The Latest on FA Research

Research is the answer to one day making FA a treatable, manageable disease.

Here, you’ll discover the most recent strides in FA research and activities funded by FCF. Every quarter, we’ll bring you updates on newly funded grants, ongoing projects, and significant milestones.

None of this progress would be possible without the unwavering support of our generous donors, fundraisers, and passionate researchers. Join us in fueling this vital research by making a gift today.

Last updated: December 16, 2024

Projects Awarded in 2024

Oral Cavity Gene Therapy
Markus Grompe, MD
Oregon Health and Science University
$91,173

This supplemental funding builds on the groundwork laid by the 2022 grant awarded to Drs. Markus Grompe and Raymond Monnat, titled Oral Mucosal Gene Therapy as a Prevention for FA-Associated Cancers. The proposed research focuses on reducing the risk of squamous cell carcinoma (SCC) in individuals with Fanconi anemia (FA) by correcting the FA genetic defect in K14-positive basal stem cells, which are the origin of SCC.

People with FA are at much higher risk of developing SCC because their K14 basal stem cells in the squamous epithelium are particularly vulnerable. Gene therapy that corrects this genetic defect directly in these cells offers a potentially transformative approach to cancer prevention. This research seeks to determine if gene-corrected oral stem cells have a selective advantage, allowing healthy cells to outcompete those with mutations. The results will help assess the viability of targeted gene therapies for FA, advancing a new and highly promising strategy to reduce cancer risk in this population.

Small Molecule Screening in Fanconi Anemia Mice
Markus Grompe, MD
Oregon Health and Science University
$215,991

This supplemental funding builds on the work from the 2020 Fanconi Cancer Foundation grant awarded to Dr. Grompe, titled Chemoprevention of Cancer in Fanconi Anemia, and additional research supported by the Stand Up To Cancer head and neck cancer team in 2022. Chemoprevention studies are crucial because people with FA have an extremely high risk of developing squamous cell carcinoma (SCC), and standard cancer treatments are often too toxic for them. This project uses advanced animal models to identify compounds that may delay or prevent cancer from developing. It addresses a critical need in FA care by identifying chemopreventive agents that are both safe and effective for this vulnerable population. These findings will help lay the groundwork for future clinical trials, aiming to improve cancer prevention and treatment outcomes for people with FA.

Supplemental Funding: Development of In Utero Therapies for Fanconi Anemia
Agnieszka Czechowicz, MD
Stanford University
Additional Amount Funded: $50,000

Correcting FA mutations in all cells of the body may prevent issues such as bone marrow failure and cancer in people with FA. Since mutations in FA genes start during the gestational process, the ideal time to correct genes may be in utero. The goal of this study is to use laboratory-based experiments to determine whether gene editing in utero (during gestation) can correct FA gene variants in various tissues of the body.

Spatial Analysis of FA Tumors for Detection of Their Immune Repertoire and Potential Actionable Targets
Alfredo Rodríguez, PhD
National Autonomous University of Mexico
Amount Funded: $250,000

This newly funded research project aims to better understand the unique challenges Fanconi anemia (FA) patients face when it comes to developing squamous cell carcinoma (SCC). SCC tumors consist of various cell types, including cancer cells, immune cells, and other supportive cells. By studying how these cells interact, scientists hope to uncover new ways to treat cancer in FA patients, especially by boosting the body’s immune response. Using advanced technologies, the research team will analyze archived tumor samples to identify key markers that could lead to better diagnosis, personalized treatment, and new therapies, particularly immunotherapy, for FA patients with cancer.

Supplemental Funding: Development and Characterization of FA-HNSCC DX Models
Jennifer Grandis, MD; Daniel Johnson, PhD
University of California San Francisco
Amount Funded: $50,000

This project focuses on improving treatment options for young adults with Fanconi anemia (FA) who develop squamous cell carcinoma (SCC). Because FA patients have DNA repair defects, traditional cancer treatments that damage DNA can be harmful or ineffective. To address this, researchers are creating specialized preclinical models to find cancer therapies that do not rely on DNA damage. With additional funding, they plan to expand these models, develop new ones from metastatic cancer samples, and make them widely available to help identify safer and more effective treatments for FA patients.

Transforming Treatment of Inherited Bone Marrow Failure in Fanconi Anemia by Precise In Vivo Genome Editing
Paula Rio, Jacob Corn, Andrew Deans, Hans-Peter Kiem, Branden Moriarity, David Liu, Toni Cathomen
Instituto De Investigación Sanitaria Fundación Jiménez Díaz; Harvard University; Eth Zurich; St. Vincent’s Institute Fitzroy; Fred Hutchinson Cancer Center; University Of Minnesota; Medical Center – University Of Freiburg, Institute For Transfusion Medicine And Gene Therapy
Amount Funded: $1,258,190

FA is characterized by chromosomal abnormalities and increased susceptibility to cancer. Allogeneic bone marrow transplantation is currently the only treatment for bone marrow failure, but its use is limited by the need for a suitable donor and potential side effects.

Base and prime editing will be implemented to target frequent mutations described in individuals with FA and will be combined with optimized viral and non-viral delivery systems to target HSCs in vivo to provide a promising avenue for the treatment of this inherited bone marrow failure syndrome.

Progress update: The main goal of the project is to show that it is possible to correct blood stem cells directly in the body using gene editing. In the first phase of their work, researchers have fine-tuned various gene editing tools to effectively correct FA cells. They have also created the necessary models to test these gene editing and delivery methods. Since the grant began in February 2024, the team has accomplished the following:

• Has achieved high levels of editing in human HSCs.
• Received ethics approval to use prime editor derivatives to increase the potential for allele editing,
• Begun testing RNA delivery methods,
• Used digital editing technology to correct the Spanish founder FA mutation,
• Generated a humanized mutant mouse model that has reduced stem cell fraction, craniofacial developmental defects, and increased mitomycin sensitivity, and
• Has achieved high levels of editing in human HSCs.

Projects that Wrapped Up in 2024

Precision Therapy for FA and Human Papillomavirus (HPV)-Related Head and Neck Cancer
Agata Smogorzewska, MD, PhD; Barbara Burtness, MD; Markus Grompe, MD; Silvio Gutkind, PhD; Amanda Paulovich, MD, PhD; Alexander Pearson, MD, PhD; and Bing Zhang, PhD
The Rockefeller University, Yale University, Oregon Health and Science University, University of California San Diego, Fred Hutchinson Cancer Research Center, University of Chicago, and Baylor College of Medicine

Funded in 2021 in collaboration with Stand Up to Cancer, the Farrah Fawcett Foundation, the American Head and Neck Society, and the Head and Neck Cancer Alliance

The goal of the SU2C grant was to develop new approaches to address head and neck cancers, particularly cancers related to HPV and FA. Led by Fanconi Cancer Foundation (FCF) Scientific Advisory Board Members Dr. Agata Smogorzewska and Dr. Barbara Burtness, the team tested preventive and therapeutic strategies for head and neck cancer prevention in cellular and animal models of FA- and HPV-associated head and neck cancer. Key accomplishments during the study period included the following:

• Algorithms developed by Dr. Pearson’s lab are improving in classifying head and neck cancers in individuals with FA. 
• Onvansertib works well with dacomitinib and afatinib to slow the development of HPV positive HNSCC cells.
• Metformin and naproxen administered together more efficiently prevent cancer development in mouse oral mucosa than when administered separately.
• Chemoprevention studies have revealed that treatments using combinations of drugs significantly reduce the number of abnormal epithelial tongue lesions.
• A lack of ADH5 and other aldehyde detoxification enzymes led to poorer growth of FA-deficient cells, suggesting that enzyme activity may be needed to slow cancer development in individuals with FA.

Fanconi Anemia Associated Neurological Syndrome – A Search for a Cause with Advanced Technologies
Investigators: Prashanth Ramachandran, MBBS, BMedSci and Michael Wilson, MD, MAS
Institutions: University of Melbourne and University of California, San Francisco
Funded in 2022

The goals of Dr. Ramachandran and Dr. Wilson’s study were to describe a phenotype for Fanconi Associated Neurological Syndrome (FANS), profile the peripheral blood and cerebrospinal fluid (CSF) immune response in individuals with FANS, and detect possible inflammatory triggers. FANS is characterized by the development of brain lesions, with some individuals developing large pseudo-tumors. Dr. Ramachandran and Dr. Wilson recruited six individuals with FANS into their study. All six individuals consented to phenotyping, and three individuals consented to the collection of blood and CSF for further analysis. Dr. Ramachandran and Dr. Wilson’s overall findings suggested that thickening and leakage of the blood vessels in the blood and eyes is the primary driver of FANS development. All six individuals enrolled in this study developed retinal vasculopathy, which can result in the progressive loss of vision. These findings are significant for individuals with FANS because prior studies have failed to demonstrate clear causes of FANS development, and knowledge of the cause of FANS may help develop improved screening practices and treatments. 

Psychosocial Experiences of Adults with Fanconi Anemia: A Participatory Mixed-Methods Research Study
Kathleen Bogart, PhD, and Megan Voss, DNP
Oregon State University and University of Minnesota
Funded in 2022

Dr. Bogart and Dr. Voss conducted the first large study on mental health in adults with Fanconi anemia (FA), revealing high rates of PTSD, anxiety, and depression. Interviews with participants highlighted challenges like stigma, fertility issues, and bone marrow transplants, while positives included support from the FA community, overcoming transplant, and unique opportunities because of FA. A key finding was the need for more accessible mental health care, especially for underrepresented groups. The researchers recommend standardized mental health screenings and treatments for people with FA. You can learn more about their recommendations here.

Synthetic Lethal Approaches to Treatment of Fanconi Anemia (FA) Gene Mutant Head and Neck Cancer
Barbara Burtness, MD, and Gary Kupfer, MD
Yale University and Georgetown University
Funded in 2020

Dr. Burtness and Dr. Kupfer’s study aimed to achieve several objectives: first, they sought to pinpoint and confirm specific genetic mutations in a type of head and neck squamous cell carcinoma. Next, they aimed to create laboratory models of this cancer using samples that had the identified mutations. Finally, they tested different drugs to see if they could effectively target the vulnerabilities in these mutated cells.

Their research revealed two promising approaches for treating head and neck cancer with Fanconi gene defects. One approach involves using existing drugs, which are ready for immediate testing and could soon be used in clinical trials. The other approach focuses on developing a new drug that targets a previously unexplored biological pathway. Both strategies hold potential for improving treatment outcomes for individuals with Fanconi anemia who are at risk of developing head and neck cancer.

A Small Molecule Approach to Overcome Replication Dysfunction in FA
Sharon Cantor, PhD, and Peter Kurre, MD
University of Massachusetts Medical School and Children’s Hospital of Philadelphia
Funded in 2020

Dr. Cantor and Dr. Kurre’s study aimed to address bone marrow failure in individuals with FA by targeting the DNA replication issue underlying the condition. They developed a reliable method to assess DNA replication gaps, which are elevated in cells lacking the FA pathway. Using bone marrow from mice with specific FA gene deficiencies, they successfully expanded long-term hematopoietic stem cells (HSCs) in vitro, demonstrating their potential for transplantation. This discovery is significant because hematopoietic failure due to HSPC loss is a major cause of health problems and death in FA patients. The adapted protocol for this research is available upon request by contacting Dr. Cantor or Dr. Kurre via email. Sharon.Cantor@umassmed.edu and KURREP@chop.edu. 

Acetaldehyde Exposure and DNA Damage in the Oral Cavity of FA Patients Before and After the Consumption of a Low Alcohol Dose
Investigator: Silvia Balbo, PhD 
Institution: University of Minnesota
Funded in 2021

Dr. Balbo’s study initially aimed to see how one alcoholic drink affects DNA in the mouth of people with Fanconi anemia (FA) compared to those without FA. Due to recruitment challenged, the study shifted to examining DNA damage at baseline by collecting mouthwash samples and oral swabs from people with FA. The team collected oral cell DNA from five people with FA and analyzed these samples. They found certain DNA changes (called adducts) that appeared only in the FA samples and some that were more frequent in FA compared to controls. This research is important for people with FA because understanding harmful exposures can help them make healthier lifestyle choices.

Updates From Ongoing Projects

National Institutes of Health (NIH) Center Comprehensive Program for Natural History of Development of Squamous Cell Carcinoma in Fanconi Anemia
Neelam Giri, MD, and Sharon Savage, MD
National Institutes of Health
Funded in 2022

Dr. Giri and Dr. Savage’s study aims to establish a central facility for comprehensive screening of individuals with FA, tracking cancer development through detailed evaluations and biospecimen collection. With more than 70 enrolled participants, the study collaborates with other FA investigators to uncover genetic and immunological mechanisms underlying cancer susceptibility in FA, ultimately aiding in early detection and treatment strategies for this high-risk population. Dr. Giri and Dr. Savage’s team has also developed an additional collaboration with the Fanconi Associated Neurological Syndrome (FANS) researchers at the NIH to provide comprehensive care to individuals with FANS who are participants in the FA cancer screening study.

Cytology Based DNA Analysis to Investigate the Malignant Potential of Oral Lesions in Patients with Fanconi Anemia
Martial Guillaud, PhD, and Denise Laronde, PhD
BC Cancer
Funded in 2022

Dr. Guillaud and Dr. Laronde’s main goal is to create, test, and use a semi-automatic system that analyzes DNA from cell samples to check for abnormal chromosomes (aneuploidy) in people with FA who have oral cancer. Dr. Guillaud, Dr. Laronde, and their team have processed, stained, imaged, and analyzed 155 oral brush biopsy specimens and are collaborating with the NIH to review these samples. Dr. Guillaud and Dr. Laronde hope that identifying lesions in individuals with FA early, who have a high risk of developing cancer, will allow for earlier interventions and treatments, which will lead to improved survival outcomes among individuals with FA.

Oral Mucosal Gene Therapy as a Prevention for FA-Associated Cancers
Markus Grompe, MD, and Ray Monnat, MD
Oregon Health and Science University and University of Washington
Funded in 2022

Dr. Grompe and Dr. Monnat are developing advanced imaging techniques for studying mouth tissue in mice, improve methods for delivering genes into the mouth of mice with FA, and investigate whether fixing FA-related gene defects in mouth cells provides an advantage. They found that a certain type of genetic material can effectively enter mouth cells and that a specific gene plays a role in the development of mouth cancer in mice with FA. Their work could lead to better ways of detecting early mouth cancers in both mice and humans with FA, and might eventually open the door for gene therapy trials to treat FA-related mouth problems.

Building Collaborative Partnerships to Understand Fanconi Anemia Tumor Pathogenesis, Prevention, and Treatment
Agata Smogorzewska, MD, PhD
The Rockefeller University
Funded in 2022

Dr. Smogorzewska’s study aims to unite stakeholders in the FA cancer consortium, expand clinical partnerships, establish a data-sharing platform, and create patient-derived models for research. They’ve identified a potential marker for pre-malignant oral lesions in FA individuals and are working to validate it further. Collaborating with various institutions, their research seeks to improve treatments for FA by involving patients, families, physicians, and researchers.

Development of In Utero Therapies for Fanconi Anemia
Investigator: Agnieszka Czechowicz, MD, PhD 
Institution: Stanford University
Funded in 2023

The goal of Dr. Czechowicz’s project is to develop the first in utero therapy for FA. Dr. Czechowicz and her team have successfully performed in utero hematopoietic stem cell transplantation (IUHSCT) in their mouse model. The mouse model that Dr. Czechowicz’s team developed has been able to engraft the donor cells more strongly compared to other heterozygous and wild type mice that also received IUHSCT. This study is significant for individuals with FA because IUHSCT may be a safe and curative prenatal treatment for the hematopoietic component of FA, which would prevent individuals with FA from developing bone marrow failure before they are born. If individuals with FA do not develop bone marrow failure, then they will not need to receive any toxic therapies to treat their bone marrow failure.

AFAN Trial: Phase Ib/II Study to Investigate the Safety and Efficacy of Afatinib When Administered as Therapy in Fanconi Anemia Patients with Unresectable and/or Metastatic Locoregionally Advanced Squamous Cell Carcinoma of the Oral Cavity, Oropharynx, Hypopharynx, or Larynx
Investigator: Ramon Garcia-Escudero, PhD and Jordi Surrallés, PhD
Institution: Institut de Recerca de l’Hospital de Sant Pau
Funded in 2023

The goal of Dr. Garcia-Escudero and Dr. Surrallés’ clinical trial is to examine the efficacy and safety of the drug Afatinib after it is administered to individuals with FA who have metastatic advanced squamous cell carcinoma (SCC) of the oral cavity region. Dr. Garcia-Escudero and Dr. Surrallés have created the final protocol for this clinical trial and have signed the agreement between the Afatinib manufacturer, Boehringer Ingelheim, to package and distribute Afatinib to the trial recruiting centers in Spain and Germany. This clinical trial is significant for individuals with FA because the first drugs could be developed to specifically treat FA head and neck squamous cell carcinoma (HNSCC), which would allow for individuals with FA to be treated for HNSCC without toxic medications and ultimately improve their quality of life. 

Fanconi Anemia Antibody Project and Fanconi Anemia Research Materials Program
Investigators: Markus Grompe, MD and Leslie Wakefield 
Institution: Oregon Health and Science University
Funded in 2023

The goal of the Fanconi Anemia Research Materials (FARM) program is to maintain and distribute established Fanconi-related cell lines and antibodies to the FA research community. In 2023, Dr. Grompe and Ms. Wakefield distributed approximately 50 FA cell lines, HNSCC cell lines, and antibodies to FA researchers who have requested materials as part of this program. They have continued to improve the FARM’s website and datasheets and recently added animal models to the FARM’s offerings. The FARM will help individuals with FA by making FA materials available to researchers around the world, which will help researchers to pursue better treatments for FA and FA-associated cancers. 

Reducing the Burden of SCC in FA/Health Literacy Initiative: Cancer Awareness Team
Investigators: Christine Krieg and Eunike Velleuer-Carlberg, MD 
Institutions: Heinrich-Heine-University and German Fanconi Anemia Family Support Group and Research Fund
Funded in 2023

The goal of the Cancer Awareness Team’s work is to advance and improve cancer prevention, detection, and treatment for individuals with FA and to provide education and resources that allow individuals with FA to make informed decisions about their health. Dr. Velleuer-Carlberg and Ms. Krieg have developed oral care educational programs for individuals with FA and medical professionals, translated existing oral screening teaching materials, partnered with individuals with FA to improve their clinical care trajectory, and facilitated international partnerships for the development of the Fanconi Research Initiative for Education, Networking, and Data Sharing (FRIENDS). The Cancer Awareness Team’s work will help individuals with FA by empowering them to perform regular oral mouth self-examinations and engage in general cancer screenings. 

Fanconi Anemia Cancer Cell Line Resource Project
Investigator: Raymond Monnat, MD
Institution: University of Washington
Funded in 2018

Dr. Monnat’s grant aims to create pairs of head and neck squamous cell carcinoma (HNSCC) cell lines, one set with Fanconi anemia (FA) and one set without, for comparison. These cell lines have been successfully developed and documented in a manuscript submitted to Cancer Research, which can be viewed here. The remaining grant funds are being used to expand and ship these cell line stocks to the FARM at Oregon Health and Science University and to maintain the original stocks and their derivatives. This will help ensure the availability of these cell lines for further research.

Modeling Environmental Responses of Fanconi Anemia Epithelial Stem and Progenitor Cells to Prevent Squamous Cell Carcinoma
Investigators: Hiroshi Nakagawa, MD, PhD and Kenneth Weinberg, MD
Institutions: Columbia University and Stanford University
Funded in 2022

Dr. Nakagawa and Dr. Weinberg’s grant aims to understand how FA epithelial stem and progenitor cells develop into squamous cell carcinomas (SCCs) using mouse models and lab-grown organoid models. They have confirmed abnormal cell development in their mouse model and performed single-cell RNA sequencing on the mouse’s esophageal tissue. They identified two unique cell groups: one containing FA-SCC stem cells and another containing FA-SCC epithelial cells found in mice showing early signs of cancer. This research is important for the FA community because it provides new models to develop preventive cancer treatments, which were previously unavailable. Early results suggest that delaying cancer in people with FA is possible, paving the way for new drug therapies to prevent FA-SCC.

Development and Characterization of FA-HNSCC PDX Models
Jennifer R. Grandis, MD and Daniel E. Johnson, PhD
University of California, San Francisco
Funded in 2022

Dr. Grandis and Dr. Johnson’s study aims to create and study lab models (called PDX models) of head and neck cancer in people with Fanconi anemia (FA). They compare the genetic makeup of these models with the original tumors and test how they respond to cancer treatments. So far, they have created three PDX models and shared them with other researchers. One of these models has shown a rare ability to spread (metastasize). This research is important because it provides the first PDX lab models of FA-related head and neck cancer, helping to find better treatments.

Updates on Other Research Initiatives

Data Commons Initiative (aka FRIENDS)

The FRIENDS initiative, the Fanconi Research Initiative for Education, Networking, and Data Sharing, has launched to foster collaboration in the FA community, highlighted by recent meetings to establish a data commons. Together with our partners Data for the Common Good, these efforts aim to pool global expertise and data to address various scientific priorities, including:

• Cancer
• Fertility
• Bone marrow failure
• Psychosocial research
• Breakage analysis and diagnosis
• Environmental exposures
• Developmental abnormalities
• Family history
• Demographics
• Community engagement
• Genetics
• Dietary history
• Fanconi Associated Neurological Syndrome (FANS)

On September 22, 2024, a Memorandum of Understanding (MOU) ceremonial signing party took place at the annual FCF Scientific Symposium and Adult Retreat in Charlotte, North Carolina. Twenty-nine individuals representing 13 countries gathered to sign the first page of the MOU as a ceremonial celebration of the work to-date and to discuss next steps.

Since the Scientific Symposium and Adult Retreat, FCF and Data for the Common Good have been working on the following tasks:

• Have been holding discussions with the NIH and the Rockefeller University regarding a pilot for FRIENDS data linkage
• Begun populating the FRIENDS Executive Committee, 
• Held data dictionary working group meetings for the cancer genomics and genetics working groups, and

If you are interested in participating in the data dictionary working groups, please email us.

Scientists, families, patients, and advocates are encouraged to contribute to this collaborative effort by us at info@fanconi.org

2024 Scientific Symposium

If you are interested in learning more about this year’s Scientific Symposium, you can read the following articles on FCF’s website:

• Recap of the 36th Annual Fanconi Anemia Scientific Symposium and Adult Retreat 
• FA Adult Retreat and Scientific Symposium: A Homecoming for Patients, Families and Researchers

Fanconi Anemia Neurological Syndrome (FANS)

The FANS board convened for the first time on March 8th, where Dr. Prashanth Ramachandran shared updates on his ongoing research supported by an FCF grant. Collaborating with Dr. MoY Fiesco-Roa and Dr. Eunike Velleuer-Carlberg, Dr. Ramachandran’s team has recruited six individuals with FANS and is developing a database to consolidate data from FANS cases worldwide, with the aim of integrating it into the FRIENDS initiative.

Charting a Path Forward for FA Cancer Prevention Trials

On Friday, April 12, more than 60 participants, including those with FA, researchers, clinicians, and family members, participated in a virtual meeting focused on planning FA cancer prevention clinical trials. The goal was to review existing data and agree on the next steps for launching a collaborative chemoprevention trial across multiple institutions.