Tumor microenvironment-related changes as new tools for early detection and assessment of high risk diseases - The Extension Program

The project aims at investigating tumor microenvironment-related changes and using them as novel tools for early detection and assessment of high-risk disease in the major solid tumor types.

So far, people have considered cancer as a cell-autonomous disease and searched for biomarkers mainly inside the tumors in a tumor-centered perspective. A groundbreaking method is looking for candidates not only in the tumor itself but at the interplay between the tumor and the microenvironment with the aim to identify very early biomarkers related to the biological reactivity of the host to a developing cancer.

Relevant results were achieved in the 5 years of the previous project in all research areas and cancer types. The present proposal is indeed focused on a full clinical validation of the most mature and promising translational findings that emerged from the program. We aim at validating them in extended clinical studies of five top cancer types, such as breast, colorectal, lung, and prostate cancer, and melanoma, which continue to represent the most widespread and lethal cancers worldwide.

Since we realize that these cancer types have different and specific clinical needs, in the present extended program we have designed ad hoc prospective clinical studies for each of them. Nonetheless, a common trait across the various studies will be the use of shared, noninvasive molecular biomarkers circulating in blood such as microRNAs, extracellular matrix proteins, peptides, and immune cell subpopulations with immune-suppressive features, which were all already identified and validated in training and testing series by the research teams.

One of the pillars of our project is the availability of biological material derived from screening clinical trials and the importance of this latter is exemplified by the case of lung cancer, where a truly prospective screening trial, bioMILD, using an miRNA-based classifier (MSC) with predictive, diagnostic, and prognostic value already validated at several levels will be used as a front-line test in conjunction with low-dose computed tomography (LDCT) and implemented with additional plasma biomarkers, which could add clinical value to the MSC test.

In colorectal cancer, a large external validation on FIT+ subjects of the identified plasma composite miRNA score will be concluded and its suitability in a routine clinical setting will be tested in the actual CRC screening program ongoing at INT.

For prostate cancer (PCa), we will take profit of a unique multicentric active surveillance (AS) trial, Prostate Cancer Research International: Active Surveillance (PRIAS), where subjects with indolent or progressive cancer will be tested for a previously validated plasma miRNA signature, mutation profile, and extracellular matrix (ECM) proteins to provide risk refinement and improve patient selection.

Clinical and co-clinical studies will be implemented in breast cancer (BC). A panel of plasma biomarkers including miRNAs, ECM proteins, and novel peptides will be undertaken to test their utility in replacing invasive biopsy procedures by noninvasive discrimination of breast malignant and benign diseases in a prospective mammography and ultrasound scanning clinical series. An added value in this setting will be the bed-to-bench approach, where refinement of miRNA and mRNA biomarkers will be attempted in transgenic tumor-bearing mice that will allow a time-dependent analysis of all the steps of transformation, not feasible in humans.

In melanoma, a tumor type strongly microenvironment immune-related, an original Myeloid Index Score (MIS), and myeloid markers will undergo a full validation step in large cohorts of patients undergoing targeted or immunotherapies. Such immune cell profile will be cross-tested in the lung clinical study given the recently highlighted predominant role of the immune system in the control of disease course.

Overall we plan to enroll up to 6,500 subjects distributed across the various clinical studies envisaged in the project, with almost 10,000 samples tested with the biomarkers panel.

Given the multidisciplinary nature of the project, a strong coordination effort and an efficient communication flow among the various groups will be employed to organize all the research activities within the integrated plan, and to enhance complementarities and synergy among the Units.