at the Brain Tumor Center at the University of Cincinnati Neuroscience
Institute are throwing almost everything but the kitchen sink at an aggressive type
of brain tumor that has proved stubbornly resistant to conventional forms of treatment.
In a novel, investigator-initiated study, James Driscoll, MD, PhD, and his team
are testing more than 2,000 different small-molecule compounds for signs of
effectiveness in the treatment of the high-grade glioma tumor known as glioblastoma
rapidly, they have developed a high-throughput, automated screen to rapidly
test hundreds of compounds at the same time. And although not yet prepared to
discuss the results, Driscoll says he hopes to be able to pursue funding for a
phase-1 clinical trial involving one or more of the compounds within the next 12
months. The trial would take place at the Brain Tumor Center, a center of
excellence within the UC Neuroscience Institute and the UC Cancer Institute. Both
institutes are part of the UC College of Medicine and UC Health.
current laboratory study was funded in October by a $50,000 grant from the
Mayfield Education & Research Foundation’s Precision Radiotherapy Center
Fund, which is supported by physicians of Mayfield Clinic and UC Health Radiation
research holds promise for individuals who develop glioblastoma multiforme, a
malignant brain tumor diagnosed in approximately 10,000 people annually in the
United States. Glioblastoma presents special problems for doctors because it is
not solid and cannot be removed in one clean piece. The tumor is diffuse and
infiltrative, and individual cells tend to survive surgery, radiation and
traditional chemotherapy. As a result, the tumor often grows back near the site
of the initial mass.
takes a heartbreaking toll on families and patients,” says Driscoll, assistant
professor in the division of hematology oncology at UC.
Driscoll and his team are targeting mutations in the epidermal growth factor
receptor (EGFR), a protein on the surface of cells whose malfunction in several
types of cancers has been discovered only in the last few years. Mutations or
amplification of EGFR can lead to faulty signaling or "overactivation,” which causes
cells to multiply too rapidly and to result in cancer. At least 30 to 50 percent
of glioblastoma cases involve a malfunction of the EGFR receptor.
Warnick, MD, medical director of the UC Brain Tumor Center and a
co-investigator in the study, has likened EGFR overexpression to a "switch that
has been set permanently in the ‘on’ position.” A medication
that could turn off the switch, he says, "could potentially suppress or inhibit
the tumor’s rapid, uncontrolled growth.”
other types of cancer that involve EGFR, however, recent evidence has shown
that glioblastoma tumors are heterogeneous and can reflect two different types
of EGFR malfunction: (1) an EGFR wild-type that is overexpressed; and (2) a
specific mutation called EGFRvIII.
good in the sense that it presents us with a new target,” Driscoll says. "But
it’s also bad in that this target will require a unique treatment. Generally,
specific forms of targeted therapies against the wild-type form are not
effective against EGFRvIII and vice versa.”
things more complicated, both the wild-type and EGFRvIII forms can co-exist in
a single patient, making therapies that target only one form deficient.
accomplish the massive and rapid screen, called a "high-throughput screen,”
Driscoll and his team have developed an automated plate-reader-based screen to
identify compounds that kill brain tumor cells that are genetically identical
except for expression of different versions of EGFR: namely the wild-type form,
the EGFRvIII variant, and a kinase-inactive form of EGFR that does not modify
and his team are looking for small molecules that kill all three or that are
best at killing just one of the brain tumor cell types. "Our dream is to find something
that kills both the EGFR wild-type and the EGFRvIII,” Driscoll says.
compounds have been drawn from pharmacological "libraries” of small molecules.
Some are already FDA-approved, while others are in preclinical stages within
the pharmacological industry.
the initial screening is complete, the Driscoll lab will refine its results.
The third step, Driscoll says, will involve seeking national or pharmaceutical-based
funding for a phase-1 clinical trial.
was recruited to UC in 2011 by George Atweh, MD, director of the division of hematology
oncology and director of the UC Cancer Institute. Although Driscoll’s primary
focus is cancers of the blood (myeloma, lymphoma and leukemia), he is also
drawn to the challenges posed by high-grade gliomas, tumors he describes as
the attractive features of this area of research is that any insights could be
valuable,” he says.
includes research associates Sajjeev Jagannathan and Arasakumar Subramani and
collaborates extensively with Atsuo Sasaki, PhD, assistant professor in the
division of hematology oncology.