Incorporating Molecular Tools into Early-Stage Clinical Trials
et al.
(2008) Antitumor activity of rapamycin
in patients with recurrent PTEN-
deficient glioblastoma. PLoS Med 5: e8.
doi:10.1371/journal.pmed.0050008
In a phase I trial Charles Sawyers
and colleagues investigated the role
of rapamycin in patients with PTEN
Incorporating Molecular Tools into Early-Stage Clinical Trials
Robert J. Weil 0 1
0 Robert J. Weil is at the Brain Tumor and Neuro- Oncology Center, Department of Neurosurgery and the Neurological Institute, Cleveland Clinic , Cleveland, Ohio , United States of America
1 Abbreviations: EGFR , epidermal growth factor receptor; GBM, glioblastoma; MGMT, methyl guanine methyl transferase; MR, magnetic resonance; mTOR , mammalian target of rapamycin; PI3K , phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10; TK, tyrosine kinase; TKI, tyrosine kinase inhibitor; UCLA , University of California , Los Angeles
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Dand with an accelerating pace
uring the past several decades,
in the past several years, a
primary focus of cancer research and
treatment has been the development
and refinement of specific, biologically
directed therapies [1,2]. A number of
attractive targets have been identified,
dissected, and validated molecularly
and biochemically, including multiple
members of the family of receptor
tyrosine kinases [1,2]. These potent
enzymes, frequently concentrated or
overexpressed on the surface of cancer
cells, phosphorylate target proteins,
with varied and manifold effects on
numerous downstream, intracellular
signaling pathways, leading to
profound alterations in transcription
and translation, cell growth,
differentiation, apoptosis, angiogenesis,
and invasion and metastatic potential
[1,2]. A number of small molecular
inhibitors of these tyrosine kinases
(TKs) have been developed in recent
years. Imatinib, for example, has shown
impressive activity in many patients with
chronic myelogenous leukemia [3,4].
The success of imatinib in human
trials, and subsequent work in the
laboratory and the clinic in several
other cancers in which TKs appear
causative and where TK inhibitors
(TKIs) appeared likely to be
efficacious, spurred a great deal of
interest and enthusiasm throughout
the oncologic community [1,2]. This
was equally true in neuro-oncology,
where progress in treating patients
with malignant gliomas, especially
glioblastoma (GBM), has been slow and
incremental [47].
Treating Glioblastomas
GBM is an aggressive, primary tumor
of the central nervous system [8].
Because of their intrinsic, infiltrative
Research in Translation discusses health interventions
in the context of translation from basic to clinical
research, or from clinical evidence to practice.
nature, GBMs follow a malignant
clinical course. Classified as World
Health Organization grade IV
astrocytic tumors, GBMs have a
pronounced mitotic activity, substantial
tendency toward neoangiogenesis
(microvascular proliferation), necrosis,
and proliferative rates three to five
times higher than grade III tumors, the
anaplastic astrocytomas. The clinical
behavior of GBMs is often mimicked
by unusual pathological presentations,
which gave rise to the old moniker of
glioblastoma multiforme (Figure
1). Even with the survival advantage
provided by the recently developed
protocol of concurrent chemoradiation
followed by adjuvant alkylating
chemotherapy with temozolomide
(the Stupp regimen), the prognosis of
patients with GBM remains poor, with
median overall survival in the range of
915 months and two-year survival rates
of 26% in the most favorable subgroup
[9].
Several common genetic alterations,
such as EGFR (epidermal growth
factor receptor) amplifications on
chromosome 7p, as well as losses on
9p (p16), 10q (PTEN, or phosphatase
and tensin homolog deleted on
chromosome 10), and 17p (p53)
have been identified in a significant
proportion of patients with malignant
gliomas (reviewed thoroughly in
[8]). Two clinically recognized forms
of GBM, de novo or primary and
secondary or progression, have been
identified clinically and recapitulated
at the molecular genetic level [8]. In
de novo or primary GBMs, EGFR gene
amplifications, often combined with
gene rearrangements that lead to a
constitutively active, truncated receptor
(the most common is EGFRvIII), occur
in GBMs that generally express
wildtype p53 [8,1016]. In secondary
tumors, progression from a low-grade
glioma to a GBM involves the serial
accumulation of genetic alterations that
inactivate tumor suppressor genes such
as p53, p16, Rb, and PTEN, or activate
oncogenes such as MDM2 and CDKs
4 and 6; alterations in EGFR are less
common or absent [8]. Frequently, loss
of PTEN function is a common feature
in both types of GBMs [8]. Response to
chemotherapy may be modified by the
level of expression of methyl guanine
methyl transferase (MGMT) [9].
MGMT hypermethylation decreases
production of MGMT, which leads
to a diminished ability to repair DNA
damage caused by an alkylating agent;
Competing Interests: T (...truncated)