Targeting Aurora Kinase to Enhance the Curative Potential of Radiotherapy in HPV Related Cancers

Abstract

Purpose/Objective(s): Cervical cancer is caused by human papilloma virus (HPV), a sexually transmitted environmental agent. Approximately 40% of cervical cancer patients treated with radio(chemo)therapy (RTCT) develop recurrence that can be difficult to treat. New approaches for overcoming treatment failures are needed. Alisertib is a clinically approved, oral selective inhibitor of Aurora kinase A (AurkA), which causes G2/M cell cycle arrest and apoptosis. High E7 oncogene expressing tumors and/or those carrying the ARID1A mutation are found in several disease sites, including cervix, and are more sensitive to AurkA inhibition. The goal is to identify a clinically relevant treatment strategy, using AurkA as a therapeutic target in patients, to advance curative combination treatments with RTCT for HPVE7 related cancers. We hypothesize Alisertib influences the sensitivity to RT to improve primary tumor response and reduce lymph nodal disease compared to RT or drug alone. The aims are: Aim 1: To determine the efficacy of fractionated RT combination with Alisertib in HPVE7/ARID1A expressing orthotopic cervical cancer PDXs on tumor growth delay response. Aim 2: To determine the effect on metastases development in response to AurkA inhibition with RT treatment. Materials/Methods: HPVE7 expression profiles of the cervix PDX models were determined by qRT-PCR. An orthotopic patient derived cervix cancer xenograft was treated with RT (30Gy;2Gy/day) with or without Alisertib (30mg/kg/day) given concurrently with RT daily (3wks). Expression of anti-apoptotic and DNA damage response proteins was evaluated by western blot at the end of treatment. Tumor growth delay and lymph node metastasis was/will be assessed. Results: The PDX HPV subtypes reflect the patient’s clinical HPV status at diagnosis. In an E7 expressing PDX model, RT combined with Alisertib treatment shows prolonged tumor growth delay compared with RT alone. Reduced lymph node metastasis was observed with Alisertib alone compared to control. These studies are still in progress. Tumors analyzed at end of treatment suggest that AurkA inhibition resulted in the loss of RT-induced anti-apoptotic expression and g-H2AX phosphorylation was enhanced by the combined treatment relative to RT alone. This suggests that Alisertib may reduce repair of DNA damage induced by RT treatment, which is consistent with its expected action on AurkA. Further investigation is ongoing to assess mechanisms underlying the RT induced effects with Alisertib on tumor response. Conclusion: Alisertib may enhance the curative potential of RT in patients with high E7 expressing cancers, and/or ARID1A mutations, which impacts on the sensitivity to treatment response. This study presents a promising approach to treating aggressive HPV cancers and may apply to other HPVrelated cancers where RT plays a curative role and supports successful translation of new radiation-drug combinations to the clinic.