Protecting spermatogonial stem cells from chemotherapy-induced damage for fertility preservation in childhood cancer

Childhood cancer rates have increased dramatically (38% since 1960) over recent decades and currently 1 in 500 adults (~35000 in UK) is a survivor of childhood cancer. The increasing incidence, coupled with remarkable improvements in cure rates (>80% 5-year survival), have resulted in an increase in young adults experiencing subsequent health effects of their cancer treatment. Ensuring long-term health of this new and expanding patient cohort is one of the most pressing areas of clinical need in paediatric oncology. Infertility occurs in the majority of males receiving high-dose chemotherapy with drugs known as alkylating agents. Alkylating agents are used commonly in childhood cancer and increasingly for stem cell transplant in non-malignant disorders. Unlike the situation in men, semen cryopreservation is not an option to preserve fertility in these boys as their testicles are not capable of making sperm in childhood. As a result, there is currently no established clinical option to prevent infertility in prepubertal boys receiving chemotherapy.

Preservation of fertility in children receiving cancer treatment is dependent on survival of the spermatogonial stem cells (SSC) in the testicle. These stem cells will generate sperm in males after puberty. Experimental approaches for fertility preservation in children undergoing cancer treatment could include taking a biopsy of the testicle before the patient receives their treatment and storing it for future use to restore fertility, although no methods to restore fertility using this approach have been developed so far. In addition, this requires invasive surgery, may carry a risk of re-introducing malignant cells and may require artificial reproductive techniques to restore fertility. Therefore, developing strategies to protect the testicles during chemotherapy treatment would represent a major advance for the clinical care of children with cancer.

The aim of this project is to understand more about the SSCs in the prepubertal human testicle and how they are affected by chemotherapy. We will determine how the chemotherapy agents enter the SSC and how this causes the cell to die. The potential for recovery of the SSC population over time following chemotherapy treatment will also be determined. Having established the mechanisms that make SSC sensitive to chemotherapy, we will develop and test drugs that can protect the SSC and allow them to survive chemotherapy. These drugs could potentially be given to the patient at the time of their chemotherapy to preserve future fertility. We have developed experimental approaches that allow us to test the effects of chemotherapy exposure on the prepubertal human testicle using tissue obtained from boys with cancer prior to receiving cancer treatment. We can combine the exposure to chemotherapy with an additional drug from a wide-range of known and newly developed drugs to identify those that protect the SSC from the chemotherapy damage. Identification of such 'chemo-protective' agents would then be taken forward into future clinical trials aimed at preserving fertility in children with cancer.

We anticipate that this project will be an important step towards development of treatments that will preserve fertility in boys receiving chemotherapy treatment.

Childhood cancer is increasing in incidence and whilst survival rates have improved, managing the long-term effects of cancer treatment has become a significant health and economic burden worldwide. This project will have impact on a wide-range of beneficiaries.

Patient Impact
Our research will have impact over the short-term for the growing number of male patients undergoing cancer treatment. This will include enhanced understanding of how their cancer treatment can damage the stem cells that are responsible for making sperm in the testis. This information will inform patients on the likely effects of their treatment on future fertility and will also assist with joint decision-making along with clinicians with regard to potential clinical cryopreservation and storage of testicular tissue prior to treatment. Over the long-term the project will provide direct patient benefit by providing the foundation for development of clinical strategies to preserve future reproductive function in males at risk of infertility.

Clinical and Health Policy Impact
The project will have impact over the short-term for clinicians in the UK and worldwide by providing an evidence base for clinical guidelines relating to fertility preservation in males. This will enhance clinical decision-making regarding patient selection criteria for cryopreservation of testicular tissue prior to treatment. In the long-term, the project will lead to clinical strategies to protect the testis from damage by chemotherapy and lead to preservation of fertility in patients who are currently rendered infertile by their treatment. The project will impact on local, national and international governmental health policy-makers by providing the evidence on which to base the development of clinical guidelines as well as recommendations regarding the provision of clinical fertility preservation services for patients.

Academic Impact
Short-term impact within the academic community will result from a detailed understanding of the mechanisms involved in stem cell biology in the testis and how this can be impacted by cancer treatment. Refinement of experimental models for human testicular development will provide technological advance that will impact the fields of reproductive biology, stem cell research and regenerative medicine. Long-term benefits will involve manipulating the stem cell environment of the testis (and potentially other stem cell systems) to protect stem cells from damage. I am committed to openness and therefore academic benefit will be enhanced by ensuring that data and resources generated (including publications, datasets and model systems) from the project are open-access and freely available through publically accessible websites and repositories.

Commercial Impact
Economic benefits to spin-out companies and industrial partners can be achieved through identification of mechanisms that could be exploited to develop novel drugs aimed at limiting the effects of treatment on fertility. This will include partnering with Edinburgh Innovations to facilitate links between the University and commercial sector to maximise economic and health impacts. The project may also have a wider applicability and vastly enhanced impact in terms of potential for generating therapeutics that could protect other healthy stem cells and tissues from damage induced by conventional and newer cancer treatments.

Public Impact
We will build on our extensive recent public engagement activities (see Pathways to Impact) by disseminating our research activities to a general public audience and also by specifically targeting cancer charities (e.g. Teenage Cancer Trust), including those with which we are currently partnered (e.g. Children with Cancer UK). This will raise public awareness and generate future funding to address the challenges relating to childhood cancer treatment.