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 Climate Impact Research in Hannover: Small Plants against Large Waves
17.08.2018 | Leibniz Universität Hannover

nachricht First transcription atlas of all wheat genes expands prospects for research and cultivation
17.08.2018 | Leibniz-Institut für Pflanzengenetik und Kulturpflanzenforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Color effects from transparent 3D-printed nanostructures

New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference

Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...

Im Focus: Unraveling the nature of 'whistlers' from space in the lab

A new study sheds light on how ultralow frequency radio waves and plasmas interact

Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

Im Focus: The “TRiC” to folding actin

Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.

Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

LaserForum 2018 deals with 3D production of components

17.08.2018 | Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

 
Latest News

Smallest transistor worldwide switches current with a single atom in solid electrolyte

17.08.2018 | Physics and Astronomy

Robots as Tools and Partners in Rehabilitation

17.08.2018 | Information Technology

Climate Impact Research in Hannover: Small Plants against Large Waves

17.08.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>