Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New combination treatment strategy to 'checkmate' glioblastoma

11.05.2015

Three different classes of anti-cancer drugs work synergistically against brain tumors

Therapies that specifically target mutations in a person's cancer have been much-heralded in recent years, yet cancer cells often find a way around them. To address this, researchers at University of California, San Diego School of Medicine and Moores Cancer Center identified a promising combinatorial approach to treating glioblastomas, the most common form of primary brain cancer.


This image showsn normal cell dividing (left) and stressed cancer cell dividing (right). PLK1 inhibitors stress cancer cells, making them easier to kill.

Credit: UC San Diego Health System

The study, published May 5 by Oncotarget, demonstrates that a mouse model of glioblastoma and human glioblastoma tissue removed from patients and cultured in the lab can be effectively treated by combining three classes of anti-cancer drugs: a drug that targets a cancer mutation in the Epidermal Growth Factor Receptor (EGFR) gene, a drug that increases stress in cancer cells and a drug that damages cancer cell DNA.

"Developing therapies against glioblastoma is like a chess game. For each therapy administered, or move, by the physician, the cancer makes a counter-move," said senior author Clark Chen, MD, PhD, associate professor of neurosurgery and vice-chair of Research and Academic Development at UC San Diego.

In up to 50 percent of glioblastomas, mutations in the EGFR gene render cancer cells insensitive to growth regulation by environmental cues, allowing them to grow uncontrollably. Yet highly specific EGFR inhibitors are not particularly effective against glioblastomas with EGFR mutations.

"When glioblastoma cells are treated with EGFR inhibitors, they turn on another receptor to bypass the need for EGFR," said Chen. "Any hope of an effective treatment requires a combination of moves strategically designed for a checkmate."

To develop such a strategy, Chen and his group turned to PLK1, a protein that regulates stress levels within glioblastoma cells and is essential for their survival. Chen and his group found that glioblastoma cells that developed resistance to EGFR inhibitors remain universally dependent on this protein.

In mouse models of glioblastoma and in explants of human glioblastoma, singular treatment with an EGFR inhibitor, a PLK1 inhibitor or the current standard of care drug (a DNA-damaging agent), each temporarily halted glioblastoma growth. But, like the human disease, the tumor eventually grew back. However, no detectable tumor recurrence was observed when a combination of all three classes of drugs was administered. The treated mice tolerated this combination regimen without showing significant side-effects.

"It is often assumed that if we find the cancer-causing mutation and inhibit the function of that mutation, we will be able to cure cancer," said study co-author Bob S. Carter, MD, PhD, chief of neurosurgery at UC San Diego. "Our study demonstrates that the reality is far more complex. Our results provide a blueprint for how to leverage fundamental biologic concepts to tackle this challenging complexity."

The three drugs administered to mice in this study were: BI2536, a PLK1 inhibitor; Gefitnib, an EGFR inhibitor; and TMZ, the standard-of-care chemotherapy for glioblastoma. The study authors note that while the safety or side effects of treating human patients will all three drugs is unknown, all are individually well-tolerated in humans. The clinical safety profiles of Gefitinib and TMZ are well-established for glioblastoma patients and PLK1 inhibitors have so far been well-tolerated in clinical trials (one has advanced to Phase III clinical trials for acute myeloid leukemia).

###

Co-authors of this study include Ying Shen, UC San Diego and Shanghai Jiao Tong University; Jie Li, Diahnn Futalan, Tyler Steed, Jeffrey M Treiber, and Zack Taich, UC San Diego; Masayuki Nitta, Dana-Farber Cancer Institute; Deanna Stevens, Jill Wykosky, Frank B. Furnari, Webster K. Cavenee, and Arshad Desai, UC San Diego and Ludwig Cancer Research; Hong-Zhuan Chen, Shanghai Jiao Tong University; Oren J. Becher, Duke University Medical Center; Richard Kennedy, Queen's University of Belfast; Fumiko Esashi, University of Oxford; and Jann N. Sarkaria, Mayo Clinic.

This research was funded, in part, by the Sontag Foundation, Burroughs Wellcome Foundation, Kimmel Foundation, Doris Duke Foundation and Forbeck Foundation.

Media Contact

Heather Buschman
hbuschman@ucsd.edu
619-543-6163

 @UCSanDiego

http://www.ucsd.edu 

Heather Buschman | EurekAlert!

More articles from Health and Medicine:

nachricht Study shows novel protein plays role in bacterial vaginosis
13.12.2019 | University of Arizona Health Sciences

nachricht Illinois team develops first of a kind in-vitro 3D neural tissue model
12.12.2019 | University of Illinois College of Engineering

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Virus multiplication in 3D

Vaccinia viruses serve as a vaccine against human smallpox and as the basis of new cancer therapies. Two studies now provide fascinating insights into their unusual propagation strategy at the atomic level.

For viruses to multiply, they usually need the support of the cells they infect. In many cases, only in their host’s nucleus can they find the machines,...

Im Focus: Cheers! Maxwell's electromagnetism extended to smaller scales

More than one hundred and fifty years have passed since the publication of James Clerk Maxwell's "A Dynamical Theory of the Electromagnetic Field" (1865). What would our lives be without this publication?

It is difficult to imagine, as this treatise revolutionized our fundamental understanding of electric fields, magnetic fields, and light. The twenty original...

Im Focus: Highly charged ion paves the way towards new physics

In a joint experimental and theoretical work performed at the Heidelberg Max Planck Institute for Nuclear Physics, an international team of physicists detected for the first time an orbital crossing in the highly charged ion Pr⁹⁺. Optical spectra were recorded employing an electron beam ion trap and analysed with the aid of atomic structure calculations. A proposed nHz-wide transition has been identified and its energy was determined with high precision. Theory predicts a very high sensitivity to new physics and extremely low susceptibility to external perturbations for this “clock line” making it a unique candidate for proposed precision studies.

Laser spectroscopy of neutral atoms and singly charged ions has reached astonishing precision by merit of a chain of technological advances during the past...

Im Focus: Ultrafast stimulated emission microscopy of single nanocrystals in Science

The ability to investigate the dynamics of single particle at the nano-scale and femtosecond level remained an unfathomed dream for years. It was not until the dawn of the 21st century that nanotechnology and femtoscience gradually merged together and the first ultrafast microscopy of individual quantum dots (QDs) and molecules was accomplished.

Ultrafast microscopy studies entirely rely on detecting nanoparticles or single molecules with luminescence techniques, which require efficient emitters to...

Im Focus: How to induce magnetism in graphene

Graphene, a two-dimensional structure made of carbon, is a material with excellent mechanical, electronic and optical properties. However, it did not seem suitable for magnetic applications. Together with international partners, Empa researchers have now succeeded in synthesizing a unique nanographene predicted in the 1970s, which conclusively demonstrates that carbon in very specific forms has magnetic properties that could permit future spintronic applications. The results have just been published in the renowned journal Nature Nanotechnology.

Depending on the shape and orientation of their edges, graphene nanostructures (also known as nanographenes) can have very different properties – for example,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

The Future of Work

03.12.2019 | Event News

First International Conference on Agrophotovoltaics in August 2020

15.11.2019 | Event News

Laser Symposium on Electromobility in Aachen: trends for the mobility revolution

15.11.2019 | Event News

 
Latest News

Supporting structures of wind turbines contribute to wind farm blockage effect

13.12.2019 | Physics and Astronomy

Chinese team makes nanoscopy breakthrough

13.12.2019 | Physics and Astronomy

Tiny quantum sensors watch materials transform under pressure

13.12.2019 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>