Magnus Ingelman-Sundberg

Biomarkers for tolerability of clozapine and risk of treatment discontinuation in patients with therapy-resistant schizophrenia<br/><br/>NOResearch stay abroadClozapine (Leponex) is the drug with the best effect in the treatment of schizophrenia. However, the risk of serious side effects limits its use. It is desirable to identify biomarkers that reflect the tolerability of the drug so that it can be used by more patients.Schizophrenia is the most serious of all mental disorders and normally requires lifelong drug treatment. Clozapine has the best clinical effect in the treatment of schizophrenia, but is also associated with an increased risk of agranulocytosis, a very serious side effect that places restrictions on its prescription. Current knowledge indicates that the mechanism behind clozapine-induced toxicity against granulocytes is linked to immunological reactions. To trigger an immunological reaction, a ‘substrate’ is required. Our hypothesis is that one or more breakdown products (metabolites) of clozapine represent ‘substrate(s)’ for such a reaction. <br/><br/>Clozapine has a complicated metabolism. Among these metabolites are so-called nitrenium ions, which are chemically very reactive substances. They bind to all types of proteins, including proteins in granulocytes. These metabolites are difficult to analyze in blood samples, precisely because they bind (covalently) to proteins in various cells. However, the body has a type of enzymes that can deactivate/capture the metabolites 'before they have time' to bind to proteins. These metabolites are quickly converted further into so-called cysteine metabolites, which are stable substances, and can thus be analyzed in blood samples. By analyzing the concentration of cysteine metabolites of clozapine in serum samples, one can thus get a picture of how much of the reactive nitrenium ions is formed.<br/><br/>The project has established a unique analysis method for measuring the level of cysteinyl metabolites in serum samples. The method is based on advanced chromatography coupled to a high-resolution mass spectrometer, which can analyze molecules with an exact mass. In total, the method can analyze the concentration/level of three cysteine metabolites of clozapine. Over the past year, the PhD fellow in the project has analyzed complete metabolite profiles of clozapine in 582 patients and compared levels of the different metabolites in relation to the genotype of "nuclear factor 1 B (NFIB)", which we have previously discovered regulates the activity of metabolizing enzymes. The results of the study show that patients who have the NFIB variant (approximately 10% of the population) have twice as high a concentration of the metabolites N-desmethylclozapine-cysteinyl, which probably reflects that these patients form more of the toxic metabolites and therefore have an increased risk of side effects and reduced tolerability of clozapine. However, these results must be verified in studies where there is better access to clinical data that reflect tolerability. We are already working on a study that will investigate both genotypes and levels of toxic metabolites in patients who terminate clozapine treatment (the hypothesis is increased prevalence of the NFIB variant and/or levels of cysteinyl metabolites in patients who terminate treatment). It is also planned to study the extent to which combination treatment with fluvoxamine, an antidepressant drug, affects the formation of cysteinyl metabolites. The hypothesis in the latter study is that fluvoxamine reduces the formation of toxic metabolites, since combination treatment with fluvoxamine is associated with better tolerability of clozapine. <br/><br/>A manuscript describing the formation of clozapine metabolites in relation to NFIB genotype has been submitted for publication, and is currently "under review" in the journal Drug Metabolism and Disposition. This article will be published in 2025. The ambition is also to publish one or both of the other substudies described above during 2025.<br/>

Each year, approximately 4,100 people receive colon cancer in Sweden and 500 people have liver cancer. If the cancer spreads after surgical treatment, chemotherapy is needed. We have found an enzyme (CYP2W1) that is specifically only found in colon cancer cells and liver cancer cells as well as in some other tumor forms but not in normal tissue. We find this enzyme in higher amounts in liver metastases is in primary colon tumor. We have also developed chemical compounds which by reacting by the enzyme form reactive products that kill the tumor cells. If we treat mice that have a human colon tumor containing CYP2W1 with these compounds, the tumor cannot grow. The project aims to develop even better compounds that are substrates for CYP2W1, to investigate in which other tumor forms the enzyme exists where one can imagine a similar treatment. We will investigate whether CYP2W1 mRNA and peptides from CYP2W1 and deethylated DNA fragments from CYP2W1 genes can serve as new markers for the presence of colon cancer and other human tumors. Furthermore, we want to determine the enzyme structure to produce even better cancer drugs, identify the electron donors to the enzyme needed and see how the enzyme is regulated in tumor cells to find other drugs that upregulate the expression of the enzyme in the tumors. We hope through the project to be able to identify a completely new specific biomarker for colon cancer and liver cancer and to be able to start clinical trials with the substances we identified for a principally new way of treating colon cancer and other cancer.

Each year, approximately 4,100 people receive colon cancer in Sweden and 500 people have liver cancer. If the cancer spreads after surgical treatment, chemotherapy is needed. We have found an enzyme (CYP2W1) that is specifically only found in colon cancer cells and liver cancer cells as well as in some other tumor forms but not in normal tissue. We find this enzyme in higher amounts in liver metastases is in primary colon tumor. We have also developed chemical compounds which by reacting by the enzyme form reactive products that kill the tumor cells. If we treat mice that have a human colon tumor containing CYP2W1 with these compounds, the tumor cannot grow. The project aims to develop even better compounds that are substrates for CYP2W1, to investigate in which other tumor forms the enzyme exists where one can imagine a similar treatment. We will investigate whether CYP2W1 mRNA and peptides from CYP2W1 and deethylated DNA fragments from CYP2W1 genes can serve as new markers for the presence of colon cancer and other human tumors. Furthermore, we want to determine the enzyme structure to produce even better cancer drugs, identify the electron donors to the enzyme needed and see how the enzyme is regulated in tumor cells to find other drugs that upregulate the expression of the enzyme in the tumors. We hope through the project to be able to identify a completely new specific biomarker for colon cancer and liver cancer and to be able to start clinical trials with the substances we identified for a principally new way of treating colon cancer and other cancer.

Each year, approximately 4,100 people receive colon cancer in Sweden. If the cancer spreads after surgical treatment, chemotherapy is needed. We have found an enzyme (CYP2W1) that is specifically only found in colon cancer cells and in some other tumor forms but not in normal tissue. We find this enzyme in higher amounts in liver metastases. We have also developed chemical compounds which by reacting by the enzyme form reactive products that kill the tumor cells. If we treat mice that have a human colon tumor containing CYP2W1 with these compounds, the tumor cannot grow. The project aims to develop even better compounds that are substrates for CYP2W1, to investigate in which other tumor forms the enzyme exists where one can envisage a similar treatment, to use mRNA and peptides from CYP2W1 gene expression as a new marker for the presence of colon cancer and other tumors in humans. Furthermore, we want to determine the enzyme structure to produce even better cancer drugs, identify the electron donors to the enzyme needed and see how the enzyme is regulated in tumor cells to find other drugs that upregulate the expression of the enzyme in the tumors. We hope through the project to be able to identify a completely new specific biomarker for colon cancer and some other tumor forms and to be able to start clinical trials with the substances we identified for a principally new way of treating colon cancer and other cancer.

Each year, approximately 4,100 people receive colon cancer in Sweden. If the cancer spreads after surgical treatment, chemotherapy is needed. We have found an enzyme (CYP2W1) that is specifically only found in colon cancer cells and in some other tumor forms but not in normal tissue. We find this enzyme in higher amounts in liver metastases. We have also developed chemical compounds which by reacting by the enzyme form reactive products that kill the tumor cells. If we treat mice that have a human colon tumor containing CYP2W1 with these compounds, the tumor cannot grow. The project aims to develop even better compounds that are substrates for CYP2W1, to investigate in which other tumor forms the enzyme exists where one can envisage a similar treatment, to use mRNA and peptides from CYP2W1 gene expression as a new marker for the presence of colon cancer and other tumors in humans. Furthermore, we want to determine the enzyme structure to produce even better cancer drugs, identify the electron donors to the enzyme needed and see how the enzyme is regulated in tumor cells to find other drugs that upregulate the expression of the enzyme in the tumors. We hope through the project to be able to identify a completely new specific biomarker for colon cancer and some other tumor forms and to be able to start clinical trials with the substances we identified for a principally new way of treating colon cancer and other cancer.

Each year, approximately 4,100 people receive colon cancer in Sweden. If the cancer spreads after surgical treatment, chemotherapy is needed. We have found an enzyme (CYP2W1) that is specifically only found in colon cancer cells and in some other tumor forms but not in normal tissue. We find this enzyme in higher amounts in liver metastases. We have also developed chemical compounds which by reacting by the enzyme form reactive products that kill the tumor cells. If we treat mice that have a human colon tumor containing CYP2W1 with these compounds, the tumor cannot grow. The project aims to develop even better compounds that are substrates for CYP2W1, to investigate in which other tumor forms the enzyme exists where one can envisage a similar treatment, to use mRNA and peptides from CYP2W1 gene expression as a new marker for the presence of colon cancer and other tumors in humans. Furthermore, we want to determine the enzyme structure to produce even better cancer drugs, identify the electron donors to the enzyme needed and see how the enzyme is regulated in tumor cells to find other drugs that upregulate the expression of the enzyme in the tumors. We hope through the project to be able to identify a completely new specific biomarker for colon cancer and some other tumor forms and to be able to start clinical trials with the substances we identified for a principally new way of treating colon cancer and other cancer.