Medical Experiment - Assessment of Efficacy & Safety of Local, Targeted Therapy With Neuropeptide Labelled With Alpha Emitter [225Ac]Ac-DOTA-SP (TAT) as Supplementary Therapy in Glioma (WHO G3-G4) Progression

1. Background: Brain tumors account for 1.35% of all cancer conditions and cause deaths in 2.2% of cancer patients (Cancer Facts and Figures 2005). The most common type of brain tumors are gliomas. Depending on the age group, they account for 40%-90% of central nervous system tumors. The incidence of malignant gliomas is 0.5-2 per 100,000 people per year. Men are more frequently affected, usually in their 50s and 60s. In the Polish population, approximately 1300 people are diagnosed with gliomas annually, including about 600 cases of malignant gliomas. The standard treatment approach includes surgical treatment, radiotherapy, and chemotherapy. Despite the currently accepted treatment regimen, survival times-depending on the tumor type-range from 1 to 3 years.

In a typical course, regardless of the therapy used, the extent of surgery, and other prognostic factors, the progression of the growth process occurs after some time. The use of chemotherapy extends survival time-depending on the tumor type-by several to several dozen weeks. This data indicates the need to seek other forms of treatment. Since brain gliomas are infiltrative in nature, it seems that an effective drug should exhibit the ability to diffuse freely within the tumor and specifically bind to cancer cells. Selected peptides exhibit such properties.

One of the mechanisms regulating cell (including cancer cell) function involves receptor systems located in the cell membrane. These show high specificity of reaction with specific peptides. The expression of some receptor systems significantly increases in cells of specific tumor types. This property underlies the use of radioisotope-labeled peptides in diagnosis and treatment in oncology. Peptides bind to cancer cells, and ionizing radiation emitted by the attached radioisotope leads to regression of pathological changes. This method is developed only in a few centers worldwide and is currently used, among others, in treating certain types of lymphomas (anti-CD-20 antibody labeled with 90Y or 131I) and neuroendocrine tumors (somatostatin analogs labeled with 90Y, 177Lu).

The benefit of this method is the ability to treat tumors that exhibit resistance to conventional chemotherapy and radiotherapy. Based on own experiences and literature data, it is known that gliomas show increased expression of selected receptor systems. In grade II-IV gliomas, a significant increase in expression for neurokinin-1 (NK-1) receptors, for which substance P is the ligand, has been noted. When administered directly to the tumor, substance P undergoes rapid diffusion and binding to glioma cells.

At the center in Basel (Institute of Nuclear Medicine, University Hospital Basel), a derivative of substance P (1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid) was developed. It was shown that over 95% of gliomas exhibit significantly increased expression of the NK-1 receptor system, and that the proposed peptide has a capacity for specific binding to this type of receptor (out of 34 glioma tissue samples, 32 samples showed significantly increased NK-1 receptor system expression).