Uncover new drug targets for cancer immunotherapy
- Reference number
- FFL21-0043
- Project leader
- Mao, Yumeng
- Start and end dates
- 220801-271231
- Amount granted
- 15 000 000 SEK
- Administrative organization
- Uppsala University
- Research area
- Life Sciences
Summary
The overarching goal of the proposal is to uncover and develop novel drug targets to combat human cancers. The proposal is built on our recently completed genome-wide CRISPR/Cas9 screens and more than 10 years of experimental expertise in cancer immunology. There are three main objectives: 1)"To validate the neddylation pathway as an immunotherapy drug target. 2)"To uncover cancer intrinsic immune regulatory mechanisms using a data-driven approach. 3)"To address unmet medical needs by translating research findings into drug discovery initiatives. We will use our expertise in CRISPR/Cas9 genome editing to investigate the functional contribution of the neddylation pathway in human cancer cells and in tumor-bearing mice. We will uncover and validate novel targets to inhibit the neddylation pathway. We will establish a bioinformatics pipeline to identify a list of data-driven genes (DDG) that are both clinically relevant and functionally meaningful. These DDG will be studied in order to identify potential new targets to improve immunotherapy. We aim to translate our research to drug discovery projects. We will also explore how the upcoming research could boost the significance of an ongoing national drug discovery project supported by the SciLifeLab. We expect to observe improved response to the ICB therapy in vitro and in vivo when drug targets were genetically deleted or pharmacologically inhibited. Patents and spin-off companies will be pursued for novel findings.
Popular science description
Treating human cancers with medicines that can boost immunity has shown unprecedented benefits in patients. However, challenges remain as most patients fail to gain long-term benefits. One possible cause for resistance to immunotherapy is the intrinsic mechanisms in cancer cells. In this proposal, my team aims to employ hypothesis-driven as well as data-driven approach to unravel key inhibitory pathways that hamper efficient immune activation. In detail, we will genetically modify human cancer cells using CRISPR/Cas9 technology to search for genes or pathways that can make immunotherapy work better in cell culture dishes and to make tumors smaller in mice. To ask whether our research is of relevance to patients, we will study whether the genes or pathways can be found at different levels in patients who do well after immunotherapy, as compared to those who did not benefit. In the case where drug candidates have already been developed, we will test whether they can improve immunotherapy in our experimental models. Alternatively, we will explore the possibility to develop new medicines for the most promising and robust drug targets that are derived from our research. Our long-term goal is to conduct original research that enables the discovery of the next generation immunotherapies against human cancers.