Exploiting the Ubiquitin System to Target the "Undruggable" Cancer Proteome

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.