Lucas Pontel
Profile
Dr. Lucas B. Pontel graduated in Biotechnology from the National University of Rosario, Argentina, and obtained his PhD in Biological Sciences from the Institute of Molecular and Cell Biology of Rosario, supported by a CONICET fellowship. In 2010, he visited Prof. McClelland’s lab at the University of California, Irvine, funded by the American Society for Microbiology (ASM).
In 2012, Dr. Pontel joined Prof. KJ Patel’s laboratory at the prestigious MRC Laboratory of Molecular Biology (Cambridge, UK), where he spent five years investigating how metabolism drives the human condition Fanconi anaemia. During this time, he uncovered the toxic effects of endogenous formaldehyde (FA) in mammals, demonstrating its role as a stem cell toxin and carcinogen. His contributions include the groundbreaking discovery that folate degradation releases genotoxic FA and the identification of patients with mutations in FA-detoxifying enzymes who develop the bone marrow failure syndrome AMeDS (Pontel, Mol Cell 2015; Burgos Barragan, Nature 2017; Dingler, Mol Cell 2020).
In 2017, Dr. Pontel was appointed Group Leader at the Institute for Research in Biomedicine of Buenos Aires (IBioBA-MPSP), where he studied metabolic sources of cellular damage and their impact on human health. Funded by the Max Planck Society and CONICET, his group revealed that cellular formaldehyde reacts with the antioxidant glutathione, disrupting redox homeostasis. This work led to a novel therapeutic strategy for acute leukaemia based on inhibiting glutathione synthesis (Umansky et al, Nat Commun 2022; Pontel et al, Redox Biol 2022; Morellato et al, Redox Biol 2021; Umansky et al, Nat Commun 2021).
In 2023, Dr. Pontel joined the Josep Carreras Leukaemia Research Institute as Group Leader in Cancer Metabolism, supported by a Ramón y Cajal fellowship. His research continues to focus on the biology of endogenous aldehydes and their role in haematological malignancies, with a particular emphasis on the cancer predisposition syndromes Fanconi anaemia and AMeDS.
Research
Our laboratory is dedicated to understanding and exploiting the unique characteristics of cancer that could be targeted to halt the disease. We focus on the metabolic reprogramming of tumor cells, which has been recognized as a defining feature of cancer. Tumor cells often alter their metabolism to support their rapid growth and proliferation. However, these same metabolic reactions also produce harmful toxins, such as formaldehyde and reactive oxygen species, that can damage the cancer cells. Our research aims at identifying the mechanisms that cancer cells use to protect themselves from these toxins, and on exploiting these mechanisms to develop new cancer therapies.
Cellular defenses against toxic metabolites in acute leukemia.
Glutathione (GSH) is likely the most abundant antioxidant protecting cells from oxidative damage caused by reactive oxygen species (ROS). It is also an important molecule required to initiate the metabolization of the cellular toxin formaldehyde, an environmental and ubiquous mutagen. GSH is also particularly important in preventing ferroptosis, a non-apoptotic type of cell death. This project focused on studying the basic biology of GSH, building on our discovery that acute lymphoblastic leukemia (ALL) cells are vulnerable to inhibition of GSH synthesis and to ferroptosis-inducing agents. To this end, we combine genetic engineering with genome-wide transcriptomics, proteomics, epigenomic and metabolic studies. By understanding the role of GSH in cancer cells, we hope to uncover new potential therapeutic targets for the treatment of leukemia.
Metabolic vulnerabilities in DNA repair deficient tumors
Mutations in genes coding for DNA repair factors are recognized drivers of breast and ovarian tumors, and are found in 3 % of pediatric B-ALL tumors (Target II Cohort). We have recently discovered that cancer cells with mutations in the Fanconi Anemia DNA repair pathway require GSH synthesis for growth. In this project, we aim to further study this selective vulnerability in cancer cells with mutations in the Fanconi Anemia DNA repair or in the breast cancer susceptibility genes (BRCA1/2). By characterizing the role of GSH metabolism in these cancer cells, we anticipate gaining a better understanding of the underlying mechanisms and identifying potential therapeutic targets.
Exploiting tumor-specific vulnerabilities for personalized treatment of refractory myeloid and lymphoblastic leukemias
The current pipeline to treat a cancer patient usually consists of a conventional chemotherapy that might lead to remission. In most of the cases, cancer returns, and a second chemotherapy is given. Immunotherapy is likely to be used if available for the tumor under treatment. After a new relapse, very few therapeutic options are still available, and the cancer cells have become resilient to them. For example, in acute myeloid leukemia (AML), relapse is usually observed within the first 18 months after initial chemotherapy in 60-70% of patients. After a first relapse, 29% of the patients survive more than 12 months and only 11% survive 5 years. In ALL, between 10-20% of patient relapse with a medium survival after relapse of only 4.5 months.
This project focuses on uncovering druggable vulnerabilities in relapsed patients with AML and ALL, who have exhausted all current therapeutic options. We are developing a novel technology to identify druggable dependencies in patient-derived tumor biopsies, thus advicing a personalized off-the-shelf drug for the treatment of these refractory cancers.