Researchers at the University of California, San Diego School of Medicine and the UC San Diego Moores Cancer Center have identified a new drug discovery approach enabling the destruction of the most highly proliferative tumors.
The discovery, published in the Nov. 13 online issue of the journal Nature Medicine, points to an effective, alternative method for killing fast-growing cancer cells without causing some of the negative effects of current therapies.
The scientists, led by David A. Cheresh, PhD, professor of pathology and associate director for translational research at the Moores Cancer Center, used an innovative chemical and biological approach to design a new class of drugs that arrests division in virtually all tumor cells by binding to and altering the structure of an enzyme called RAF.
RAF has been long-studied, but its role in cell division – critical to cell proliferation and tumor growth – was a surprise. "By designing a new class of drugs that changes the shape of RAF, we were able to reveal this previously undiscovered role for RAF in a wide range of highly proliferative tumors," Cheresh said.
Current cancer drugs that target enzymes like RAF are generally designed to interact with the active site of the enzyme. Unfortunately, these drugs often lack specificity, Cheresh said. "They hit many different targets, meaning they can produce undesired side effects and induce dose-limiting toxicity." More of a concern is that tumor cells often develop resistance to this class of drugs rendering them inactive against the cancer.
Cheresh and colleagues pursued development of a new class of RAF inhibitors that do not bind to the active site of the enzyme and so avoid the limitations of current drugs. Instead, this new class, called allosteric inhibitors, changes the shape of the target enzyme and in doing so, renders it inactive. The specific drug tested, known as KG5, singles out RAF in proliferating cells, but ignores normal or resting cells. In affected tumor cells, RAF is unable to associate with the mitotic apparatus to direct cell division, resulting in cell cycle arrest leading to apoptosis or programmed cell death. KG5 in a similar manner effectively interferes with proliferating blood vessels, a process called angiogenesis.
"It's an unusual discovery, one that really challenges current dogma," said Cheresh. "Before this drug was designed, we had no idea RAF could promote tumor cell cycle progression. This may be only one example of how, by designing drugs that avoid the active site of an enzyme, we can identify new and unexpected ways to disrupt the growth of tumors. In essence, we are attacking an important enzyme in a whole new way and thereby discovering new things this enzyme was intended for."
KG5 produced similar results in tests on cancer cell lines, in animal models and in tissue biopsies from human cancer patients. The research team has since developed variants of KG5 that are 100-fold more powerful than the original drug. They hope one of these more powerful compounds will soon enter clinical trials at Moores Cancer Center.
The new RAF targeted compounds are being developed by Amitech Therapeutic Solutions, Inc a start-up company in San Diego.
Co-authors of the study, all from the departments of Pathology or Radiation Oncology at the UC San Diego Moores Cancer Center, are Ainhoa Mielgo, Laetitia Seguin, Miller Huang, Fernanda Camargo, Sudarshan Anand, Aleksandra Franovic, Sara M. Weis, Sunil Advani and Eric Murphy.
Funding for this research came from the National Institutes of Health.
Scott LaFee | EurekAlert!
Inhaling air pollution-like irritant alters defensive heart-lung reflex for hypertension
19.06.2019 | University of South Florida (USF Innovation)
Nitric oxide-scavenging hydrogel developed for rheumatoid arthritis treatment
06.06.2019 | Pohang University of Science & Technology (POSTECH)
The quality of additively manufactured components depends not only on the manufacturing process, but also on the inline process control. The process control ensures a reliable coating process because it detects deviations from the target geometry immediately. At LASER World of PHOTONICS 2019, the Fraunhofer Institute for Laser Technology ILT will be demonstrating how well bi-directional sensor technology can already be used for Laser Material Deposition (LMD) in combination with commercial optics at booth A2.431.
Fraunhofer ILT has been developing optical sensor technology specifically for production measurement technology for around 10 years. In particular, its »bd-1«...
The well-known representation of chemical elements is just one example of how objects can be arranged and classified
The periodic table of elements that most chemistry books depict is only one special case. This tabular overview of the chemical elements, which goes back to...
Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.
Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...
Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.
The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...
Discovery by Brazilian and US researchers could change the classification of two species, which appear more akin to jellyfish than was thought.
The tube anemone Isarachnanthus nocturnus is only 15 cm long but has the largest mitochondrial genome of any animal sequenced to date, with 80,923 base pairs....
29.04.2019 | Event News
17.04.2019 | Event News
15.04.2019 | Event News
19.06.2019 | Physics and Astronomy
19.06.2019 | Information Technology
19.06.2019 | Materials Sciences