Cancer treatment

In prof. C. Schmitt’s laboratory, molecular mechanisms of cell’s response on stress are studies. Stress-mediated responses are accompanied by the induction of apoptosis or cell aging that stops precancer state of the cell and afterwards kills (or isolates) the changed cell. However, when the cell undergoes oncogenic stimulation over a long period of time, it can overcome the barrier and irretrievably acquire oncogenic phenotype. In prof. C. Schmitt’s laboratory, mouse models of lymphoma and other tumors caused by known genetic disorders were created to study cell’s response on stress, which is induced by the anticancer therapy. On the basis of those models, antitumor role of Suv39h1 histone methylase was shown. Suv39h1 histone methylase inhibition in mice led to the development of the B-cell lymphoma directed by the constitutive expression of the embedded Ras proto-oncogene. Methylation of the H3R9 histone (it is a target for the Suv39h1 methylase) prevented formation of lymphomas and initiated the process of B-cell aging as protective mechanism against aging in the Suv39h1-deficient mice. It was also established that genetic disorders in the INK4a/ARF locus had modulatory role in sensitivity/resistance of different lymphoma types to anticancer therapy. Oncogenic signals activated stress response in normal cells. That stress response is a peculiar barrier on the way of cell transformation from the normal cell into the tumor one. So cell aging or apoptosis induced by antitumor therapy is a protective mechanism that prevents further expansion (metastasis) of tumor cells.

Scientists supposed two ways how this problem can be solved. The first way is following. New chimeric receptor is «suspended» upon T-cell surface. The receptor has external structure similar to that of antibodies, and it has a cytosolic domain transmitting a signal into the cell. That construction can retarget T-cells in vitro and force them to attack neoplasms. The second way is following. T-cells can be modified so they can express the natural heterodimer αβTCR detecting tumor cells. In the first clinical trial, T-cells with surface TCR specific to glycoprotein 100 (gp100) were created. A patient suffered from melanoma got an injection with those T-cells and IL-2 admixture. The aim of that method was to generate additional receptors through pairing transgenic TCR chains with natural ones. Scientists did not observe any toxic side effects. However, investigations show that expression level of gp100-specipic TCRs falls that can reduce TCR avidity and therefore minimize effector functions. Another important restriction of this method lies in the fact that every TCR is particular for the given peptide-MHC complex. Transplantation of T-lymphocytes is successfully used in various clinical cases deal with immunodeficiency and neoplasms. However, this treatment is less effective when a tumor has deficiency in the antigens. Prospective lines of the treatment based on the transplantation of modified immune cells is creation of T-cells insensitive to HIV. Preclinical trials show that such a cure is possible but its safety still should be established.