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Genomics of Cancer and Targeted Therapies

Alberto Bardelli - PI

Alberto Bardelli
Biographical sketch

  • Since 2016 Full Professor, Dept. of Oncology, University of Torino, Italy.

  • Since 2022 Scientific Director, IFOM ETS – The AIRC Institute of Molecular Oncology.

Bardelli lab
Main group members
  • Mariangela Russo Associate Professor and co-PI
  • Federica Gentile, Gaia Grasso, Elisa Mariella, Alberto Sogari Postoctoral Fellows
  • Martina Miotto, Luca Russolillo, Alessia Subrizio PhD students
  • Simona Lamba Research Technicians
  • Simona Destefanis Adminstrative Staff

Group members at IFOM ETS – The AIRC Institute of Molecular Oncology

  • Giovanni Germano Associate Professor
  • Giovanni Crisafulli, Rosaria Chilà Staff Scientist
  • Vito Amodio, Paolo Battuello, Veera Ojala, Flaminia Pedretti, Eleonora Piumatti, Nadia Saoudi Gonzalez, Sharon Scardellato, Pietro Paolo Vitiello Postoctoral Fellows
  • Vittorio Battaglieri, Federico Lazzarini, Giorgio Patelli PhD students
  • Alessia Anastasia Research Technicians

 

Research activity

Colorectal (CRC) cancer is the second worldwide cancer leading cause of death. Treatment of metastatic colorectal cancer (mCRC) has improved over the last 15 years since the introduction of EGFR-targeted therapy, antiangiogenic agents, and the use of intensive triplet chemotherapy regimens based on fuoropyrimidines, oxaliplatin, and irinotecan. Our research is focused specifcally on precision oncology for CRC, in particular on the characterization of tumor heterogeneity and mechanisms of tumor evolution during therapy administration, with the fnal aim to identify novel vulnerabilities and therapeutic strategies to prevent or delay the onset of resistance, thus improving survival of cancer patients. By using CRC 2D cell lines, 3D patients-derived organoids (PDO) and xenopatients (PDX) we defned the mechanisms of primary and secondary resistance to targeted therapies, including how metastatic CRC escape from EGFR, BRAF, TRK, and HER2 inhibition (Fig. 1). Our preclinical fndings defning the efectiveness of combinatorial EGFR-BRAF therapy led to practice changes of the clinical guidelines for mCRC carrying BRAF mutations (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-combination-cetuximab-metastatic-colorectal-cancer-…) (Fig. 1). We developed new therapeutic approaches for CRC patients which led to clinical trials in which our laboratory was actively engaged. The HERACLES (https://clinicaltrials.gov/ct2/show/NCT00490841) and ARETHUSA (https://clinicaltrials.gov/ct2/show/NCT03519412) trials are paradigmatic example (Fig. 1). Our studies in the liquid biopsies feld demonstrated that analysis of circulating tumor DNA (ctDNA) can detect mechanisms of resistance to targeted therapies in mCRC and can be used for the clinical follow up of patients. The clinical trial CHRONOS (https://clinicaltrials. gov/ct2/show/NCT03227926) represents the first time interventional liquid biopsy to direct EGFR therapy in CRC patients (Fig. 1). 

We recently unveiled that cancer cells, alike bacteria in response to antibiotic stress, adaptively down-modulate DNA mismatch repair (MMR) and homologous recombination (HR) proteins, and switch to an error prone-mediated DNA replication process in presence of increased DNA damage when exposed to targeted therapy (Fig. 2). This adaptive mutability stress-response, in turn, leads to genetic instability and a transient increase of the mutation rate of surviving cancer persister cells (Fig.2), thus favoring the probability that mutations conferring fitness advantage in the presence of the drug (i.e., conferring drug resistance) eventually emerge (Fig. 2).

 Additionally, immune checkpoint inhibitors have been shown to induce durable responses in a subset of approximately 5% patients with mCRC that carry defective mismatch repair (MMRd) or are microsatellite unstable (MSI). We discovered that inactivation of MMR genes in microsatellite stable (MSS) immune refractory CRCs leads to immune surveillance and response to immune therapy, and proposed that this could be pursued for therapeutic purposes (Fig. 3). These results led to the ongoing clinical trial ARETHUSA. On the same line, aiming at converting MSS non-immunogenic “cold” CRC to immunogenic “hot” tumors sensitive to immunotherapy, we generated preclinical models of heterogeneous tumors in which cold components (mismatch repair proficient, MMRp) and hot counterparts (mismatch repair deficient, MMRd) coexist in the same shared microenvironment. We observed that the modulation of tumor composition by pharmacological enrichment of MMRd component could enhance immune surveillance towards heterogeneous murine tumors (Fig. 3).

The evidence that target therapies induce DNA damage in cancer cells and that, cancer cells switch from oncogenic dependencies to DNA damage tolerance (DDT) dependency, in order to create a permissive milieu for the emergence of mutations, uncover new vulnerabilities that could be therapeutically exploit. We plan to use molecular, pharmacological and CRISPR-CAS9 genetic screenings to characterize markers and features of cancer persister cells and to investigate the role of DNA Damage Response (DDR) in the evolution of tumor recurrence aiming at identifying new therapeutic regimens for CRC patients. Additionally, our future goals are based on the discovery and validation of new targets and therapeutic regimens that are able to increase the immunogenicity of otherwise “cold” and immune refractory CRCs

  • 2021 PI, Funder European Commission ERC-2020- ADG. Proposal no.: 101020342: “TARGET: Targeting DNA repair pathways, sparking”.

  • 2021 Participant, Funder-European Commission and European Federation of Pharmaceutical Industries and Associations. H2020-JTI-IMI2-2020-20 Tumour Plasticity: “PERSIST-SEQ: Building a reproducible single-cell experimental workflow to capture tumour  drug persistence”.

  • 2018 Principal Investigator, Funder-AIRC-Italian Association for Cancer Research. Special Program 5 per mille Metastases Project n. 21091: “Insights into the evolving heterogeneity of metastatic colorectal cancer: from mechanisms to therapies”.

  • 2019 Principal Investigator, Funder-AIRC-Italian Association for Cancer Research. AIRC IG2018 Project n. 21923: “Inactivation of DNA repair to improve cancer immune surveillance”.

  • 2018 Participant, Funder-AIRC - CRUK - FC AECC. Accelerator Award Project n. 22795: “ACRCelerate: Colorectal Cancer Stratified Medicine Network”.

  • 2018 Participant, Funder-Ministero dell’Istruzione, dell’Università e della Ricerca. PON ARS01_00492: “Biopsie liquide per la Gestione Clinica dei Tumori”.

Publications (PubMed)
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