Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Small Molecular Bodyguards Kill HPV-Infected Cancer Cells by Protecting Tumor-Suppressing Protein

27.04.2012
Researchers at The Wistar Institute announce the discovery of small molecules that kill cancer cells caused by infection with human papillomavirus (HPV). Their results, in both cell and mouse models, demonstrate that the small molecule inhibitors protect a tumor-suppressing protein targeted by viral proteins, thus killing the infected tumor cells.
The Wistar scientists presented their findings in the April 20 issue of the journal Chemistry & Biology. The researchers believe that, with further testing and refinement, their inhibitors could provide a therapeutic for HPV-caused tumors, such as those seen in cervical cancer.

“While there is an effective vaccine for preventing HPV infection, there is currently no therapeutic that specifically targets cancers caused by the virus,” said Ronen Marmorstein, Ph.D., senior author, Hilary Koprowski, M.D. Professor, and leader of The Wistar Institute Cancer Center’s Gene Expression and Regulation program.

“HPV often turns cells cancerous for the virus’s own reproductive advantage, and we have found a class of small molecules that effectively prevents a key HPV protein from allowing cells to become cancerous,” Marmorstein said. “We think that this could be the start of an effective drug strategy for cancers caused by HPV.”

HPV is one of the primary infectious causes of cancer, responsible for most cases of cervical cancer, nearly 20 percent of all head and neck cancers, and has been implicated in cancers of the vagina, penis, and anus. American Cancer Society statistics estimate that over 4,000 women will die this year from cervical cancer alone.

The US Centers for Disease Control estimates that about 50 percent of sexually active men and women will be infected with HPV at one point in their lives. While most infected people will naturally fight off the infection, the virus frequently becomes “latent,” residing within the body for decades at a time. When HPV re-emerges from its latent state, it may cause host cells to become cancerous as the virus replicates.
According to Marmorstein, research has shown that the HPV protein, E7, targets an important tumor-suppressing protein called the retinoblastoma protein (pRb). When E7 binds to pRb, it disturbs the normal process of cell division, allowing the cells to grow out of control and unhindered and thus become cancerous.

In this latest study, the Wistar researchers describe the results of an exhaustive search for potential small molecule drug candidates to prevent E7 from binding to pRb. They screened a library of over 88,000 molecular compounds to find a class of small molecules that can prevent HPV-E7 from disabling pRb. Surprisingly, these inhibitors work by binding to pRb itself, yet do not seem to keep pRb from doing its normal job within the cell.

“Typically, you would think that an inhibitor would bind to the disease-causing ‘bad’ protein, in this case HPV-E7, but instead the inhibitor latches onto pRb itself,” Marmorstein said. “In any event, these inhibitors bind to the same spot on pRb that E7 clamps onto in order to disable pRb.”

Once attached to pRb, these inhibitors allow pRb to trigger the molecular mechanisms of normal cell division without the disruptive effect of E7 upon HPV infection.

In subsequent studies, conducted with Wistar Associate Professor Joseph Kissil, Ph.D., of Wistar’s Molecular and Cellular Oncogenesis program, one of these small molecular bodyguards proved effective in killing HPV-positive cells in mice.

“With this new class of inhibitors, we have a promising scaffold on which we can build therapies to treat HPV-related diseases,” Marmorstein said.

The Marmorstein laboratory is currently involved in additional research towards developing inhibitors that block the ability of another key HPV protein called E6 to inactivate another important tumor suppressor protein called p53, a protein that is inactivated in the majority of human cancers. In addition, refinement of the HPV-E7 inhibitors is continuing. Their work will involve gaining a better molecular understanding of how their HPV-E7 inhibitors bind to pRb, which will enable them to make more informed decisions on how to best refine the inhibitors so that they are both more effective and suitable for human use.

Funding for this project was through the National Institutes of Health’s National Cancer Institute.

The lead author of this study is Daniela Fera, a graduate student working at the Wistar Institute from the University of Pennsylvania Department of Chemistry. Other co-authors of this study include, David C. Schultz, Ph.D., Santosh Hodawadekar, Ph.D., and Scott Troutman from The Wistar Institute; Donna M. Huryn, Ph.D., and Jason Melvin from the University of Pennsylvania’s Department of Chemistry; and Melvin Reichman, Ph.D., and Preston Scott Donover, from the Chemical Genomics Center at The Lankenau Institute for Medical Research.

Contact: Greg Lester, 215-898-3943

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today’s Discoveries – Tomorrow’s Cures. On the web at www.wistar.org.

Greg Lester | EurekAlert!
Further information:
http://www.wistar.org

More articles from Life Sciences:

nachricht Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH

nachricht Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Helmholtz International Fellow Award for Sarah Amalia Teichmann

20.01.2017 | Awards Funding

An innovative high-performance material: biofibers made from green lacewing silk

20.01.2017 | Materials Sciences

Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery

20.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>