Periodic Reporting for period 2 - ALTER-brain (Metastasis-associated altered molecular patterns in the brain)
Periodo di rendicontazione: 2022-01-01 al 2023-06-30
We want to challenge an unmet clinical need such as brain metastasis, which is emerging as a serious societal problem given the increasing incidence among cancer patients and the ineffective therapies and yet aggressive therapeutic approaches available. Our approach to complete our main objective of offering better options to treat brain metastasis is based on the fact that they become dependent on establishing novel crosstalk with multiple cells from the microenvironment. Indeed, cells from the brain or reaching the brain from the periphery trying to fight the metastasis are rewired by the tumor that make them work for its own benefit. Thus, we are focusing on identifying such emerging crosstalk that are crucial to allow the metastasis to survive in this otherwise difficult to colonize organ. We are convinced that developing this organ-specific therapies against metastasis will be necessary if we aim limit cancer-associated deaths.
Our findings until the middle of the project cannot be more exciting. We have found a novel way to systematically identify vulnerabilities in the altered brain metastasis-microenvironment that allows us to move faster in the process of discovering novel drugs to challenge brain metastasis. Interestingly this novel drug-screening platform we have called METPlatform, is fully compatible with patient-derived material and we are exploiting it in the context of a large network of hospitals nation-wide. In addition to METPlatform, we have discovered that resistance to one of the most prevalent therapies against brain metastases, radiotherapy, is originated in the microenvironment. By exploiting this finding, we have reported the first strategy to apply radiotherapy following a criterion that allows to avoid resistance either by the identification of a biomarker detectable in non-invasive liquid biopsies and/or the possibility to use a new drug that blocks resistance in those patients positive for the biomarker. In summary, our strategy will allow to personalize radiotherapy for brain metastasis for the first time, improving its efficacy and limiting unnecessary toxicities. Our findings are already in a clinical study and in a clinical trial, which confirms that by the end of the ERC project we will be able to confirm the impact of our research not only experimentally but also in cancer patients.
Besides the two major aspects already reported and the clinical efforts ongoing, we are in the process of completing additional projects dissecting the importance of altered patterns in the brain metastasis-microenvironment in the lack of efficacy of immunotherapies based on blocking antibodies as well as the major contribution of the crosstalk between cancer cells and endothelial cells to promote the development of metastases. In both aims of the project we envision a major impact in the field given our ability to propose specific novel therapeutic approaches and their validation in patient-derived material at the functional level.