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The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 16

The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 16

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Published by Sri Harsha
The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 16
The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 16

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Published by: Sri Harsha on Jan 31, 2013
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07/26/2013

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Chapter 16
The
Rational Treatment
of
Cancer
Ali
substances
are
poisonous
,there
is
none that
is
not
a poison; theright dose differentiates a
poison
from a remedy.Paracelsus (Auroleus Phillip us Theostratus Bombastus von
Hohenheim
), alchemist
and
physician,1538Doctors are
men
who
prescribe medicines of which they know little, to cure diseases of which they know less, in
human
beings of
whom
they know nothing.Voltaire (Franc,:ois-Marie Arouet),
author
and
philosopher,1760
T
he
research described
throughout
this book represents a revolution in
ourunderstanding of cancer pathogene
si
s.
In 1975,there were virtually
no
insights into the molecular alterations within
human
cells
that
lead to the
appearance
of malignancies.One generation later, we possess this knowledge in
abundance.
Indeed, the available information
and
concepts
aboutcancer
's origins
can
truly
be
said to
constitute
ascience with a logical
and
coherent
conceptual structure.In spite of these extraordinary leaps forward, relatively little progress has
beenmade
in exploiting these insights into etiology
(Le.,
the causative
mechanismsof
disease)to prevent the disease and, equally important, to treat it. Most of theanti-cancer
treatments
in widespread use today were developed prior to 1975, ata time
when
the development of therapeutics was
not
yet informed by detailedknowledge
of
the genetic
and
biochemic
al
mechanisms
of
cancer
pathogenesis.
 
I
Chapter 16:
The
Rational Treatment
of
Cancer
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yea r
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r
of
death
Figure
16.1
Statistics
of
cancer 
This explains the widely felt frustration among molecular oncologists
that
the
mortality
over the
past
three-
potential of their research for contributing to new anti-cancer therapeutics has
quarters
of
a
century:
the
lay
of
the 
not
yet been realized.
land
The
statistics compiled
in
theUnitedStateson theage-adjusteddeath
This frustration
is
fueled
most
strongly by the slow pace at which advances have
rates from various types
of
cancer
reveal
been
made
in the treatment of
common
solid tumors. For example, in 1970 in
two
different long-term trends.
the United States,
7%
of the patients diagnosed with lung cancer were still alive
(A)
Mortalityfromseveralmajorkillers
5 years after their initial diagnosis. Three decades later, this
num
ber
had
risen to
has
declined significantly since
1930.
only
14%,
a relatively minor improvement. And even this degree of therapeutic
This
is
dueto changesin foodstorage practicesandpossibly
Helicobacter pylori
success may be illusory, since
modern
diagnostic techniques often detect
infection rates,
in
the
case
ofstomach
tumors far earlier
in
their clinical course, creating a greater time
span
between
cancer,
and
to
screening,
in
the
cases
of
initial diagnosis
and
ultimate progression to end-stage disease.Death rates for
cervicalandcolorectal cancers.
colon cancer have begun to fall, because of early detection
and
surgicalremoval
(B
)Anumber
of
majorsources
of
of grovvths that have advanced through only the early stages of
tumor
progres
cancer-related death have proven
sion (Figure
16.1A;
see also Figure 11.8C). However, mortality caused
by
the
resistantto most forms of traditional
more advanced colorectal tumors has changed little in recent
decades-a
testi
therapy, especially when thesetumors
monial to the failures of chemotherapy
and
radiation to eliminate these malig
progresstoa highly malignant,
nancies once they have invaded and begun to metastasize(Sidebar
45
0
).
metastaticstage. (
From
A.Jemal,
/
T.
Murray,E.Ward et
aI.,
CA
Cancer
1.
Clin.
55:10-
30,
2005.) 
Surely the
now-abundant
information on the molecular
and
cellular mechanisms of cancer pathogenesis will inspire new ways to effectively treat the disease. In this chapter, we explorea
number
of strategies of therapy
under
devel
opment
or recently introduced into the clinic. The goal here
is
not
tosurveythe
full
range
of
current research in these areas. That would be unreachable:a2003compilation of anti-cancer therapies in pre-clinical development or in clinicaltesting listed more
than
1300 research
and
development projects
that
werebeing pursued
by
various large pharmaceutical companies
and
smaller biotechnology firms. The therapeuticagents
under
development included
small
molecular-weight drugs, proteins, monoclonal antibodies,
and
gene therapystrategiesincluding viral vectors.Rather
than
being encyclopedic, we will concentrate here onasmall
number
ofrecently developed therapies that illustrate how discoveries described in theprevious chapters have inspired novelstrategiesfor treating cancer,
and
howmolecular diagnosis will increasingly
playa
part in the development and clinical introduction of novel therapies.
At
the same time, we will pass over discussions of how molecular biology ischangingcancerprevention strategies. Thus, we will
not
examine
the
majoradvances that have been
made
in developing vaccines that protect against hepatitis B virus
(HBV)
and
human
papillomavirus
(HPV)
infections; these vaccinesshould be highly effective in reducing the incidence of hepatomas
and
cervical
4030
20
 
Trends
in
cancer
mortality
carcinomas, which are
rampant
in certain parts
of
the world. (If the
past
history
of
public health
is
any guide,
the
prevention
of
cancer will ultimately yield fargreater reductions in disease-related mortality
than
will therapies
of the
sortdiscussed in this chapter; seeSidebar
45
0
.)
The present chapter concentrates
on
small-molecule therapeutics
and
on
theirintracellular targets
that
have
been
identified through research
on
the signalingpathways within cancer cells. These strategies all hold great promise,
and
invariably their true potential
is
yet to be realized. The anecdotes surrounding thedevelopment
of
each
of
these drugs are interesting
and
provocative, becausethey teach
important
lessons
about
the triumphs
and
pitfalls
of
developingnovel anti-cancer treatments. Note
that
a
number of
monoclonal
antibody-based
therapeutic strategies have already
been
discussed in some detail in previous chapters, as have several therapies focused
on
preventing or blocking
tumor
angiogenesis. Note also
that
the conventional
means of
treating cancer,most
of
which have
been
in use for decades, are
not
discussed
hete,
becausetheir development was not informed by the more recent discoveries describedin this book.Almost all
of
the research findings described
throughout
this textbook will
stand
the test of time
and
be considered credible
and
correct (though
perhapsnot that
interesting) a generation from now. However, those who love certainty
and
eternal truths will find the stories that follow to be unsatisfying for a very simple reason: the work reported
is
in great flux
and
is
therefore far more time-sensitive.Many
of
these therapies will
seem
quaint
and
anachronistic a decade after thischapter
is
written. The campaign to convert insights
about
cancer's molecularcauses into
new
ways of curing disease has just begun. And so we
encounter
itsfirst few stumbling steps.
16.1 
The
development and clinical use
of
effectivetherapies will depend on accurate diagnosis
of
disease
In previous chapters, we repeatedly categorized cancers
in
terms of their tissues
of
origin
and
their stages
of
clinical progression. Almost always, these assign
ments
have
been
dictated by the
appearance of
normal
and
malignant tissues
under
the microscope. On
some
occasions, to
be
sure, we have refined theseclassifications by describing certain molecular markers (e.g., expression
of
HER2
in breast cancers)
and the
implications that they hold for prognosis. Butin general, histopathology has reigned
supreme
in
our
discussions, as it has inthe practice of clinical oncology for more
than
half a century.Even without insights into the molecular
ongms of
human
cancers, it hasbecome increasingly clear
that
the traditional ways of classifying cancers havelimited utility. Truly useful diagnoses must inform the clinician
aboutthe
underlying nature
of
diseases and, more important, how each disease entity willrespond to various types oftherapy.
As
we have learned more
about
human
cancers, we have come to realize
that many
human
cancers
that
have traditionally
been lumped
together as examples
of
a single disease entity should, in fact, beseparated into several, distinct disease subcategories. This helps to explain why
many
existing anti-cancer therapeutic strategies used over
the
past
threedecades have
had
such low overall success rates. These response rates also have
important
implications for the development
of new
drugs (Sidebar
46
0
).
For patients bearing the subtype
of
a
tumor that
responds to a particular treatment, this therapy may prove to
be
a boon, extending life
and
even offeringcures
on
occasion. For
the
remaining patients, a uniformly applied therapyyields no positive clinical effect
and
may divert these patients from receiving

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