Targeted Protein Degradation as a New Experimental and Therapeutic Approach for Pancreatic Ductal Adenocarcinoma

Informations projet

PROTAC-PDAC

N° de convention de subvention: 101087045

DOI

10.3030/101087045

Date de signature de la CE 12 Avril 2023

Date de début 1 Decembre 2023

Date de fin 30 Novembre 2028

Financé au titre de

• European Research Council (ERC)

Coût total

€ 1 999 401,00

Contribution de l’UE

€ 1 999 401,00

Coordonné par

CHRISTIAN-ALBRECHTS-UNIVERSITAET ZU KIEL
Germany

Periodic Reporting for period 1 - PROTAC-PDAC (Targeted Protein Degradation as a New Experimental and Therapeutic Approach for Pancreatic Ductal Adenocarcinoma)

Période du rapport: 2023-12-01 au 2026-05-31

Résumé du contexte et des objectifs généraux du projet

Pancreatic ductal adenocarcinoma (PDAC) is a life-threatening disease with few treatment options. Recently, the chemical space for targeted therapeutics was significantly increased by the development of compounds that induce protein degradation (PROTACs), but
so far, they are unavailable for PDAC. The main motivation of PROTAC-PDAC is to develop novel targeted therapies for PDAC. The project is based on our accomplishments in three crucial areas. First, my group identified – as target candidates – a series of
transcription factors that are absolutely required for PDAC growth in vivo. Second, we developed dozens of potent, specific PROTACs, thereby gaining deep insight into the underlying design principles and synthesis procedures. Third, we established genetic models in
mice for simulating PROTAC function and discovering ideal target–E3 ligase pairs.

In PROTAC-PDAC, we will develop compounds that degrade key oncogenic transcription factors and inhibit pancreatic tumor growth with minimal toxicity in healthy tissues. We will start by implementing the Auxin degron system in a murine PDAC model, to induce
degradation of the target candidates and select four priority targets with the highest therapeutic index (Aim I). Then, we will assess their oncogenic functions by analyzing molecular, cellular and organismic consequences of acute depletion in mice (Aim II). In
parallel, we will develop pharmaceutical PROTACs to induce target degradation and analyze their efficacy in PDAC models (Aim III). Finally, with the aim of developing less toxic PDAC therapy, we will identify pancreatic E3 ligases for the design of the first tissue specific
PROTACs that induce target degradation primarily in pancreatic tumor cells (Aim IV). While the main goal of PROTAC-PDAC is to develop new PROTAC-based therapeutic strategies, we will also establish groundbreaking methods and models leading to fundamental discoveries in PDAC biology.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

During the first 30 months of the ERC project PROTAC-PDAC, the project has largely developed as expected and as outlined in the original proposal. PROTAC-PDAC aims to identify new therapeutic targets for Pancreatic ductal adenocarcinoma (PDAC), validate them in mouse models, and therapeutically exploit them using targeted protein degradation, in particular through so-called PROTAC molecules. PROTAC-PDAC is structured into four work packages. The first work package aims to test candidate targets identified in a previous genetic screen in mouse models and to select those that appear most suitable for PROTAC development. In particular, we investigate whether induced degradation of the target using the Auxin Degron system is feasible in pancreatic tumors in vivo and whether depletion leads to tumor regression. We have successfully established this system and applied it to the target protein RUVBL1. Together with data from the second work package, we were able to publish these results in the journal Gut (Vogt et al.; PMID: 38821858). Based on these experiences, we are now evaluating the therapeutic effect of depleting additional targets. Currently, we are focusing on experiments involving the elongation factor SPT6. In addition, we have used the Auxin Degron system to characterize further proteins, both independently and in collaboration (PMID: 39698826, 41651844).
The second work package was designed to investigate the molecular and cellular consequences of target depletion in greater detail and to understand the underlying mechanisms. For RUVBL1, we demonstrated using genome-wide approaches that its depletion leads to inhibition of the oncogene MYC and reversal of immune-evasive effects in tumors (Vogt et al.). We have also applied our expertise in the molecular analysis of oncogenes in additional collaborations (PMID: 39443725, 39547226, 39833612, 40016419). Another important component of this work package is the depletion of target candidates throughout the entire murine organism to assess potential essential functions of these targets in healthy tissues and thus to estimate possible future on-target toxicities of inhibitors. To this end, we have commissioned the generation of transgenic mouse lines and are currently breeding them in our animal facility in Kiel.
The third work package focuses on developing PROTACs for the identified targets. PROTACs are bifunctional small molecules that induce ubiquitination and subsequent degradation of a target protein by simultaneously binding the target and a cellular E3 ubiquitin ligase. We have already developed ligands for our target RUVBL1 and are currently generating first-generation PROTAC molecules based on these ligands. In addition, we have developed PROTACs for several other targets (PMID: 39539259, 39729064, 39932098, 41524954, 41575171).
The final work package aims to identify suitable E3 ubiquitin ligases. We have already developed and published an assay that enables us to test whether specific E3 ligases can degrade selected targets (PMID: 39641357, 40246979). Furthermore, we have identified approximately 15 candidate E3 ligases with tissue-specific expression patterns. In the near future, we will use the established assay to investigate whether these ligases can efficiently degrade our targets.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

I consider the inhibition of MYC function upon depletion of RUVBL1 a breakthrough discovery (Vogt et al), since MYC is one of the most important oncogenes in human cancers and considered undruggable. We now need molecules, that mimick the action of the genetic depletion system we used so far.