Cohesin Therapeutics. Precision medicine for treating STAG2 mutated cancers

Project Information

Cohesin-Tx

Grant agreement ID: 101069277

DOI

10.3030/101069277

Project closed

EC signature date 15 March 2022

Start date 1 June 2022

End date 31 May 2024

Funded under

• European Research Council (ERC)

Total cost

No data

EU contribution

€ 150 000,00

Coordinated by

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Austria

Periodic Reporting for period 1 - Cohesin-Tx (Cohesin Therapeutics. Precision medicine for treating STAG2 mutated cancers)

Reporting period: 2022-06-01 to 2024-05-31

Summary of the context and overall objectives of the project

The cohesin gene STAG2 has emerged as a significant tumour suppressor, frequently mutated in bladder cancer, Ewing sarcoma, and acute myeloid leukaemia (AML). Currently, these cancers are treated by cytotoxic therapies and surgery. These treatment plans are limited by unwanted side effects, have not improved over the last few decades, and have not been able to eliminate the high mortality caused by AML. As such, STAG2 mutations serve as critical biomarkers for patients with urgent medical needs.
Our research has discovered that cancer cells with STAG2 mutations are highly vulnerable to the inactivation of another protein, STAG1, while healthy cells remain unaffected. This selective sensitivity offers a promising avenue for precision medicine. Our long-term goal is to develop a STAG1 inhibitor, which could greatly reduce side effects and treatment costs, benefiting patients, doctors, and health insurance companies.
To develop a STAG1 inhibitor, it is essential to explore the innovation potential. With support from the ERC-PoC grant, we aimed to achieve several key milestones: (1) optimizing our building blocks for a STAG1 inhibitor, (2) developing an intellectual property strategy, (3) assessing commercial feasibility, and (4) creating a business plan. These efforts culminate in a comprehensive proposition package to present the commercial potential to strategic partners.
We have assembled a dedicated team, united by a shared enthusiasm to develop precision medicine for patients suffering from STAG2-mutated cancers.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The main goal of Activity 1 was to obtain structural information on the binding mode of STAG1-binding molecules. For this purpose, biochemical assays based on isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) were established with which the binding affinity of small molecule ligands to STAG1 can be measured, as well as screening conditions were set up to allow for large-scale testing of analogue molecule libraries by NMR. STAG1 crystallisation trials were initiated to determine the actual binding of these molecules, and buffer conditions to improve the solubility of STAG1 were systematically screened. In addition to the actions proposed for Activity 1, human cell lines as well as mouse lines were generated and validated for functionality. These lines can be used as reporter cell lines for screening and for testing the safety of STAG1 inhibitors. Altogether, these tools and assays will be instrumental for the future identification and validation of optimised STAG1 inhibitor molecules.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

In addition to our experimental developments, market analysis and commercial feasibility were crucial pillars of our project. With support from a consulting company with biomedical expertise we analysed the disease “landscape” of bladder cancer and Ewing sarcoma, the two cancers with the highest occurrence of STAG2 mutations. This assessment revealed the following:
1. Bladder cancer therapy has a large market with many assets currently in development.
2. The standard of care and treatment options for bladder cancer are inadequate, resulting in a high unmet medical need.
3. Ewing sarcoma has seen no therapeutic advancements in the last 20 years, leading to a high unmet need for novel drugs.
4. Both cancers require agents with novel modes of action, including targeted therapies, that offer increased efficacy and tolerability.
Legal experts also assessed the IP landscape and found no patents or commercial drug development pipelines involving STAG1 or STAG2, except for one patent protecting STAG1 oligonucleotides. These findings highlighted the commercial potential of our project.
We developed a comprehensive business plan to present the commercial opportunity to investors. This plan includes the presentation of Cohesin-Tx and its application for precision medicine, a marketing plan, market size and dynamics, IPR position and strategy, regulatory strategy, logistics, SWOT analysis, business management team, business model, potential partners, financial forecast, and funding strategy. The business plan has been reviewed and approved by several experts.
In summary, the activities of this ERC-PoC grant have paved the way for the establishment of Cohesin-Tx with the aim to develop a selective, safe, and efficacious STAG1 inhibitor.