"And that's the promise of precision medicine -- delivering the right treatments, at the right time, every time to the right person". B.Obama, January 30, 2015
Translating preclinical research into clinical benefit for cancer patients is a challenge that can only be accomplished by a multidisciplinary research network. Using colorectal cancer as model-disease our group has developed a unique integrative platform that feeds research laboratories with "the right sample at the right time, for the right experiment" to enable an innovative reinterpretation of the molecular bases of CRC metastatic evolution.
Preclinical results issued within our research network are then converted into hypothesis-driven, "transformative" clinical studies to advance the rational application of more effective therapies.
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths. The 5-year survival rate for early stages 90% but drops to 10% in metastatic patients (mCRC)(Punt et al., 2017).
In the last decade advances have been made thanks to new chemotherapies and genetic-based strategies for patient’s selection. However, their impact has reached a plateau (Dienstmann et al., 2017; Iveson et al., 2018). To overcome the impass research has to satisfy a number of still unmet key medical needs such as the post-surgical management of molecular minimal residual disease, how to overcome 'one-type-fits-all' chemotherapy, thwart resistance to targeted agents (Misale et al., 2014a) and turn tumour immunophenotype from 'cold' to 'hot' (Le et al., 2015).
By capitalizing on our new platform AlfaΩmega, which will follow a cohort of 500 newly diagnosed patients from diagnosis to death or cure, we aim to assist our translational and clinical partners in the understanding of the molecular bases of metastatic evolution in colon cancer to advance the rational application of more effective therapies.
To understand and track the molecular landscape of mCRC we developed the PROFILING, FUNNEL and CORNUCOPIA platforms. These translational pipelines helped to establish patient-derived preclinical platforms (liquid biopsies, cell lines and patient-derived xenografted avatars) for functional analysis of molecularly characterized subsets of CRCs (Barault et al., 2017; Bardelli et al., 2013; Bertotti et al., 2011, 2015, 2015; Germano et al., 2017; Isella et al., 2015, 2017; Medico et al., 2015).
These platforms enabled the translational labs in our network to characterize the mechanisms of primary and acquired of resistance to EGFR inhibitors, a mainstay in the treatment of mCRC, in preclinical models and men (Arena et al., 2016; Misale et al., 2012, 2014b, 2015; Russo et al., 2016; Siravegna et al., 2015).
These results were then 2translated2 from bench to bedside via several proof-of-concept trials. In the 5% of CRC patients carrying in their tumor an ERBB2 amplification, the HERACLES trials established a diagnostic algorithm, a new treatment paradigm and defined the evolution of individual metastases during HER2 blockade (Sartore-Bianchi et al., 2016; Valtorta et al., 2015), highlighting the significance of coupling molecular pathology, radiographic analysis, liquid biopsies and avatar models in precision oncology (Siena et al., 2018; Siravegna et al., accepted for publication).
The ongoing CHRONOS trial (NCT03227926) exploits the pulsatile dynamics of RAS-mediated resistance in patients with multiple wild-type tumors progressing during anti-EGFR treatment, offering the opportunity of a "re-challenge" in patients otherwise destined to palliative chemotherapy. CHRONOS is the first trial in Europe using liquid biopsy as an interventional tool for treatment choice.
To navigate the evolutionary pathways of CRC during their natural history and under the darwinian pressure of therapies, we are setting up the AlfaΩmega platform (AΩP).
AΩP will provide our partners with continuous, longitudinal accessibility to samples, imaging and clinical data from patients with local or metastatic disease through flexible and integrated logistics.
AΩP will allow the molecular story-telling of CRC metastatic spread in genetic, functional and immunological terms along time and space, and the selection of appropriate patients for experimentally-driven trials focused on tumor evolution.
The first of such trials, ARETHUSA, attempts to turn mismatch repair proficient (MMRp), KRAS mutated, 'immune-cold' tumors, into hypermutated ‘immune-hot’ tumors by ectopically increasing the mutational burden in cancer cells with genotoxic agents that can drive inactivation of the MMR machinery (ref).
Patients with 'cold-turned-hot' tumors will be treated with the check-point inhibitor pembrolizumab. ARETHUSA is a multicentric, no-profit trial sponsored by IFOM, chaired by Prof. Salvatore Siena from Niguarda Cancer Center (Milan), also involving the National Cancer Institute (Milan) and the Istituto Oncologico Veneto (Padua).
MSD-Global is kindly supporting the study by providing pembrolizumab free-of-charge and support for clinical trial service. The protocol is undergoing regulatory approval with first patient in expected by Fall 2018.
The RHABDOMANCER trial address the attrition of false negatives in the determination of Minimal Residual Disease (MRD) after 'curative' surgery. Recently it has been proven that patients with molecular (m)MRD in their plasma after surgery have an almost 100% risk of metastasis within 2 years from surgery. mMRD positivity is thus a hallmark of radio-imaging undetectable metastatic spread, suggesting the use of adjuvant therapies even in stage I-II patients who currently go untreated.
On the other hand, the false negative rate in patients with a negative test is still too high to guide treatment withholding in routinely overtreated stage III. RHABDOMANCER tries to increase the sensitivity of mMRD determination by combining genetic and epigenetic DNA liquid biopsy testing 30 days post-surgery.
The study is instrumental to support a molecular-based strategy for tailored post-surgical therapeutic interventions.
Our trials are investigator sponsored and grant-funded by charities including AIRC, FPRC, Niguarda. The pharma industry generously contribute by supplying the drug free-of-charge and the occasional clinical trial service.Clinical platforms intra-institutional design service
How to design your translational protocols, what’s the right way to access to clinical samples, how to deal with the logistics of collection, these are just some of the issues that need to be planned in advance when performing clinical studies.
The Precision Oncology Units provides assistance to IFOM research teams in the implementation of “translational” studies, in order to help basic researchers to bring their projects to the bedside, for the benefit of cancer patients.
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