Scientists at the Johns Hopkins Kimmel Cancer Center, working with Danish researchers, have developed a novel anticancer drug designed to travel -- undetected by normal cells -- through the bloodstream until activated by specific cancer proteins. The drug, made from a weedlike plant, has been shown to destroy cancers and their direct blood supplies, acting like a "molecular grenade," and sparing healthy blood vessels and tissues.
In laboratory studies, researchers said they found that a three-day course of the drug, called G202, reduced the size of human prostate tumors grown in mice by an average of 50 percent within 30 days. In a direct comparison, G202 outperformed the chemotherapy drug docetaxel, reducing seven of nine human prostate tumors in mice by more than 50 percent in 21 days. Docetaxel reduced one of eight human prostate tumors in mice by more than 50 percent in the same time period.
In a report June 27 in the journal Science Translational Medicine, the researchers also reported that G202 produced at least 50 percent regression in models of human breast cancer, kidney cancer and bladder cancer.
Based on these results, Johns Hopkins physicians have performed a phase I clinical trial to assess safety of the drug and have thus far treated 29 patients with advanced cancer. In addition to Johns Hopkins, the University of Wisconsin and the University of Texas-San Antonio are participating in the trial. A phase II trial to test the drug in patients with prostate cancer and liver cancer is planned.
The drug G202 is chemically derived from a weed called Thapsia garganica that grows naturally in the Mediterranean region. The plant makes a product, dubbed thapsigargin, that since the time of ancient Greece has been known to be toxic to animals. In Arab caravans, the plant was known as the "death carrot" because it would kill camels if they ate it, the researchers noted.
"Our goal was to try to re-engineer this very toxic natural plant product into a drug we might use to treat human cancer," says lead study author Samuel Denmeade, M.D., professor of oncology, urology, pharmacology and molecular sciences. "We achieved this by creating a format that requires modification by cells to release the active drug."
By disassembling thapsigargin and chemically modifying it, the researchers created a form that Denmeade likens to a hand grenade with an intact pin. The drug can be injected and can travel through the bloodstream until it finds the site of cancer cells and hits a protein called prostate-specific membrane antigen (PSMA). PSMA is released by cells lining tumors of the prostate and other areas, and in effect "pulls the pin" on G202, releasing cell-killing agents into the tumor and the blood vessels that feed it, as well as to other cells in the vicinity. Specifically, G202 blocks the function of a protein called the SERCA pump, a housekeeping protein necessary for cell survival that keeps the level of calcium in the cell at the correct level, the researchers report.
"The exciting thing is that the cancer itself is activating its own demise," says senior study author John Isaacs, Ph.D., professor of oncology, urology, chemical and biomedical engineering at Johns Hopkins.
Because the drug is targeted to the SERCA pump, which all cells need to stay alive, researchers say it will be difficult for tumor cells to become resistant to the drug, because they cannot stop making the protein.
The study's co-authors were Annastasiah M. Mhaka, D. Marc Rosen, W. Nathaniel Brennen, Susan Dalrymple, Bora Gurel, Angelo M. DeMarzo, and Michael Carducci of Johns Hopkins; Ingrid Dach, Claus Olesen, Jesper V. Møller, and Poul Nissen of the Danish National Research Foundation and Aarhus University; and Craig A. Dionne of GenSpera Inc.; and S. Brøgger Christensen of the University of Copenhagen.
The work was supported by the Department of Defense Prostate Cancer Research Program, the Prostate Cancer Foundation and David Koch, the Danish Cancer Society, the Danish Research Council for Strategic Research, the Danish National Research Foundation, the Danish Medical Research Council, the Aarhus University Research Foundation, and the National Institute of Health's National Cancer Institute Specialized Program of Research Excellence (CA058236 and CA006973).
Denmeade and Isaacs are consultants for GenSpera Inc. and have received equity and financial compensation. This relationship has been disclosed and is under the management of the Johns Hopkins University School of Medicine Conflict of Interest Committee.
On the Web:
Science Translational Medicine
Vanessa Wasta | EurekAlert!
The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie
How protein islands form
15.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
Researchers from the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science, the Italian Space Agency (ASI), and the Instituto Geofisico--Escuela Politecnica Nacional (IGEPN) of Ecuador, showed an increasing volcanic danger on Cotopaxi in Ecuador using a powerful technique known as Interferometric Synthetic Aperture Radar (InSAR).
The Andes region in which Cotopaxi volcano is located is known to contain some of the world's most serious volcanic hazard. A mid- to large-size eruption has...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
16.08.2017 | Physics and Astronomy
16.08.2017 | Materials Sciences
16.08.2017 | Interdisciplinary Research