Research
Clinicians and scientists at the University of
Pennsylvania are involved in a large variety of
research endeavors aimed at understanding the
basic biology of glial tumors. The National Institute
of Health (NIH)/National Cancer Institute (NCI),
the American Cancer Society, the Department of
Veterans Affairs and the Brain Tumor Society are
among several agencies that have funded this research.
Examples of some of our current research efforts
is given below.
Signal Transduction:
Dr.
Donald O’Rourke (Department of Neurosurgery)
is studying the molecular biology of the erbB
family receptor tyrosine kinases, including erbB1/EGFR
and p185ErbB2/neu. Studies are aimed at elucidating
the mechanisms of erbB signal attenuation in normal
and transformed astrocytes. Using several approaches
to inhibit erbB signaling this group has characterized
domain-specific receptor interactions that lead
to activated or diminished signaling from erbB
receptor complexes. In addition to studying the
mechanisms of cell growth and transformation induced
by EGFR family proteins, Dr. O'Rourke has developed
receptor-based strategies that facilitate apoptotic
cell death in EGFR-containing glioblastoma cells.
Following the induction of genomic damage by gamma-irradiation,
studies have shown that genetic or pharmacologic
inhibition of EGFR signaling results in apoptosis.
The biochemical basis for this apoptotic response
is being characterized. One translational aim
of these studies is to enhance the effects of
cell death resulting from radiation therapy of
malignant astrocytomas through inactivation of
EGFR kinase. Collaborative efforts are ongoing
to develop new classes of anti-erbB receptor pharmaceuticals
that are based on structural design.
Dr.
Amit Maity (Department of Radiation Oncology)
is studying vascular endothelial growth factor
(VEGF) signaling in glial tumors. VEGF is a key
mediator of angiogenesis and is over-expressed
in many cancers, including primary malignant glial
tumors. In many in vivo models, inhibition of
VEGF function arrests tumor growth. While hypoxia
has long been recognized to be a potent inducer
of VEGF, VEGF can also be expressed in a normal
oxygen environment (normoxia). Evidence indicates
that angiogenesis may develop in tumors before
they have grown to a size large enough to contain
hypoxic regions, suggesting that angiogenic factors
may be expressed by these tumors under normoxic
conditions. In contrast to the induction of VEGF
mRNA under hypoxia that involves the hypoxia-inducible
factor-1 (HIF-1), the upregulation of VEGF under
normoxic conditions is not well understood. Dr.
Maity is investigating the mechanisms of VEGF
up-regulation in normoxia by alterations commonly
found in glial tumors such as EGFR activation
and mutations in Ras and PTEN.
Gene Transfer:
Malignant glial tumors have received substantial
attention as targets for gene therapy. Gliomas
are highly infiltrative into surrounding brain,
preventing complete resection. However they rarely
metastasize outside the brain and their growth
is therefore, relatively well localized, simplifying
the targeting of gene vectors to the tumor. While
the systemic delivery of viral (and other) vectors
to widespread systemic metastases is currently
not achievable with high efficiency and low toxicity,
local vector delivery to the bulk of a brain tumor
can be achieved through either stereotactic injection
or infiltration of residual tumor with vector
at the time of resection. The direct injection
of vectors limits systemic exposure to the therapeutic
agent and therefore, minimizes systemic toxicity.
Dr.
Myrna R. Rosenfeld (Department of Neurology,
Division of Neuro-oncology) is developing a phase
I clinical trial to determine the safety of a
novel therapeutic gene, mda-7. Studies have demonstrated
that over-expression of MDA-7 protein induces
growth suppression and apoptosis in a variety
of cancer phenotypes but not in normal epithelial
cells, fibroblasts or astrocytes. The objectives
of this trial will be to determine the maximum
tolerated dose of adenoviral vector mediated mda-7
gene transfer, to evaluate the long-term clinical
response of patients with recurrent malignant
glial tumors to this gene transfer strategy, and
to determine the molecular effects of mda-7gene
transfer on tumor cells.
Gene Imaging:
Investigators at Penn synthesized a fluorinated
analog of ganciclovir (18F-GCV) suitable for PET
imaging. 18F-GCV can be used for non-invasive
and quantitative assessment of the extent of gene
transfer in vivo. For example, an adenoviral vector
expressing HSV-tk and control vector with no transgene
were injected intravenously into mice. When 18F-GCV
was administered two days later only the bladder
was seen on imaging (non-metabolized drug) in
control treated animals, whereas the liver was
readily imaged in HSV-tk treated animals as expected
since it is established that systemically delivered
adenovirus preferentially infects liver. Based
in these promising results, gene-imaging with
serial 18F-GCV PET will be incorporated into the
adenoviral HSV-tk trial noted above. Investigators
at Penn are also synthesizing alternative chemical
substrates for HSV-tk that may prove superior
for imaging (i.e. penciclovir, an analog of GCV
that has greater intracellular stability).
Tumor Hypoxia:
Dr. Sydney Evans (Department of Radiation Oncology)
is developing methods to measure glial tumor hypoxia
in an effort to determine relationships to prognosis
and response to therapy. Hypoxia is an important
factor in the resistance of brain tumors to radiation
therapy. One of the major limitations to attacking
this problem has been the inability to identify
and quantify the presence of hypoxic cells in
individual patients. Recent molecular studies
have confirmed that hypoxia-associated factors
such as VEGF and HIF-1 are present in brain neoplasms
and that PTEN mutations, which are common in GBM
facilitate the expression of these genes. Studies
on the use of hyperbaric oxygen and tirapazamine
have suggested that treatment for hypoxia can
modify the outcome of patients with malignant
gliomas. Dr. Evans has shown that tumor hypoxia
can be measured using the binding properties of
2-nitroimidazole drugs such as EF5. Given intravenously,
EF5 binds to hypoxic cells in an oxygen-dependent
manner and can be detected in tissues using monoclonal
antibody techniques. Furthermore, the formulation
of EF5 under study is appropriate for non-invasive
imaging.
Paraneoplastic Neurologic Disorders:
Drs.
Josep Dalmau and Myrna
R. Rosenfeld (Department of Neurology, Division
of Neuro-oncology) are studying neurologic disorders
caused by cancer-induced immunologic mechanisms.
These disorders, called paraneoplastic neurologic
syndromes, can affect any part of the central
and peripheral nervous system. As a result of
these immune responses, patients develop severe
neurologic symptoms, including seizures, memory
problems, hypothalamic dysfunction, and paralysis
or sensory deficits that usually precede the diagnosis
of the cancer. Their laboratory has demonstrated
that many of these disorders are mediated by the
immunological system. The current concept is that
the expression of neuronal proteins by the cancer
triggers an immune response against the tumor
that is misdirected against the nervous system,
resulting in the paraneoplastic disorder. This
immune response is characterized by high titer
of serum antibodies (often accompanied by cytotoxic
T-cell responses) that specifically react with
proteins exclusively expressed by neurons and
the cancer cells (onconeuronal antigens). Detection
of these serum antibodies allows the diagnosis
of the neurologic disorder as paraneoplastic,
saving the patient from extensive and sometimes
invasive tests, and directs the search of the
tumor to a few organs, depending of the type of
antibody. Studies have resulted in the clinical
characterization of several paraneoplastic disorders,
and in discovery of a number of antibodies and
target antigens, which are currently used as diagnostic
tests for these syndromes.
Paraneoplastic syndromes are also important
because they are natural models of effective anti-tumor
immunity. The cancers of patients with some paraneoplastic
neurologic syndromes are usually small and often
escape detection by standard tests. Drs. Dalmau
and Rosenfeld have shown in clinical and experimental
studies that the paraneoplastic immune response
contributes to the less aggressive behavior of
cancers associated to paraneoplastic syndromes.
Current projects are directed to model the anti-tumor
immune response in animals in order to develop
novel strategies for cancer therapy.
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