New prECision thErapieS for uveal melanoma (targeting the Gαq/GNAQ oncogenic Signaling cIrcuiTrY)

Project Information

NECESSITY

Grant agreement ID: 101027731

DOI

10.3030/101027731

Project closed

EC signature date 16 April 2021

Start date 1 January 2022

End date 31 December 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 269 002,56

EU contribution

€ 269 002,56

Coordinated by

UNIVERSITA DI PISA
Italy

Periodic Reporting for period 2 - NECESSITY (New prECision thErapieS for uveal melanoma (targeting the Gαq/GNAQ oncogenic Signaling cIrcuiTrY))

Reporting period: 2024-01-01 to 2024-12-31

Summary of the context and overall objectives of the project

Uveal melanoma, the most common primary eye cancer in adults, has a high risk of metastasis to the liver within 5-10 years after diagnosis. Large tumors or relapses increase this risk. Despite dormancy in the liver after primary tumor treatment, once active, metastatic uveal melanoma is resistant to current therapies, resulting in rapid patient death within a year. Current treatments are ineffective, highlighting an urgent need for new strategies to address the significant threat of metastatic uveal melanoma and develop therapies for those facing a short life expectancy.
Our studies have identified a promising approach to overcoming drug resistance in metastatic uveal melanoma. Specifically, we discovered that venetoclax, an approved BCL2 inhibitor, works synergistically with FAK/MEK blockade to restore treatment effectiveness. This suggests that resistance to FAK/MEK inhibitors in uveal melanoma cells may result from an adaptive increase in Bcl2, an anti-apoptotic protein. Targeting this pathway with BCL2 inhibitors could significantly enhance therapeutic responses, offering a more effective treatment strategy for patients facing limited options

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

We discovered that using a combination of drugs targeting FAK and the MEK-ERK pathway could enhance the effectiveness of treatment for uveal melanoma. Taking advantage of a screening using a cancer signaling library, we revealed specific genetic changes and pathways that make the cancer resistant to the FAK plus MEK inhibitors. To prioritize potential treatments, we created drug resistant cell lines and identified a promising drug that, when combined with FAK and MEK inhibitors, showed strong effects in both lab and animal tests, indicating a potentially more effective treatment strategy for UM patients. Our study provides valuable insights into overcoming resistance and improving outcomes for individuals with uveal melanoma.
Furthermore, we provided and demonstrated the efficacy of more combinations for Uveal Melanoma treatment; indeed, FAK inhibitor combined with PKC inhibitor or MEK inhibitor combined with mTORi induce cell death in cultured cells and in preclinical mouse models with metastasis, revealing a vulnerable signaling pathway that can be targeted for a precise, multimodal therapy against metastatic uveal melanoma.
Finally, from the lesson learned from the uveal melanoma, we expanded our studies in the field of Skin Cutaneous Melanoma, providing a rationale for the clinical development of MAPK inhibitor combined with FAK inhibitor in patients with BRAFV600E mutation following progression on current therapy.

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)

We explored the specific mechanisms through which the sustained activation of Gαq-driven pathways contributes to the survival of uveal melanoma cells under the current treatment (FAK + MEK inhibition).
The findings we obtained hold substantial potential impact on the scientific community and cancer therapy. We have identified potential and viable targets that could be treated in conjunction with FAK and MEK inhibitors, aiming to enhance their efficacy and reduce the development resistance in the Uveal Melanoma. Providing multiple treatment options for the UM disease and a new treatment for the cutaneous melanoma patient, we believe that these discoveries could have an impact on patients affected by these diseases, since there is still a critical and urgent need for novel therapeutic strategies.

3 manuscripts detailing the results of this innovative and ambitious projects have been or are in submission process to high-impact journals. I anticipate that their publications will significantly contribute to both my future career as a researcher and the broader scientific community.

Darovasertib combined with FAK inhibition is highly synergistic in Uveal Melanoma