermatol 140:1504-1507, 2004

Reichle A, Bross K, Vogt T, Bataille F, Wild J, Berand A, Krause S, Andreesen R. Pioglitazone and rofecoxib combined with angiostatic sceduling of trofosfamide in far advanced malignant melanomas and soft tissue sarcomas. Cancer 101:2247-56, 2004

Vogt T, Hafner C, Bross K, Bataille F, Jauch KW, Berand A, Landthaler M, Andreesen R, Reichle A. Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors. Cancer 98:2251-6, 2003.