Olle Sangfelt

Despite significant progress in cancer treatment, a considerable number of patients continue to experience relapse or inadequate responses, even when undergoing aggressive multimodal therapies. A major obstacle in devising effective therapeutic strategies lies in the difficulty of targeting key proteins that drive cancer metastasis and immune evasion, thereby contributing to the development of drug resistance. This underscores the importance of developing therapies that target these aspects of cancer biology to improve treatment outcomes. The purpose of this collaborative project between Dr. Guardavaccaro at the University of Verona and Dr. Sangfelt at Karolinska Institutet is to utilize ubiquitin ligases as an innovative strategy to prevent cancer metastasis and combat immune evasion. To execute this project, we have assembled a focused consortium of scientists who possess diverse expertise in SCF ubiquitin ligases, DNA replication stress and repair, cell motility and invasion, drug screening and medical chemistry. This consortium, which includes early-career researchers as well as tenured scientists, has been meticulously assembled to ensure the successful implementation of each research work package within the stipulated three-year timeframe. We will employ a unique combination of methodologies, merging an in vitro high-throughput nanoBRET-Ubiquitin screen with an in vivo functional compound screen in Zebrafish. This approach is designed to identify innovative compounds capable of disrupting the signaling of two clinically significant ubiquitin ligase-substrate pairs, FBXL12-FANCD2 and betaTrCP-SHARP1. The outcomes of this proof-of-concept project may unveil novel therapeutic strategies for combating cancer immune evasion and impeding the spread and metastatic growth, especially in aggressive basal-like breast cancer.

Protein degradation (proteolysis) is a central biological mechanism that regulates basal functions of the cell such as cell division, cell death and gene activity. The degradation itself is performed by the so-called ubiquitin proteasome system and the discovery of this process was awarded in 2004 with the Nobel Prize. Proteins to be destroyed are first labeled with a small label, a protein called ubiquitin (Ub), and then rapidly broken down into the cellular debris, proteasomes. The degradation process is regulated by three enzyme activities

E1, E2 and E3, where the so-called E3 ubiquitin enzymes determine which proteins to be broken down in the cell. We are studying an E3 enzyme in cancer cells. These have been shown to control a variety of cancer proteins that have been shown to be vital for cancer cell survival. The E3 enzyme Fbw7 is a protein that normally prevents cancer development and we have found that Fbw7 is often damaged in the cancer cells and that makes the cancer cells extra sensitive to certain cancer drugs. We have also discovered new E3 enzymes that play a very important role in the development and spread of cancer. In continuing studies, we will examine how these E3 enzymes affect the sensitivity of the cancer cells to various types of cancer drugs. The hope is that the results of our studies can be used in risk assessment and treatment strategy, but also lead in principle to new forms of cancer diagnosis and therapy. Several E3 enzymes have also been shown to be particularly attractive as molecular targets and we believe that the increased knowledge of how these enzymes control protein degradation will lead to increasingly individualized cancer treatments developing in the future.

Protein degradation (proteolysis) is a central biological mechanism that regulates basal functions of the cell such as cell division, cell death and gene activity. The degradation itself is performed by the so-called ubiquitin proteasome system and the discovery of this process was awarded in 2004 with the Nobel Prize. Proteins to be destroyed are first labeled with a small label, a protein called ubiquitin (Ub), and then rapidly broken down into the cellular debris, proteasomes. The degradation process is regulated by three enzyme activities

E1, E2 and E3, where the so-called E3 ubiquitin enzymes determine which proteins to be broken down in the cell. We are studying an E3 enzyme in cancer cells. These have been shown to control a variety of cancer proteins that have been shown to be vital for cancer cell survival. The E3 enzyme Fbw7 is a protein that normally prevents cancer development and we have found that Fbw7 is often damaged in the cancer cells and that makes the cancer cells extra sensitive to certain cancer drugs. We have also discovered new E3 enzymes that play a very important role in the development and spread of cancer. In continuing studies, we will examine how these E3 enzymes affect the sensitivity of the cancer cells to various types of cancer drugs. The hope is that the results of our studies can be used in risk assessment and treatment strategy, but also lead in principle to new forms of cancer diagnosis and therapy. Several E3 enzymes have also been shown to be particularly attractive as molecular targets and we believe that the increased knowledge of how these enzymes control protein degradation will lead to increasingly individualized cancer treatments developing in the future.

A very important biological mechanism that regulates cell division, cell death and gene expression is the degradation of proteins (proteolysis). The degradation itself is performed by the so-called ubiquitin proteasome system and the discovery of this process was awarded in 2004 with the Nobel Prize. Proteins to be destroyed are labeled with a small label, a protein called ubiquitin (Ub). Proteins labeled with Ub are then rapidly degraded into the cellular debris, proteasomes. The degradation process is mainly regulated by three enzyme activities

E1, E2 and E3, where the so-called E3 ubiquitin ligases determine which proteins in the cell to degrade. We study a certain family of E3 ligases, so-called SCF ligases. We have previously identified an E3 ligase, SCFFbw7, which controls the breakdown of several important cancer proteins. Fbw7 is a protein that normally prevents cancer development and we have found that Fbw7 is often damaged in cancer cells. We have also discovered new SCF ligases that play a very important role in the development and spread of cancer. In continuing studies, we will investigate whether these SCF ligases affect the cancer cells' sensitivity to various types of cancer drugs. It is hoped that the results of these studies can be used in risk assessment and treatment strategy, but also lead in principle to new forms of cancer diagnosis and therapy. Several SCF E3 ligases have proven to be particularly attractive as molecular target targets and we believe that the increased knowledge of how these enzymes control protein degradation will lead to increasingly individualized cancer treatments developing in the future.

A very important biological mechanism that regulates cell division, cell death and gene expression is the degradation of proteins (proteolysis). The degradation itself is performed by the so-called ubiquitin proteasome system and the discovery of this process was awarded in 2004 with the Nobel Prize. Proteins to be destroyed are labeled with a small label, a protein called ubiquitin (Ub). Proteins labeled with Ub are then rapidly degraded into the cellular debris, proteasomes. The degradation process is mainly regulated by three enzyme activities

E1, E2 and E3, where the so-called E3 ubiquitin ligases determine which proteins in the cell to degrade. We study a certain family of E3 ligases, so-called SCF ligases. We have previously identified an E3 ligase, SCFFbw7, which controls the breakdown of several important cancer proteins. Fbw7 is a protein that normally prevents cancer development and we have found that Fbw7 is often damaged in cancer cells. We have also discovered new SCF ligases that play a very important role in the development and spread of cancer. In continuing studies, we will investigate whether these SCF ligases affect the cancer cells' sensitivity to various types of cancer drugs. It is hoped that the results of these studies can be used in risk assessment and treatment strategy, but also lead in principle to new forms of cancer diagnosis and therapy. Several SCF E3 ligases have proven to be particularly attractive as molecular target targets and we believe that the increased knowledge of how these enzymes control protein degradation will lead to increasingly individualized cancer treatments developing in the future.

A very important biological mechanism that regulates cell division, cell death and gene expression is the degradation of proteins (proteolysis). The degradation itself is performed by the so-called ubiquitin proteasome system and the discovery of this process was awarded in 2004 with the Nobel Prize. Proteins to be destroyed are labeled with a small label, a protein called ubiquitin (Ub). Proteins labeled with Ub are then rapidly degraded into the cellular debris, proteasomes. The degradation process is mainly regulated by three enzyme activities

E1, E2 and E3, where the so-called E3 ubiquitin ligases determine which proteins in the cell to degrade. We study a certain family of E3 ligases, so-called SCF ligases. We have previously identified an E3 ligase, SCFFbw7, which controls the breakdown of several important cancer proteins. Fbw7 is a protein that normally prevents cancer development and we have found that Fbw7 is often damaged in cancer cells. We have also discovered new SCF ligases that play a very important role in the development and spread of cancer. In continuing studies, we will investigate whether these SCF ligases affect the cancer cells' sensitivity to various types of cancer drugs. It is hoped that the results of these studies can be used in risk assessment and treatment strategy, but also lead in principle to new forms of cancer diagnosis and therapy. Several SCF E3 ligases have proven to be particularly attractive as molecular target targets and we believe that the increased knowledge of how these enzymes control protein degradation will lead to increasingly individualized cancer treatments developing in the future.