Williams, Luke Robert; (2021) CDC like kinase 3 regulation of human papillomavirus oncogene expression. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Human papillomaviruses (HPVs) are the cause of cancers at several anatomical sites and are responsible for 5% of the worldwide cancer burden. In recent years, prophylactic vaccines have been introduced against the common high-risk HPV subtypes. Although these vaccines will reduce the future disease burden of HPVrelated cancers, due to a latency period from initial infection to development of a malignancy and due to individuals who are un-immunised, there will remain a significant number of patients who will develop cancers as a result of HPV that will require treatment. The current standard of care for the treatment of HPV-associated cancers is a combination of surgery, radiotherapy and chemotherapy leading to significant morbidity for survivors. Despite the introduction of HPV vaccines there will continue to be a significant number of cases of HPV-associated cancer and there will remain cases of recurrent disease where the established treatment modalities have failed, therefore there is an urgent need to identify alternative therapeutic strategies to ameliorate the significant morbidity associated with current therapies for HPV-driven cancer. Kinases are a diverse group of enzymes that play critical roles in the maintenance of a healthy, normally functioning cell. In recent years, a number of very successful treatments targeting kinases that are critical for the survival of cancer cells have been introduced into clinical practice. These targeted therapies have transformed the way in which some cancers are treated. An example is imatinib used to treat chronic myelogenous leukaemia. Treatment with imatinib can be so effective that the life expectancy of patients with chronic myelogenous leukaemia can be normal and comparable to those without the disease. The survival of HPV driven cancers is dependent on the continued presence of two viral proteins named E6 and E7. Under certain conditions in HPV-infected cells the E6 and E7 proteins disrupt normal cellular processes resulting immortality of cells and establishment of a cancer. Kinases that are critical to the pathways that are necessary for continuous production of the HPV E6 and E7 proteins and survival of HPV-driven cancers may make attractive novel therapeutic targets. This thesis identifies a kinase, CLK3 as a potential novel target for HPV-driven cancer. Disruption of CLK3 function in HPV-positive cancer cells results in decreased production of the viral E6 and E7 proteins and is associated with a significant loss of cancer cell viability suggesting that inhibiting CLK3 may be an effective treatment for HPV-driven malignancy. The work presented also shows how this loss of cell viability is achieved, namely by inducing a state of irreversible cell growth arrest called senescence. Additionally, this work has identified a novel function for CLK3, namely as a regulator of gene transcription rather than gene splicing which is the currently only known function of CLK3. Ultimately this thesis presents proof of concept that targeting CLK3 may be an effective treatment for HPV-driven cancers and forms the basis for future work to develop specific CLK3 inhibitors for potential use in clinical practise.

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