Projects & Collaborations 42 foundShow per page10 10 20 50 RBM39 arginine Research Project | 2 Project MembersImported from Grants Tool 4704397 Metabolic Reprogramming in Liver Cancer Research Project | 1 Project MembersImported from Grants Tool 4701414 PTES Research Project | 1 Project MembersImported from Grants Tool 4701181 Development of an MCT1/4 dual inhibitor as an anti-cancer drug Research Project | 2 Project MembersNo Description available Preclinical in vivo proof of mechanism study of selective mTORC1 inhibitors Research Project | 2 Project MembersLaufzeit 01.04.2022-31.01.2024 Increased activity of mammalian target of rapamycin complex 1(mTORC1) is linked to multiple disorders. We identified ten small compounds that selectively and efficiently inhibit mTORC1 in vitro with an innovative mode of action. We now aim to achieve precinlincal proof of mechanism in mice. Selective mTORC1 inhibitors to treat TSC Research Project | 3 Project MembersTuberous sclerosis complex (TSC) is a rare multisystem genetic disease caused by loss-of-function mutations in the tumor suppressor genes TSC1 or TSC2. As a consequence, the protein kinase mammalian target of rapamycin complex 1 (mTORC1) is constitutively active, which leads to uncontrolled cell growth. mTORC1 is thus a very attractive pharmacological target for the treatment of TSC. The clinical applicability of the currently available mTORC1 inhibitors (rapamycin and its derivatives, termed rapalogs) is limited by their specificity, effectiveness, and safety. Chronic treatment with rapamycin/rapalogs is often associated with undesirable side effects on metabolism due to undesired mTORC2 inhibition. These side effects include high blood glucose, high blood lipids, and insulin resistance. We seek support i) to gain a deeper mechanistic understanding of mTORC1-TSC signaling pathways, ii) to continue developing an innovative anti-TSC strategy based on selective mTORC1 inhibition with a novel mechanism of action (rapamycin/rapalog unrelated), and iii) to perform in vivo (mouse) studies to gain insight into the translation of the in vitro data. The specific aims of this study are as follows: i) to determine the efficacy of selective mTORC1 inhibitors on mTORC1 activity in TSC1/2-deficient cell lines, ii) to identify optimized compounds that justify performing experiments in mice, iii) to determine if our optimized compounds selectively inhibit mTORC1 in wild type mice and in mice lacking TSC1 in the liver, and iv) to determine if our optimized compounds exhibit tumor reducing abilities in a mouse xenograft TSC model. This project may lead to a new generation of (rapamycin-rapalog unrelated) selective mTORC1 inhibitors and eventually to new treatment options for TSC as well as for other diseases characterized by mTORC1 hyperactivation that have not been addressable by the previous generations of (non-selective) mTORC1 inhibitors. The clinical potential of these novel compounds would be immense and readily testable. We believe our approach could represent a paradigm shift, as we predict it to be more effective, more selective, and safer than the current standard of care in th selective mTORC1 inhibitors may greatly improve the health of TSC patients ii. Translation regulation in adipose tissue in obesity Research Project | 1 Project MembersChronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. We found that a high fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in white adipose tissue (WAT). Adipose-specific knockout of Hk2 caused enhanced gluconeogenesis and lipogenesis in the liver, a condition known as selective insulin resistance, leading to glucose intolerance. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to a loss of HK2 by inhibiting the elongation of Hk2 mRNA translation. Thus, our findings identify adipose HK2 as a critical mediator of systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia. Here, we propose to investigate the mechanism of translational regulation of Hk2 mRNA in adipose tissue. Selective mTORC1 inhibition as an innovative anti-cancer approach Research Project | 3 Project MembersMammalian target of rapamycin (mTOR) is a central controller of cell growth and metabolism. mTOR forms two structurally and functionally distinct protein complexes termed mTORC1 (mTOR complex 1) and mTORC2. mTOR in general, and mTORC1 in particular, is upregulated in approximately 70% of all cancers. Thus, mTOR(C1) is a very attractive target for anti-cancer therapy. Current approaches to inhibit mTORC1 focus on targeting mTOR. Currently approved drugs that inhibit mTORC1 (rapamycin/rapalogs) are used in a limited subset of cancers but are non-efficient and partially non-selective. ATP-competitive mTOR inhibitors (currently in dozens of clinical trials for cancer) are efficient but non-selective and toxic. Thus, there is an unmet medical need for new mTORC1 inhibitors with improved pharmacological profiles that could be applied in multiple cancer indications. This project arises from our fundamental research. We have discovered an innovative approach to selectively inhibit mTORC1 by targeting RAPTOR, the mTORC1-specific subunit responsible for the substrate recruitment. Our approach is unconventional and thus innovative as it targets the mTORC1-specific subunit RAPTOR. Conventional inhibitors target mTOR. Based on a small molecule screen in vitro, we have identified seven promising candidates. We seek support from Krebsliga to determine the effect of the candidates on mTORC1 signaling in particular and on metabolism in general, in a broad variety of human cancer cell lines. The results from this laboratory-oriented research project will be highly significant for the development of new mTORC1-related cancer treatments: i) the compounds with promising effects in cultured cells will be tested in mouse models of cancer (beyond this project) thereby bringing new anti-cancer treatments one step closer to clinical trials and ultimately to cancer patients. ii) In light of emerging efforts in personalized cancer treatments, determination of the effect of the compound candidates in different cancer cell lines will help characterize the most responsive cancer types. Used in the right set of cancer patients, RAPTOR-targeted mTORC1 inhibitors might be particularly effective. Deregulation of acetyl-CoA metabolism reduces global acetylation in HCC Research Project | 2 Project MembersHepatocellular carcinoma (HCC) is a major health problem with more than 850,000 new cases annually and the 4th leading cause of cancer deaths worldwide, due to the limited therapeutic options and late diagnosis. It is well known that cellular metabolism is dramatically changed during tumorigenesis. However, the mechanisms underlying deregulation mechanism of metabolic enzymes have not been studied in depth. We found that acetyl-CoA metabolism is significantly downregulated in an mTOR driven HCC mouse model and in human HCC patients. Acetyl-CoA is an essential metabolite that is involved in many metabolic conversions and cellular functions, including regulation of gene transcription by histone acetylation and de novo fatty acid synthesis. Protein acetylation relies on the availability of acetyl-CoA, the levels of which can change depending on metabolic conditions. In cancer, oncogenic signaling pathways reprogram cellular metabolism and affect acetyl-CoA levels. However, acetyl-CoA availability and protein acetylation status, especially non-histone acetylation during tumorigenesis is unknown. Our unpublished data indicate that deregulation of acetyl-CoA homeostasis and global protein acetylation in HCC due to downregulation of acetyl-CoA production pathways. Furthermore, we identified transcriptional regulators that are induced during tumorigenesis and negatively control expression of enzymes in acetyl-CoA production pathways. Moreover, modulation of these transcriptional regulators affects proliferation of cancer cells. Our findings suggest that deregulation of acetyl-CoA metabolism and global acetylation is a hallmark of liver tumorigenesis and correlates with the aggressiveness of tumour. Our findings may lead to new strategies for the treatment of HCC. Histidine phosphorylation in cancer and metabolism Research Project | 1 Project MembersReversible phosphorylation of proteins is a vital regulatory mechanism that touches virtually every aspect of cellular biology. The overwhelming majority of studies in higher eukaryotes have focused on phosphorylation of just 3 amino acid residues: serine, threonine and tyrosine. While phosphorylation of these residues is undoubtedly of great importance, recent evidence suggests that non-canonical protein histidine phosphorylation, which is widespread in bacteria, may be of equal importance in eukaryotes. Study of histidine phosphorylation has lagged not because of a lack of intrinsic importance, but due to the extreme heat and acid lability of the phosphohistidine (pHis) phosphoramidate (P-N) bond which precludes the use of standard protein enrichment and analytical methods. However, recent advances in the development of reliable pHis antibodies for immunodetection and immunoprecipitation, coupled with ongoing advances in mass spectrometric methods and analysis, present a window of opportunity for making substantial and rapid progress in this area. We are well poised to seize this opportunity. We have published in the field and have in-house experience working on histidine phosphorylation. Our preliminary results show that pHis may be relevant to other core areas of interest in our laboratory, namely cancer and metabolism. We propose to clarify this potential link using cell and animal models, with the final aim of establishing clinical relevance. We also propose to identify novel substrates of the two known mammalian histidine protein kinases (NME1 and NME2), to add to what is only a handful of currently known histidine-phosphorylated proteins. 12345 1...5
Metabolic Reprogramming in Liver Cancer Research Project | 1 Project MembersImported from Grants Tool 4701414
Development of an MCT1/4 dual inhibitor as an anti-cancer drug Research Project | 2 Project MembersNo Description available
Preclinical in vivo proof of mechanism study of selective mTORC1 inhibitors Research Project | 2 Project MembersLaufzeit 01.04.2022-31.01.2024 Increased activity of mammalian target of rapamycin complex 1(mTORC1) is linked to multiple disorders. We identified ten small compounds that selectively and efficiently inhibit mTORC1 in vitro with an innovative mode of action. We now aim to achieve precinlincal proof of mechanism in mice.
Selective mTORC1 inhibitors to treat TSC Research Project | 3 Project MembersTuberous sclerosis complex (TSC) is a rare multisystem genetic disease caused by loss-of-function mutations in the tumor suppressor genes TSC1 or TSC2. As a consequence, the protein kinase mammalian target of rapamycin complex 1 (mTORC1) is constitutively active, which leads to uncontrolled cell growth. mTORC1 is thus a very attractive pharmacological target for the treatment of TSC. The clinical applicability of the currently available mTORC1 inhibitors (rapamycin and its derivatives, termed rapalogs) is limited by their specificity, effectiveness, and safety. Chronic treatment with rapamycin/rapalogs is often associated with undesirable side effects on metabolism due to undesired mTORC2 inhibition. These side effects include high blood glucose, high blood lipids, and insulin resistance. We seek support i) to gain a deeper mechanistic understanding of mTORC1-TSC signaling pathways, ii) to continue developing an innovative anti-TSC strategy based on selective mTORC1 inhibition with a novel mechanism of action (rapamycin/rapalog unrelated), and iii) to perform in vivo (mouse) studies to gain insight into the translation of the in vitro data. The specific aims of this study are as follows: i) to determine the efficacy of selective mTORC1 inhibitors on mTORC1 activity in TSC1/2-deficient cell lines, ii) to identify optimized compounds that justify performing experiments in mice, iii) to determine if our optimized compounds selectively inhibit mTORC1 in wild type mice and in mice lacking TSC1 in the liver, and iv) to determine if our optimized compounds exhibit tumor reducing abilities in a mouse xenograft TSC model. This project may lead to a new generation of (rapamycin-rapalog unrelated) selective mTORC1 inhibitors and eventually to new treatment options for TSC as well as for other diseases characterized by mTORC1 hyperactivation that have not been addressable by the previous generations of (non-selective) mTORC1 inhibitors. The clinical potential of these novel compounds would be immense and readily testable. We believe our approach could represent a paradigm shift, as we predict it to be more effective, more selective, and safer than the current standard of care in th selective mTORC1 inhibitors may greatly improve the health of TSC patients ii.
Translation regulation in adipose tissue in obesity Research Project | 1 Project MembersChronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. We found that a high fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in white adipose tissue (WAT). Adipose-specific knockout of Hk2 caused enhanced gluconeogenesis and lipogenesis in the liver, a condition known as selective insulin resistance, leading to glucose intolerance. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to a loss of HK2 by inhibiting the elongation of Hk2 mRNA translation. Thus, our findings identify adipose HK2 as a critical mediator of systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia. Here, we propose to investigate the mechanism of translational regulation of Hk2 mRNA in adipose tissue.
Selective mTORC1 inhibition as an innovative anti-cancer approach Research Project | 3 Project MembersMammalian target of rapamycin (mTOR) is a central controller of cell growth and metabolism. mTOR forms two structurally and functionally distinct protein complexes termed mTORC1 (mTOR complex 1) and mTORC2. mTOR in general, and mTORC1 in particular, is upregulated in approximately 70% of all cancers. Thus, mTOR(C1) is a very attractive target for anti-cancer therapy. Current approaches to inhibit mTORC1 focus on targeting mTOR. Currently approved drugs that inhibit mTORC1 (rapamycin/rapalogs) are used in a limited subset of cancers but are non-efficient and partially non-selective. ATP-competitive mTOR inhibitors (currently in dozens of clinical trials for cancer) are efficient but non-selective and toxic. Thus, there is an unmet medical need for new mTORC1 inhibitors with improved pharmacological profiles that could be applied in multiple cancer indications. This project arises from our fundamental research. We have discovered an innovative approach to selectively inhibit mTORC1 by targeting RAPTOR, the mTORC1-specific subunit responsible for the substrate recruitment. Our approach is unconventional and thus innovative as it targets the mTORC1-specific subunit RAPTOR. Conventional inhibitors target mTOR. Based on a small molecule screen in vitro, we have identified seven promising candidates. We seek support from Krebsliga to determine the effect of the candidates on mTORC1 signaling in particular and on metabolism in general, in a broad variety of human cancer cell lines. The results from this laboratory-oriented research project will be highly significant for the development of new mTORC1-related cancer treatments: i) the compounds with promising effects in cultured cells will be tested in mouse models of cancer (beyond this project) thereby bringing new anti-cancer treatments one step closer to clinical trials and ultimately to cancer patients. ii) In light of emerging efforts in personalized cancer treatments, determination of the effect of the compound candidates in different cancer cell lines will help characterize the most responsive cancer types. Used in the right set of cancer patients, RAPTOR-targeted mTORC1 inhibitors might be particularly effective.
Deregulation of acetyl-CoA metabolism reduces global acetylation in HCC Research Project | 2 Project MembersHepatocellular carcinoma (HCC) is a major health problem with more than 850,000 new cases annually and the 4th leading cause of cancer deaths worldwide, due to the limited therapeutic options and late diagnosis. It is well known that cellular metabolism is dramatically changed during tumorigenesis. However, the mechanisms underlying deregulation mechanism of metabolic enzymes have not been studied in depth. We found that acetyl-CoA metabolism is significantly downregulated in an mTOR driven HCC mouse model and in human HCC patients. Acetyl-CoA is an essential metabolite that is involved in many metabolic conversions and cellular functions, including regulation of gene transcription by histone acetylation and de novo fatty acid synthesis. Protein acetylation relies on the availability of acetyl-CoA, the levels of which can change depending on metabolic conditions. In cancer, oncogenic signaling pathways reprogram cellular metabolism and affect acetyl-CoA levels. However, acetyl-CoA availability and protein acetylation status, especially non-histone acetylation during tumorigenesis is unknown. Our unpublished data indicate that deregulation of acetyl-CoA homeostasis and global protein acetylation in HCC due to downregulation of acetyl-CoA production pathways. Furthermore, we identified transcriptional regulators that are induced during tumorigenesis and negatively control expression of enzymes in acetyl-CoA production pathways. Moreover, modulation of these transcriptional regulators affects proliferation of cancer cells. Our findings suggest that deregulation of acetyl-CoA metabolism and global acetylation is a hallmark of liver tumorigenesis and correlates with the aggressiveness of tumour. Our findings may lead to new strategies for the treatment of HCC.
Histidine phosphorylation in cancer and metabolism Research Project | 1 Project MembersReversible phosphorylation of proteins is a vital regulatory mechanism that touches virtually every aspect of cellular biology. The overwhelming majority of studies in higher eukaryotes have focused on phosphorylation of just 3 amino acid residues: serine, threonine and tyrosine. While phosphorylation of these residues is undoubtedly of great importance, recent evidence suggests that non-canonical protein histidine phosphorylation, which is widespread in bacteria, may be of equal importance in eukaryotes. Study of histidine phosphorylation has lagged not because of a lack of intrinsic importance, but due to the extreme heat and acid lability of the phosphohistidine (pHis) phosphoramidate (P-N) bond which precludes the use of standard protein enrichment and analytical methods. However, recent advances in the development of reliable pHis antibodies for immunodetection and immunoprecipitation, coupled with ongoing advances in mass spectrometric methods and analysis, present a window of opportunity for making substantial and rapid progress in this area. We are well poised to seize this opportunity. We have published in the field and have in-house experience working on histidine phosphorylation. Our preliminary results show that pHis may be relevant to other core areas of interest in our laboratory, namely cancer and metabolism. We propose to clarify this potential link using cell and animal models, with the final aim of establishing clinical relevance. We also propose to identify novel substrates of the two known mammalian histidine protein kinases (NME1 and NME2), to add to what is only a handful of currently known histidine-phosphorylated proteins.
