?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 118 Number 3 March 2008
and long-term immunological and clinical
benefits of this approach need to be thor-
We thank Rogier van Gent, Mette Hazen-
berg, and Jose Borghans for their input.
Address correspondence to: Frank Mie-
dema, University Medical Center Utrecht,
Department of Immunology, Lundlaan
6, PO Box 85090, Utrecht UNK 3508 AB,
The Netherlands. Phone: 31-88-755-7674;
Fax: 31-30-250-4305; E-mail: f.miedema@
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Discovering early molecular determinants
Grover C. Bagby
Departments of Medicine and Molecular and Medical Genetics, Oregon Health and Sciences University,
and Northwest Veterans Affairs Cancer Research Center, Portland, Oregon, USA.
Advances in biotechnology and genomics
have catalyzed enormously important dis-
coveries in the field of cancer biology. Some
of the findings from studies of molecular
pathogenesis have led to the development
of new therapeutic agents that have nota-
bly controlled the growth of malignant
cells in vivo (1). Truly targeted therapy is
that which effectively interdicts a survival
or replication pathway on which the malig-
nant cell depends but normal cells do not.
To develop this kind of therapeutic agent
requires that one first identify such a defect
in a malignant cell population, then devel-
op an agent that attacks it in a specific way.
The target must also be validated in clini-
cal trials. That is, clinical responses must
be attributable to the capacity of the thera-
peutic agent to interdict the function of the
target molecule in the neoplastic cells.
Not only have advances in molecularly
targeted therapy saved thousands of lives
(1), the successes to date have validated the
simple principle that if you understand
it you can fix it. For cancer therapeutics
this idea is widely accepted today and is
supported by massive investments in this
approach by pharmaceutical and biotech-
nology firms. However, while few would
argue with the idea that preventing can-
cer is better than treating it, investigators
in the field of cancer prevention have not
particularly warmed to the notion that the
molecular strategies used for developmen-
tal therapeutics can support their goals as
well. This situation has to change because
there is clear-cut experimental evidence
that the earliest control points for carcino-
genic change in stem cells can be identified
by focusing on stem cell pools under stress.
The natural implication is that by inter-
dicting this stress one might prevent the
evolution of neoplastic clones.
Stressed stem cell pools are
vulnerable to neoplastic change
Most leukemias evolve as clonal out-
growths of single, somatically mutated
HSCs. Studies of patients with inherited
myeloid leukemia;?ELA2, elastase 2;?FA, Fanconi ane-
mia;?MDS, myelodysplastic syndrome; SCN, severe
Conflict?of?interest: The author has declared that no
conflict of interest exists.
Citation?for?this?article: J. Clin. Invest. 118:847–850