DOPPLER-LC

Background and Rationale:
Lung cancer remains the leading cause of cancer death globally. Despite advancements in targeted therapies for oncogene drivers like EGFR and KRAS mutations, both intrinsic and acquired resistance ultimately limit their effectiveness. While in vitro studies using 2D cultures have identified resistance mechanisms, they do not adequately reflect the complexity of the tumor microenvironment (TME) and 3D tumor structure seen in vivo.

Hypothesis and Aims:
Partner 3 has developed a robust collection of patient-derived xenografts (PDX) from lung cancer. Using these tools, our consortium published seminal studies on FGFR, Notch and Farnesyltransferase pathways in EGFR-driven lung cancer resistance.

Now, two breakthroughs enable us to further mimic the human disease:
1. In vivo development of PDX models resistant to targeted therapy.
2. Development of patient-derived organoids (PDXDO), which now allow us to study both intrinsic and acquired resistance at high scale.

The goal of DOPPLER-LC is to standardize PDXDO protocols across the consortium, improving reproducibility and creating platforms for testing novel therapies targeting resistance. Additionally, Partner 5 introduces mRNA switching technology, which offers the potential to control mRNA translation in resistant cancer cells, providing an innovative strategy to overcome resistance.

Methods:
1. New PDX Models:
We will establish PDX models with MET, RET, ALK, ROS, and BRAF alterations, which are less common but clinically significant.
2. Development of PDXDO Models:
Patient-derived organoids (PDXDO) will be generated from these PDX models.
3. OMICs Analysis:
We will perform OMICs on resistant PDXs models to identify common biomarkers of resistance. These will be compared to their parental PDXs counterparts to uncover pathways critical for therapy evasion.
4. Therapeutic Targeting:
We will test using available drugs to target the resistant signatures identified through OMICs first in PDXDOs and confirm our best strategies in PDXs.
5. mRNA Switching Technology:
We will evaluate mRNA switching technology in the PDXDO models offering a potential approach to overcome treatment resistance.

Expected Results and Impact:
• Insights into Resistance Mechanisms: This research will deepen our understanding of both intrinsic and acquired resistance, enabling the identification of predictive biomarkers and therapies to overcome resistance.
• Improved Patient Outcomes: By improving progression-free survival (PFS) and overall survival (OS) through better therapeutic targeting, this work will lead to innovative clinical trials in our clinical network.

The DOPPLER-LC consortium aims to push the boundaries of precision oncology, offering new opportunities to address resistance and improve survival on the main cause of death by cancer in the world.