Lombardy partner:
- Michela Anna Polidoro, Humanitas Research Hospital
| Pathology of interest: | New personalised treatment for cancer1 |
| Area of research: | Cancer |
| Start date: | 01/01/2026 |
| End date: | 31/12/2028 |
| Funding: | € 447.600,00 |
| Project partners: | Biogipuzkoa Health Research Institute (Spain) University of the Basque Country (Spain) Cordeliers Research Center, Inserm Unit (France) Humanitas Research Hopital (Italy) The Roger Williams Institute of Hepatology (UK) |
Background
Cancer remains a leading cause of mortality worldwide, with the WHO reporting 10 million deaths in 2020. Projections indicate a 77% increase in new cancer cases by 2050, driven by population aging, socioeconomic changes, and environmental factors. Platinum (Pt)-based chemotherapeutic agents are fundamental in treating multiple solid cancers and have contributed to significantly increased patient survival rates. However, the emergence of drug resistance in up to 70% of patients limits their efficacy. Current Pt-based drugs, like Cisplatin (CisPt), primarily cause single-strand DNA breaks, enabling cancer cells to activate DNA repair mechanisms and develop resistance.
Hypothesis
We hypothesize that novel Pt(II) derivatives designed to induce high-frequency of double-strand DNA breaks would prevent the development of DNA repair mechanisms in cancer cells. This approach aims to enhance cancer cell death and stimulate a tumor immunogenic response, potentially improving the response to immunotherapy. A recent collaboration between Biogipuzkoa and UPV/EHU groups led to the design, synthesis, and patenting (PCT/EP2023/083500) of a novel family of Pt(II)-derived chemotherapeutic agents with unique polyelectrophilic features against cancer, named “Aurki-Pts”. Aims
The primary aim of this project is to assess the therapeutic potential of Aurki-Pts, both alone and in combination with immune checkpoint inhibitors (ICIs), utilizing novel patient-derived models developed by our Consortium. This initiative will encompass various cancer types as a proof of concept, with a focused investigation into biliary cancer, also known as cholangiocarcinoma (CCA). Specific aims include: 1) Computational and molecular characterization of Aurki-Pts binding to DNA; 2) Evaluation of the antitumor effects and molecular mechanisms of action of Aurki-Pts using advanced 2D and 3D in vitro and in vivo cancer models; 3) Assessment of combination therapies using Aurki-Pts and ICIs in cutting-edge experimental in vitro and in vivo models; 4) Profiling of tumor mutation burden, molecular characteristics, and neoantigens of cancer cells following Aurki-Pts treatment in vitro and in vivo.
Methods
We will use pioneer 2D and 3D human in vitro cancer models, including Patient-Derived Organoids (PDOs), human Precision-Cut Tissue Slices (PCTS), and a human Cancer-on-CHIP platform. Additionally, we will employ various cancer animal models with different etiological backgrounds. Expected Results and Potential Impact
In TITAN, our goal is to develop a next-generation targeted therapy for both treatment-naïve and CisPt-resistant cancers using innovative personalized models. The outcomes from this Consortium have the potential to revolutionize drug design, personalized cancer modelling, and clinical practices, ultimately driving research advancements and improving the management and outcomes for patients with cancer.