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

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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.