Therapeutic research in the crystal chromosome disease Fanconi anemia

Minguillón, Jordi; Surrallés, Jordi

doi:10.1016/j.mrgentox.2018.05.012

Cited by 4 publications

(5 citation statements)

References 51 publications

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“…Twenty years ago, FA was mainly a pediatric disease, as most patients died in the first two decades due to bone marrow failure or leukemias (5). With improved transplantation protocols, patients with FA now reach their fourth decade of life.…”

Section: Discussionmentioning

confidence: 99%

“…The management of the hematologic phenotype has been remarkably improved over the last 20 years, thanks to optimized hematologic stem cell transplantation protocols, leading to an important increase in Fanconi anemia patient survival, from less than 20 years of age in the 1990s to more than 30 years observed today (3,4). The prevention and treatment of solid malignancies are expected to further impact the survival and quality of life of these patients (5). While there are some studies on chemoprevention, with chronic treatment proposals such as quercetin or metformin (6,7), few therapeutic options are available beyond surgical resection once solid malignancies appear (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia–Related Head and Neck Cancer

Montanuy

Martínez-Barriocanal

Casado

et al. 2020

Clinical Cancer Research

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Purpose: Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in patients with Fanconi anemia.Experimental Design: We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify nongenotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied in vitro and in vivo for efficacy and safety.Results: Several FDA/European Medicines Agency (EMA)approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in Fanconi anemia HNSCC cell lines. The two best candidates, gefitinib and afatinib, EGFR inhibitors approved for non-small cell lung cancer (NSCLC), displayed nontumor/tumor IC 50 ratios of approximately 400 and approximately 100 times, respectively. Neither gefitinib nor afatinib activated the Fanconi anemia signaling pathway or induced chromosomal fragility in Fanconi anemia cell lines. Importantly, both drugs inhibited tumor growth in xenograft experiments in immunodeficient mice using two Fanconi anemia patientderived HNSCCs. Finally, in vivo toxicity studies in Fancadeficient mice showed that administration of gefitinib or afatinib was well-tolerated, displayed manageable side effects, no toxicity to bone marrow progenitors, and did not alter any hematologic parameters.Conclusions: Our data present a complete preclinical analysis and promising therapeutic line of the first FDA/EMA-approved anticancer drugs exerting cancer-specific toxicity for HNSCC in patients with Fanconi anemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia–Related Head and Neck Cancer

Montanuy

Martínez-Barriocanal

Casado

et al. 2020

Clinical Cancer Research

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“…At the second decade of life they will start to develop hematological malignancies, such as acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), with an accumulative incidence of up to 20% in the adulthood. Finally, from the third decade of life FA patients will develop solid tumors, especially head and neck squamous cell carcinoma with an accumulative incidence of more than 50% beyond their fourth decade of life [1].…”

Section: Introductionmentioning

confidence: 99%

“…There are currently 22 FA genes identified, forming a complex pathway that repairs stalled replication forks and inter-strand crosslinked lesions during the S-phase of the cell cycle. FANCA is the most frequently mutated gene accounting for up to 80% of all FA patients [1,2]. The pathophysiological effects of the lack of a functional FA/BRCA pathway include hypersensitivity to DNAdamaging agents or aldehydes (from alcohol consumption or cell metabolism), oxidative stress or overexpression of proinflammatory cytokines, such as TNF-α [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

High content drug screening for Fanconi anemia therapeutics

Montanuy

Camps-Fajol

Carreras‐Puigvert

et al. 2020

Orphanet J Rare Dis

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Background: Fanconi anemia is a rare disease clinically characterized by malformations, bone marrow failure and an increased risk of solid tumors and hematologic malignancies. The only therapies available are hematopoietic stem cell transplantation for bone marrow failure or leukemia, and surgical resection for solid tumors. Therefore, there is still an urgent need for new therapeutic options. With this aim, we developed a novel high-content cellbased screening assay to identify drugs with therapeutic potential in FA. Results: A TALEN-mediated FANCA-deficient U2OS cell line was stably transfected with YFP-FANCD2 fusion protein. These cells were unable to form fluorescent foci or to monoubiquitinate endogenous or exogenous FANCD2 upon DNA damage and were more sensitive to mitomycin C when compared to the parental wild type counterpart. FANCA correction by retroviral infection restored the cell line's ability to form FANCD2 foci and ubiquitinate FANCD2. The feasibility of this cell-based system was interrogated in a high content screening of 3802 compounds, including a Prestwick library of 1200 FDA-approved drugs. The potential hits identified were then individually tested for their ability to rescue FANCD2 foci and monoubiquitination, and chromosomal stability in the absence of FANCA. Conclusions: While, unfortunately, none of the compounds tested were able to restore cellular FANCA-deficiency, our study shows the potential capacity to screen large compound libraries in the context of Fanconi anemia therapeutics in an optimized and cost-effective platform.

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“…With improved hematopoietic stem cell transplant protocols, FA patient survival has increased, leading to a progressively increased number of solid malignancies in adult patients. Therapeutic research is currently focused in targeted therapies for solid tumors as well as in preventive options in the context of drug repurposing [31].…”

Section: Introductionmentioning

confidence: 99%

Exploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models

et al. 2019

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Background: In spite of the abundance of genomic data, predictive models that describe phenotypes as a function of gene expression or mutations are difficult to obtain because they are affected by the curse of dimensionality, given the disbalance between samples and candidate genes. And this is especially dramatic in scenarios in which the availability of samples is difficult, such as the case of rare diseases. Results: The application of multi-output regression machine learning methodologies to predict the potential effect of external proteins over the signaling circuits that trigger Fanconi anemia related cell functionalities, inferred with a mechanistic model, allowed us to detect over 20 potential therapeutic targets. Conclusions: The use of artificial intelligence methods for the prediction of potentially causal relationships between proteins of interest and cell activities related with disease-related phenotypes opens promising avenues for the systematic search of new targets in rare diseases.

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Therapeutic research in the crystal chromosome disease Fanconi anemia

Cited by 4 publications

References 51 publications

Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia–Related Head and Neck Cancer

Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia–Related Head and Neck Cancer

High content drug screening for Fanconi anemia therapeutics

Exploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models

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