Unlocking new treatment possibilities in small cell lung cancer.
The challenge
Nearly 50% of human proteins are intrinsically disordered, meaning they lack a stable structure. [1] These intrinsically disordered proteins (IDPs) are involved in thousands of diseases, including many forms of cancer. [2] However, because they don’t follow the conventional rules of protein structure, they have long been considered “undruggable.” To date, fewer than 10 IDP-targeting drugs are in clinical development.
This challenge is particularly evident in small cell lung cancer (SCLC), a fast-growing, aggressive cancer that accounts for around 15% of all lung cancer cases. [3] SCLC is typically diagnosed at an advanced stage and responds poorly to current treatments. Despite initial success with chemotherapy or immunotherapy, over 90% of patients relapse within six months, and median survival remains under one year. [4] These outcomes highlight an urgent need for new treatment strategies that can address the underlying biology of the disease.
The solution
Nuage Therapeutics is tackling this challenge by focusing on IDPs – specifically, transcription factors (TFs), which are key drivers of cancer development. [5] Its lead programme targets ASCL1, a transcription factor responsible for driving a major molecular subtype of SCLC. Because ASCL1 is intrinsically disordered, it has historically been overlooked as a drug target.
Nuage Therapeutics is developing a first-in-class small molecule inhibitor designed to selectively bind and block ASCL1 activity, offering a completely new therapeutic approach for one of the most pressing unmet needs in oncology.
To support this and other drug development efforts, Nuage Therapeutics has built a proprietary IDP-focused discovery platform. This platform includes a suite of tools specifically designed to work with disordered proteins, as well as a Target Discovery Algorithm (TDA), a data-driven engine that scans the full set of human proteins to identify and prioritise high-potential, disease-relevant IDPs for future drug discovery.
Expected impact
The project led by Nuage Therapeutics, is expected to generate substantial health and social impact by addressing one of the most aggressive and underserved forms of lung cancer. Furthermore, beyond SCLC-A, the ASCL1-targeting small molecule may have broader therapeutic potential in other neuroendocrine tumors or ASCL1-driven diseases. Success in this lead indication will provide a foundation for expanding its application across additional indications with similar molecular profiles, thereby enhancing its overall clinical and commercial value.
In 2019, there were 180,730 diagnosed SCLC cases across the eight major pharmaceutical markets – the US, France, Germany, Italy, Spain, UK, Japan, and urban China. [6] This number is projected to rise at an annual growth rate (AGR) of 3.48%, reaching an estimated 302,183 cases by 2034, the expected market entry year for the drug developed in this project.
External Partners
- Nuage Therapeutics (Activity Leader)
References
[1] Uversky VN, Oldfield CJ, Dunker AK. Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys. 2008;37:215-46. doi: 10.1146/annurev.biophys.37.032807.125924. PMID: 18573080.
[2] Mészáros et al (2021) “Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies” 2021 Mar 4;11(3):381. doi PMCID: PMC8000335 PMID: 33806614
[3] Baldini, E. H., & Kalemkerian, G. P. (2024). Limited-stage small cell lung cancer: Initial management.
[4] Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021 Jan 14;7(1):3. doi: 10.1038/s41572-020-00235-0. PMID: 33446664; PMCID: PMC8177722.
[5] Gay CM, Stewart CA, Park EM, Diao L, Groves SM, Heeke S, Nabet BY, Fujimoto J, Solis LM, Lu W, Xi Y, Cardnell RJ, Wang Q, Fabbri G, Cargill KR, Vokes NI, Ramkumar K, Zhang B, Della Corte CM, Robson P, Swisher SG, Roth JA, Glisson BS, Shames DS, Wistuba II, Wang J, Quaranta V, Minna J, Heymach JV, Byers LA. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021 Mar 8;39(3):346-360.e7. doi: 10.1016/j.ccell.2020.12.014. Epub 2021 Jan 21. PMID: 33482121; PMCID: PMC8143037.
[6] GlobalData (2021). Small cell lung cancer diagnosed incident cases set to reach 240,000 in 2029. https://www.globaldata.com/media/pharma/small-cell-lung-cancer-diagnosed-incident-cases-set-reach-240000-2029-says-globaldata/