Project Details
Projekt
Lesional and intralesional treatment of cutaneous squamous cell carcinoma and melanoma with prodrugs of duocarmycin-derivatives in the mouse
Subject Area
Dermatology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 546970602
Metastatic melanoma is the most frequently fatal tumor of the skin and also one of the tumors most frequently metastasizing to the skin. Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer with a continuously increasing incidence rate, leading to inoperable or metastatic disease in about 5% -in immunosuppressed patients even in 20%- of cases. Immune checkpoint blockades are available for both melanoma and cSCC, but only about half of patients benefit from them. Cutaneous metastases or locally inoperable tumors can lead to disfigurement, pain, bleeding, development of unpleasant odors, and thus to a massive reduction in quality of life, significantly increased suffering, and morbidity. This research project will investigate the treatment of subcutaneous/cutaneous melanoma and cSCC in immunodeficient NMRI nude mice and immunocompetent C57BL/B6J and NMRI mice by intralesional application of the duocarmycin derivative LT314-Gal followed by administration of β-D-galactosidase. Duocarmycin derivatives have already been tested in phase I and II clinical trials but showed only low response rates due to dose-limiting myelotoxicity. In our studies, a novel glycosidic prodrug of a dimeric duocarmycin derivative is used, which has extremely high cytotoxicity with an IC50 = 150 fmol, and can also be reversibly detoxified by a factor of one million by glycosidation. Intralesional injection of the duocarmycin prodrug into the tumor, in which the prodrug is converted into the drug by subsequent intralesional application of β-D-galactosidase, is expected to result in fewer dose-limiting side effects. The in vitro efficacy of LT314-Gal with and without the addition of β-D-galactosidase has already been tested in the B16F10, A431, and A375 cell lines. Testing in the PECA cell line will be performed as part of this application. In addition to the direct determination of the cytotoxic effect of the prodrug or the drug, the influence of the immune system on the tumor response is determined. For this reason, the models of immunodeficient mice and immunocompetent mice were chosen. This information is relevant for a better understanding of the efficacy, especially in immunosuppressed patients. At the end of the observation period after therapy, during which daily measurement of tumor sizes took place, the spleen and lymph nodes are taken for examination of the lymphocyte population. The blood is taken from the heart as well as the brain, lung, liver, intestine, kidney, heart, and genitals for histological examination for toxicological damage. Furthermore, the individual tumors are removed for exact size determination and then also histologically examined. The goals of this project are to determine the ideal injection dose, to test for efficacy in various tumor models and to analyze for side effects of the therapy.
DFG Programme
Research Grants
Co-Investigators
Professor Dr. Lutz F. Tietze; Professorin Dr. Brigitte Vollmar
