Preclinical Evaluation of Immunomodulatory Effects of Aurora Kinase Inhibition In Human Papillomavirus Positive Cancers

<p>Human papillomavirus (HPV) is the causative agent of cervical cancer and some cancers of the penis, vulva, vagina, anus, and oropharynx. Current therapies for these cancers include a combination of surgery, radiotherapy, and chemotherapy that often results in permanent, life altering adverse effects. Immunotherapy is partially effective, but with significant recurrence and lower long-term survival. Importantly, there are no few biomarker-selective targeted therapies for these cancers. To address this unmet need, our collaborators conducted a large-scale drug screen and identified Aurora Kinase (AK) inhibitors as a unique class of reagents to induce selective apoptosis in HPV+, but not HPV- human tumor cells in vitro and in vivo in HPV+ patient derived xenografts (PDX) mouse models. We hypothesized that Aurora kinase inhibition mediated HPV+ cancer cell apoptosis would lead to immunogenic cell death (ICD) that would promote antitumor efficacy of immune checkpoint therapy. The current investigation focused on the effectiveness of alisertib, an Aurora Kinase A inhibitor using preclinical mouse tumor models of HPV+ cancers (mEER, TC-1, and C3.43). In vitro, alisertib treatment when compared to the vehicle control, reduced the level of phospho-Aurora Kinase A confirming the targeted activity. We observed morphological changes to cells suggesting cell death that was confirmed via annexin V 7-AAD staining as apoptosis. Furthermore, western blot analyses revealed DNA damage, in terms of vii increased levels of γH2AX levels, and pyroptosis, in terms of increased levels of cleaved gasdermin E. Importantly, in both mouse and human HPV+ cancer cell lines treatment with alisertib, relative to vehicle control, resulted in significantly higher cell surface expression of calreticulin (CRT), and high mobility group box 1 protein (HMGB1) in the culture supernatants, both of which are markers for (ICD). Studies with the mEER tumor cells implanted in immunocompetent syngeneic mice showed partial in vivo efficacy of Aurora Kinase inhibition that when combined with immune checkpoint blockade using anti-CTLA-4 antibody, resulted in significant tumor growth reduction and a survival advantage. Thus, data from this investigation support the suitability of targeted Aurora kinase inhibition in combination immune therapeutic approaches for the clinical management of HPV+ cancers.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2023

Authors dc:creator

• Sinha, Pragya
• <p>https://orcid.org/0000-0001-5533-6423</p>

Contributors dc:contributor

• Jagannadha Sastry, Ph.D.
• Faye M. Johnson, M.D., Ph.D.
• Roza I. Nurieva, Ph.D.

• HPV
• immunology
• preclinical
• alisertib
• aurora kinase
• cancer
• Cancer Biology
• Immunotherapy

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1281

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2338