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Inhibitors of Topoisomerases (TOPs, TOP1, TOP2) are mainstays of anticancer therapy. While they have proven effective, the toxicity of current TOP drugs in non-cancer cells, limits their use. Development of tumour-specific TOP inhibitors will require a better knowledge of TOPs. This project will define how TOP are regulated and target these regulatory mechanisms with drugs. TOPs promote transcription and replication by cleaving/resealing DNA strands, removing supercoils generated during polymerase elongation. In my works published in Cell and Mol Cell, I discovered that the activity of TOPs is regulated. The oncoprotein MYC joins TOP1 and TOP2 in a topoisome complex and stimulates their activities to boost cell proliferation. Targeting the mechanism of the topoisome instead of the single TOPs might selectively halt MYC while preserving physiological TOP activity, avoiding DNA damage associated to current TOP drugs.By using genomics, biochemical and microscopy approaches, as well as drug screens, I will define the mechanism of MYC-driven cellular proliferation via regulation of the topoisome and develop drugs blocking the topoisome to arrest tumor growth. This project is feasible based on compelling preliminary data and collaborations. The work will identify novel drugs to target TOPs that can be put forward in clinical trials for the benefit of the society. This new way of targeting TOPs to affect MYC is a beyond the state-of-the-art approach to the field of cancer biology.

Inhibitors of DNA topoisomerases (TOPs, TOP1 and TOP2) are mainstays of anticancer therapy. While they have proven effective, the toxicity of current TOP drugs in non-cancer cells, limits their use. Development of tumour-specific TOP inhibitors will require a better knowledge of the mechanisms of TOP. This proposal will define how TOP are regulated and will target these regulatory mechanisms with drugs.My works published in Cell and Molecular Cell have shown that the DNA cleavage-religation activity of TOPs is regulated. The oncoprotein MYC joins TOP1 and TOP2 in a “topoisome” complex and stimulates their activities to remove the supercoiling produced during transcription and replication, thus boosting cellular proliferation. Therefore, targeting the mechanism of the topoisome instead of the single TOPs, will selectively halt MYC oncogenic function while preserving physiological TOP activity, avoiding the generation of DNA damage associated to current TOP drugs.By using new genomic tools to study TOPs, biochemical and microscopy approaches, as well as drug screens, I will define the mechanism of MYC-driven transcriptional amplification via topoisome assembly and develop drugs blocking topoisome activity to arrest tumour growth. This proposal is highly feasible based on my background, compelling preliminary data, and strong collaborations with KI and NIH. My work will identify novel ways to target TOPs that can be put forward in clinical trials for the benefit of society.

Cancer is a biologically complex disease and is today one of the most common causes of death. Blocking topoisomerase enzymes (TOP1 and TOP2) is one of the cornerstones of today's cancer treatment, and is used against several common tumor types, such as breast, colon, lung, and ovarian cancer. Despite their good anticancer effect, the use of today's topoisomerase-inhibiting drugs is limited by their toxic effect on healthy cells. Developing new -topoisomerase inhibitors that only inhibit tumor cells is therefore of great importance, but to achieve this goal, in-depth knowledge of the mechanisms that regulate the cellular activity of topoisomerases is required. This project aims to define the molecular mechanisms that regulate the role of topoisomerases in RNA transcription. In my work, published in the prestigious journal Cell, I show that TOP1 is controlled by other enzymes and is not constantly active as previously thought. In my recent work, which is under review in Cell, I show that the oncoprotein MYC interacts with topoisomerases and stimulates their activity to promote rapid cellular growth. Our findings make the MYC/TOP system an attractive candidate for the development of drugs that target the activation of topoisomerases in the treatment of MYC-driving tumors. Using biochemical analysis, sequencing methods and drug screening, I will characterize how MYC regulates topoisomerases and identify drugs that target the MYC/TOP interaction. In fact, I have already developed a drug cocktail that has high anticancer potential but reduced toxicity. I now want to test this cocktail in preclinical models of colon and pancreatic cancer. The work will lead to the identification of a new strategy for gentler cancer treatments that can be tested in future clinical trials to improve both survival and quality of life in cancer patients.

Cancer is a biologically complex disease and one of the most common causes of death. Inhibition of the enzymes topoisomerase (TOP) TOP1 and TOP2 are one of the cornerstones of today's cancer treatment, and are used against several common tumor diseases in both men and women, such as breast, colon, lung, ovarian cancer. Despite their good anticancer effect, the use of current TOP inhibitory drugs is limited by their toxic effect on healthy cells. Developing new TOP inhibitors that only inhibit tumor cells is therefore of great importance, but in order to achieve this goal, in-depth knowledge of the mechanisms regulating the cellular activity of the topoisomerases is required. This project aims to map the molecular mechanisms that control the role of TOP enzymes in gene regulation and, based on this, find new targets to fight for specifically killing cancer cells. In my latest publication in the well-reputed Cell, I present the groundbreaking discovery that the TOP activity is stimulated by the enzyme RNA polymerase II. Because rapidly dividing cancer cells require higher gene expression than normal cells, they are also expected to require higher TOP activity. My hypothesis is therefore that specific inhibition of growing cancer cells can be achieved by blocking the proteins that stimulate TOP over its basic level of activity. By using biochemical and sequencing methods and screening of drug candidates, in this project I will identify new proteins that regulate TOP and the mechanisms for how they regulate TOP. Furthermore, based on these discoveries, I will explore new potential drugs that specifically target the proteins that regulate TOP. The work will lead to the identification of new cancer drugs that can be evaluated in future clinical trials to directly improve the survival and quality of life of cancer patients.