Research Update Winter 2020: Cancer, Fertility, Bone Marrow Failure

This report is an overview of research shared at the 2020 Fanconi Anemia Research Fund Scientific Symposium covering three main topics: solid tumors, fertility, and bone marrow failure.

Solid tumors

What is the issue and how does it affect people with FA?

Fanconi anemia (FA) is a DNA repair disease that leads to the development of squamous cell carcinoma (SCC). SCC of the head and neck and anogenital regions are the most common for people with FA as they reach adulthood. Current therapies used in the general population are toxic for people with FA; therefore, there is an urgent need for novel interventions that will safely prevent or treat SCC in this population.

What does current research in this field mean for people with FA?

Collectively, research presented in cancer sessions at the 2020 Scientific Symposium demonstrate four key areas that researchers are addressing to benefit people with FA:

  1. Understanding the natural history of FA cancer through genome sequencing of tumors and building patient registries focused on cancer;
  2. Cancer prevention using oral screening, brush biopsy of oral lesions, and liquid biopsies of plasma and saliva;
  3. Chemoprevention using compounds such as the antioxidant quercetin administered systemically, or tocilizumab (an immunosuppressive drug) delivered using Janus nanoparticles; and
  4. Targeted therapeutics of the specific pathways (PI3K and EGFR), and radiotherapy.

Overall, the research presented shows that we are beginning to understand the driving mechanisms of FA cancer and are identifying and testing potentially effective and safe therapies.

What are the next steps?

The next steps for FA cancer research are to create preclinical models that mimic the disease so that targeted therapies can be tested. Additionally, further characterization of individual FA tumors is necessary to identify targetable drivers of the disease. Lastly, cancer-focused clinical trials for people with FA are needed to test potential prevention and therapeutic modalities.


What is the issue and how does it affect people with FA?

In addition to progressive bone marrow failure and the high risk of developing squamous cell carcinoma of the head and neck and anogenital regions, patients with FA also experience reduced fertility. Females with FA may experience a variety of gynecologic issues, including structural abnormalities, delayed puberty, decreased fertility, early menopause, and a high risk of SCC of the lower genital tract. Males with FA may have numerous structural abnormalities of the reproductive system and extremely low sperm count that affect fertility. Compared to other more commonly studied aspects of FA, not much is known about infertility in people with FA. As more individuals with FA reach adulthood, there is a growing need to address the issue of fertility in this population.

What does current research in this field mean for people with FA?

Collectively, research shows that many FA investigators are pursuing fertility-related research on FA. Current research demonstrates the feasibility that fertility restoration may be possible for people with FA. Other studies highlight the functional role of the FA pathway in regulating fertility. Insight into these mechanisms may provide the framework for future therapies that can restore and repair FA-related defects in germ cells.

What are the next steps?

Future research will need to focus more on understanding the molecular role of the FA pathway in fertility and how issues presented by a faulty FA pathway can be treated to restore fertility in FA individuals.

Bone marrow failure mechanisms and clinical applications

What is the issue and how does it affect people with FA?

Individuals with FA often have progressive bone marrow failure (BMF); however, research has advanced clinical care of BMF and now patients with FA can successfully undergo curative hematopoietic cell transplants (HCT). Despite the success rates of HCT for FA patients, issues related to chronic graft-versus-host disease and secondary cancers from genotoxic treatments used during HCT need to be addressed. In addition, the progression to myelodysplastic syndrome (MDS) and leukemia has not been well defined.

What does current research in this field mean for people with FA?

Research shared at the Symposium demonstrates efforts focused on preventing, treating, and understanding the progression of bone marrow failure. Drugs that can prevent DNA damage in the hematopoietic compartment have the potential to prevent BMF and circumvent the need for hematopoietic cell transplants. Studies focused on understanding the progression of FA hematopoietic stem cells to MDS or acute myeloid leukemia (AML) can offer potential screening mechanisms for early detection and treatment. Research focused on improving HCTs by using nontoxic conditioning antibodies may lead to less toxic HCT procedures that have less risk of longer-term complications, graft-versus-host disease, and the development of solid tumors.

What are the next steps?

The next steps for bone marrow failure research fall into four categories:

  1. Identifying potential drug targets to prevent and treat bone marrow failure;
  2. Understanding the progression of MDS and AML;
  3. Nontoxic transplants using conditioning antibodies; and
  4. Gene therapy and editing.

Identifying potential drug targets will require continued preclinical work to demonstrate the efficacy of drug candidates. Newly identified compounds that pass testing in the preclinical stage will then need to be tested in clinical trials. Studies focused on understanding the genetic changes that lead to the progression of MDS and the development of AML will need to demonstrate efficacy in patient populations before clinical screening can be implemented routinely.

The antibody conditioning field will need to determine efficacy and safety in the FA patient population prior to the widespread implementation of this type of transplant. A clinical trial at Stanford is set to begin in 2021.

Gene therapy and editing are the final frontiers for treating bone marrow failure and the root cause of the genetic defects in FA patients. Gene editing is currently in the preclinical phase of research. Gene therapy clinical trials for people with FA are ongoing in both the United States and Spain, with more sites opening in the US and the United Kingdom.

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