Community News

Key Takeaways from the 30th Scientific Symposium

Jan 15th, 2019

​One of FARF’s guiding principles is to gather the best researchers and clinicians in the FA community every year to share updates in research and care. In late 2018, we held the 30th Fanconi Anemia Scientific Symposium in Newport Beach, CA. Forty-six presenters gave talks and a record 60 people presented posters. Presentations addressed a number of topics relevant to the understanding or treatment of Fanconi anemia. Topics included rare disease drug development, the FA pathway, gene editing and gene therapy, hematopoietic stem cell biology, and an entire day of cancer in FA. Here are the main takeaways from the sessions.

Cancer in FA:

  • Early detection using brush biopsy can detect the development of cancer.
  • When an FA patient does have a tumor, the earlier the surgery is performed, the better the outcome, indicating the need for early surveillance measures. Basic monitoring now is done by doing a visual oral exam (once every two to three months in at-risk FA populations).
  • Next generation sequencing will be necessary to identify genomic signatures (changes in genes) of FA patients and will enable us to define what drugs can be used for precision medicine.
  • There is a higher risk of cancer in FA patients with graft-versus-host disease (GvHD).
  • At this point, we need to treat FA patients as we would non-FA head and neck squamous cell (HNSCC) patients.
  • Preclinical model development for FA squamous cell carcinoma will help identify pathways and mechanisms that can be targeted clinically. Development of FA HNSCC cell lines will aid in identifying mechanisms of cancer development and provide an avenue to test drugs in a preclinical setting for efficacy and toxicity.
  • Machine learning to expand knowledge of connections between phenotype and genotype will aid in predicting disease phenotypes for FA patients.
  • Researchers are looking at changes in chromosomes in tumors. Changes in chromosomes can lead to having genes in the wrong place, which can increase the chance of getting cancer.
  • Prevention measures are not enough to combat the prevalence of HNSCC tumors, even in the general population. We also need to develop treatments.
  • Currently, surgery is the best option for treating solid tumors in FA patients, but radiation therapy can be used in some cases. Certain people are more sensitive to radiation, so this kind of therapy has to be evaluated on an individual basis.
  • There is an impressive number of potential FA cancer drugs that are in pre-clinical testing:
  1. Gefinitib and afatinib are already FDA-approved for other cancer types
  2. Alda-1 (activates ALDH2)
  3. Glycosphingolipid modulators that block ganglioside accumulation
  4. JP-4 (protects normal tissue from radiation killing in FA models)
  5. Kinase inhibitors for HNSCC (Wee1-like kinase inhibitor)
  6. Small molecules to activate the FA pathway
  7. Clinical testing of FA chemoprevention: Quercetin has a strong safety profile and reduced DNA damage in oral brushings from patients with FA

Our focus is on: (1) profiling FA tumor samples to identify key pathways and genomic signatures; (2) developing models that mimic FA SCC to determine efficacy of targeted therapies and natural history of cancer disease state in individuals with FA; (3) developing noninvasive screening methods for precancerous lesions; (4) developing models for precision medicine to target multiple pathways using new drugs or FDA-approved drugs.

HNSCC Panel Drs. John Wagner, Ruud Brakenhoff, Joel Greenberger, and Carter van Waes during the panel on head and neck cancer in FA

Hematopoietic Stem Cell (HSC) Biology

  • Researchers have created stem cells from other cells in the body. They’re making progress to characterize the stem cells to see what potential they could have in FA. It would be better to treat a patient with his/her own stem cells than a donor source, which can lead to complications.
  • The future of safe bone marrow transplant conditioning for high HSC engraftment may be antibodies that target host stem cells, which successfully clear bone marrow of defective stem cells withoutuse of harmful conditioning agents.
  • Metformin improves hematopoiesis in mice and is associated with decreased risk of solid tumors in humans. The goal of a current FARF-funded clinical trial of metformin is to test tolerability of the drug in FA patients and investigate the biologic effects of the drug.
  • Many researchers are looking at blocking certain proteins to see if that blockage will increase bone marrow function. Some of these proteins include:
  1. LNK: increases HSC replication stress, DNA damage, and genome instability
  2. P38MAPK increases overall fitness and function of FA HSPCs
  3. TGF-beta increases stem cell defects, so the inhibitor AVID200 is promising and safe for chronic treatment

Our focus is on: (1) Identifying whether targeted antibodies can eliminate the need for toxic conditioning regimens; (2) continuing to create stem cells developed from other cells in the body to reduce complications from donor cells; (3) continuing with preclinical testing of targeted inhibitors (AVID200 or LNK inhibitor) to determine if they can improve stem cell growth.

FA Pathway Functions

The FA pathway is necessary for DNA repair. People with FA do not have a functional pathway. Researchers are investigating whether blocking or activating proteins in this pathway (including those that are not FA genes) could reduce some of the detrimental effects seen in FA patients. The goal is to develop drugs to target these proteins.

Our focus is on: (1) Continuing to dissect the FA pathway in a comprehensive manner to develop a better understanding of all the players and their mechanistic relationships; (2) Using the knowledge of these interactions (or lack thereof) to identify future small molecule inhibitors that can either activate the pathway in the absence of key proteins, or block the pathway in key areas that could lead to therapeutic benefit for FA patients.

FA Gene Therapy

  • The clinical FANCA gene therapy trial in Seattle did not demonstrate that patients had gene-modified cells 1.5 years after patients received corrected cells.
  • Conversely, the clinical FANCA gene therapy trial in Spain did show expansion of gene-corrected cells up to two years after patients received corrected cells.
  • A new FA gene was discovered: FANCY, bringing the total number of FA genes to 23.
  • FARF is funding two studies that have identified the need for a functional FA pathway for gene editing. Researchers are currently looking at ways to make gene editing effective for people with FA.

Focus is on: (1) Rocket Pharma is launching a multi-institutional, international gene therapy trial for FANCA patients; (2) Continuing to identify whether gene editing is an approach that can be used in FA cells.