Periodic Reporting for period 4 - TAROX (Targeting oxidative repair proteins for treatment of cancer and inflammation)
Periodo di rendicontazione: 2021-02-01 al 2021-07-31
A fundamental problem in today’s healthcare is insufficient treatment options for highly prevalent diseases, including cancer and inflammatory disorders. The disease-causing cells often have unbalanced redox homeostasis and deregulated reactive oxygen species (ROS). Today, we have insufficient knowledge of which proteins are involved in preventing or repairing oxidative DNA damage. Surprisingly, targeting proteins involved in managing oxidative DNA damage is pharmaceutically unexplored, although this could offer great potential to make a real difference in many common diseases.
A big challenge society faces is that today’s health care is focused more on reducing symptoms rather than attacking the underlying cause of the disease. With the granted money, we are addressing this challenge by targeting the repair processes of oxidative DNA damage, known to be affected in cancer and inflammatory disorders, to develop novel therapeutics that have the potential to treat the underlying cause of the disease. The outcome of this program would be new therapeutic interventions for many forms of cancer and different autoimmune, neurological disorders, and viral infections.
The overall objective of this project is to increase the understanding of how the repair of oxidative DNA damage is involved in disease etiology. Furthermore, to introduce a completely novel therapeutic approach to cancer, inflammation, neurodegenerative and viral diseases, based on first-in-class inhibitors to proteins involved in repairing oxidative DNA lesions. To achieve this, we are taking an interdisciplinary approach to:
1. Develop tools, probes to study proteins involved in the metabolism and repair of oxidative DNA lesions.
2. Understand the biological role of oxidative repair proteins and their relevance in disease.
3. Identify and explore inhibitors (e.g. MTH1 and OGG1) in cancer, inflammation, neurodegenerative diseases, and viral infections.
A big challenge society faces is that today’s health care is focused more on reducing symptoms rather than attacking the underlying cause of the disease. With the granted money, we are addressing this challenge by targeting the repair processes of oxidative DNA damage, known to be affected in cancer and inflammatory disorders, to develop novel therapeutics that have the potential to treat the underlying cause of the disease. The outcome of this program would be new therapeutic interventions for many forms of cancer and different autoimmune, neurological disorders, and viral infections.
The overall objective of this project is to increase the understanding of how the repair of oxidative DNA damage is involved in disease etiology. Furthermore, to introduce a completely novel therapeutic approach to cancer, inflammation, neurodegenerative and viral diseases, based on first-in-class inhibitors to proteins involved in repairing oxidative DNA lesions. To achieve this, we are taking an interdisciplinary approach to:
1. Develop tools, probes to study proteins involved in the metabolism and repair of oxidative DNA lesions.
2. Understand the biological role of oxidative repair proteins and their relevance in disease.
3. Identify and explore inhibitors (e.g. MTH1 and OGG1) in cancer, inflammation, neurodegenerative diseases, and viral infections.
The first objective of the proposal was to purify, characterize and develop small-molecule probes to oxidative DNA repair proteins and Nudix hydrolases. We have been highly successful in this work. We purified the whole family, determined biochemical activity, structure, and biological functions, and published a highly appreciated comprehensive profile paper on the Nudix hydrolases. We developed new small molecule inhibitors to NUDT15, OGG1, dCTPase, as outlined in the application. Moreover, we published a methods paper on the druggability of glycosylases, which we pioneered in this grant. Producing these proteins helps reveal the biology and biochemistry behind the repair of oxidative DNA damage and is a base for identifying chemical probes (inhibitors). The availability of chemical probes is central to making advances in this field. When we started this project, small molecule inhibitors selectively targeting oxidative repair pathways were largely missing. We have produced, e.g. MTH1, NUDT5, NUDT15, and OGG1 inhibitors, published the findings in internationally recognized scientific journals (e.g. Science), and made them available to the scientific community. We have also generated numerous small molecule probes for Nudix hydrolases that are not yet published.
Our lab has made an orally available and well-tolerated MTH1 inhibitor, effective in most cancer disease models, including multi-drug resistant ones. Noteworthy, we are testing our most effective compounds in advanced cancer patients with solid malignancies.
The second objective was to gain further understanding of the molecular mechanisms of oxidative DNA repair. In this part of the project, we have uncovered many new insights and findings. We discovered a new role for NEIL3 in repairing oxidative DNA lesions at telomeres to prevent senescence, the interplay between repair proteins NEIL1, NEIL2, OGG1, a role for OGG1 in the repair of oxidative damage at telomeres, and the altering process of OGG1 chromatin dynamics by small-molecule inhibition. We have also continued our work on replication stress and linked protein involved in oxidative DNA repair and transcription to these processes. We have found a new function of the NUDT22 enzyme.
The final and most challenging objective was to translate our inhibitors into clinical use in diseases primary beyond cancer. This part is complicated but has also been the part where we have made the most significant breakthroughs. For MTH1 inhibitors, we demonstrate a new role in T cell-driven autoimmune diseases. Following the COVID 19 pandemic, we have escalated our work on anti-viral drugs, and the additional ERC PoC grant received in 2016 on novel anti-viral drugs has been helpful. We have shown that the OGG1 inhibitors show proof-of-concept in different viruses, including SARS-CoV2, which has led to the initiation of two new projects, including a newly funded project collaborating with Wuhan. An unexpected new role of NUDT15 in CMV viral therapy was uncovered and published.
The most striking achievement is the discovery of the requirement of OGG1 for pro-inflammatory gene expression. Also, our OGG1 inhibitors are an entirely new way of suppressing pro-inflammatory gene expression, which we published in the journal Science. This discovery represents an unprecedented breakthrough that opens up numerous novel potential applications, and we have received massive attention for this work. While we report many papers in journals with high international standing, the work in the Science paper probably outweighs all other work and will make a considerable breakthrough. Since then, we have also come across a novel class of OGG1 activators showing an outstanding example of a small molecule inducing a new biochemical function for the protein. This work has been submitted to a top journal and received overall positive feedback from reviewers. The work to complete the requests from the reviewers has occupied a significant part of the lab, and we have stepped up with more staff to complete this task within the time frame. Overall, this was successful, and all additional experiments were completed just in time to complete this grant.
Our lab has made an orally available and well-tolerated MTH1 inhibitor, effective in most cancer disease models, including multi-drug resistant ones. Noteworthy, we are testing our most effective compounds in advanced cancer patients with solid malignancies.
The second objective was to gain further understanding of the molecular mechanisms of oxidative DNA repair. In this part of the project, we have uncovered many new insights and findings. We discovered a new role for NEIL3 in repairing oxidative DNA lesions at telomeres to prevent senescence, the interplay between repair proteins NEIL1, NEIL2, OGG1, a role for OGG1 in the repair of oxidative damage at telomeres, and the altering process of OGG1 chromatin dynamics by small-molecule inhibition. We have also continued our work on replication stress and linked protein involved in oxidative DNA repair and transcription to these processes. We have found a new function of the NUDT22 enzyme.
The final and most challenging objective was to translate our inhibitors into clinical use in diseases primary beyond cancer. This part is complicated but has also been the part where we have made the most significant breakthroughs. For MTH1 inhibitors, we demonstrate a new role in T cell-driven autoimmune diseases. Following the COVID 19 pandemic, we have escalated our work on anti-viral drugs, and the additional ERC PoC grant received in 2016 on novel anti-viral drugs has been helpful. We have shown that the OGG1 inhibitors show proof-of-concept in different viruses, including SARS-CoV2, which has led to the initiation of two new projects, including a newly funded project collaborating with Wuhan. An unexpected new role of NUDT15 in CMV viral therapy was uncovered and published.
The most striking achievement is the discovery of the requirement of OGG1 for pro-inflammatory gene expression. Also, our OGG1 inhibitors are an entirely new way of suppressing pro-inflammatory gene expression, which we published in the journal Science. This discovery represents an unprecedented breakthrough that opens up numerous novel potential applications, and we have received massive attention for this work. While we report many papers in journals with high international standing, the work in the Science paper probably outweighs all other work and will make a considerable breakthrough. Since then, we have also come across a novel class of OGG1 activators showing an outstanding example of a small molecule inducing a new biochemical function for the protein. This work has been submitted to a top journal and received overall positive feedback from reviewers. The work to complete the requests from the reviewers has occupied a significant part of the lab, and we have stepped up with more staff to complete this task within the time frame. Overall, this was successful, and all additional experiments were completed just in time to complete this grant.
The TAROX project has been completed as stated in the overall objective and provided some entirely novel scientific insights into how small molecules can increase the repair of oxidative damage. These understandings have significant implications as potential treatments for age-related diseases. Our work has also translated into a spin-out company.
We will continue identifying novel targets and effective tool compounds, further understanding oxidative repair pathways, and developing selective and potent drugs to treat cancer, inflammation-based autoimmunity, and viral infections.
We will continue identifying novel targets and effective tool compounds, further understanding oxidative repair pathways, and developing selective and potent drugs to treat cancer, inflammation-based autoimmunity, and viral infections.