Programs

Small Molecule Screens to Identify Inhibitors of the Human Papilloma Virus Oncoprotein E6 - YIA Interim Progress Report

Michael T. Spiotto, MD, PhD

Instructor, Department of Radiation Oncology, University of Chicago

2010 Young Investigator Award - 2011 Fall Interim Report

Dr. Spiottos’s long-term research goal is to improve the treatment of patients with virally induced
cancers. The Human Papillomavirus (HPV) oncogene E6 degrades and inhibits the tumor
suppressor p53 allowing cells to escape apoptosis (programmed cell death). He hypothesizes that
these E6 inhibitors will be specifically cytotoxic to HPV cancer cells while leaving the normal cells
of patients unharmed. Dr. Spiotto has developed a novel cell based reporter assay to detect the
interaction between E6 and p53.


The preliminary reporter system that Dr. Spiotto initially planned used E6 alone to degrade a
p53 reporter protein. However, when this system was constructed it did not provide a significant
separation in signal between the experimental and control cell populations that would be appropriate
for high throughput screening. Several revisions were made to arrive at a final novel protein
knockdown system that specifically monitors E6 mediated degradation of p53. Additionally, he
has implemented several means within this assay to increase the chance of finding a specific E6
inhibitor, such as optimizing the reporter screen to detect specific E6 inhibitors and selecting for cell
permeable compounds that are less likely to be toxic.


Using the reporter system described above, Dr. Spiotto conducted several screens for compounds
that inhibit the E6-p53 interaction. 77,570 compounds were screened, and 54 compounds were
selected for further testing. Dr. Spiotto will use the E6 specific inhibitors identified in the screen to
determine whether they can restore p53 levels in and inhibit growth of HPV-induced cancer cells
which could eventually translate into clinically useful adjuvant therapies. He is currently gathering
information on the candidate compounds to determine their specific toxicity levels and whether they
increase p53 expression levels in HPV cancer cells. Results of these efforts are expected in the next
few months.

Read the original Young Investigator Award Proposal