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Fourth, an approach to actively reduce intratumoral
genetic heterogeneity, followed by therapy by molecular
targeted drugs, may be a viable option. If we can design an
initial therapy to impose a specific selection pressure on
tumors, in which only cells with specific genetic variations
survive the therapy, then a reduction in genetic heteroge-
neity may be achieved. Then, if a tumor cell population is
sufficiently homogeneous, a drug that specifically targets
a certain molecule may have significant impact on the
remaining tumor cell population. An important point here is
that the drugs used should not enhance mutation and
chromosomal instability. If mutations and chromosomal
instability are enhanced, particularly by the initial therapy,
heterogeneity may quickly increase so that the second-line
therapy will be ineffective. The drawback of this approach
is that it does not eliminate the fundamental chromosome
instability that continues to generate tumor cells with
diverse genetic backgrounds.
Alternatively, a method to enhance chromosomal
instability selectively in cells that already have unstable
chromosomes could be one candidate. The point here is
whether or not such effects can be achieved with sufficient
selectivity. A non-selective approach to increase chromo-
somal instability has been proposed [59] , but it may
enhance chromosome instability of cells that are relatively
stable, so it potentially promotes malignancy.
Fifth, one may wish to retake control of feedback loops
that give rise to robustness in epidemic states. Since the
robustness of a tumor is often caused by host
measure the quantitative upper bound of genes that can be
over-expressed without perturbing cellular functions such
as proliferation [63] . This method, when extended to
mammalian cell systems, may help us discover differences
of robustness between target and off-target cells against
perturbation. The same perturbation may hit the point of
fragility in target cells but be tolerable for normal cells. As
such differences may stem from the properties of networks,
focusing on such differences between cells may provide us
a broader margin of therapeutic windows than from current
dosage-based methods. At the same time, the use of
multiple components to explore differences of robustness
has been proposed. The spread spectrum control and the
Long-tail problem have been proposed as mathematical
problems that may provide us the means to design drugs
with large numbers of components [64] .
A PROPER INDEX OF TREATMENT
EFFICACY
It is important to recognize that, in the light of cancer
robustness theory, tumor mass reduction is not an appro-
priate index for therapy and drug efficacy judgment. As
already discussed, reduction of tumor mass does not mean
that the proliferation potential of a tumor is generally
decreased. It merely means that a sub-population of tumor
cells that respond to the therapy were eradicated or
significantly reduced. The problem is that remaining tumor
cells may be more malignant and aggressive, so that ther-
apies for the relapsed tumor could be extremely ineffective.
This is particularly the case when drugs used to reduce
tumor mass are toxic and potentially promote mutations
and chromosomal instability in non-specific ways. It may
even enhance malignancy by imposing selective pressures
favoring resistant phenotypes and enhancing genetic
diversity, as well as providing niches for growth by eradi-
cating a fragile sub-population of tumor cells.
A proper index should rather be based on control of
robustness, either to minimize increased robustness or to
reduce robustness. This can be achieved by inducing
dormancy, actively imposing selective pressure to reduce
heterogeneity, or exposing fragility that can be the target of
therapies to follow, thereby retaking control of feedback
regulation. The outcome of controlling the robustness may
vary frommoderate growth of the tumor, to dormancy where
there is no tumor mass growth or significant reduction in
tumor mass. It should be noted that robustness control does
not exclude the possibility of significant tumor mass
reduction. If we can target a point of fragility of the tumor, it
may trigger a common mode failure and result in significant
tumor mass reduction. However, this is a result of controlling
robustness, and should not be confused with therapies aimed
at tumor mass reduction, because robustness has to be
controlled first, to actively exploit a point of fragility.
tumor
feedback controls, robustness of a tumor can be seriously
mitigated if such feedback loops can be controlled. One
possible approach is to introduce a decoy that effectively
disrupts feedback control or invasive mechanisms of the
epidemic state. Such an approach is proposed in AIDS
therapy, so that a conditionally replicating HIV-1 (crHIV-1)
vector which has only a cis region but not a trans region is
introduced [60,61] . This decoy virus dominates the repli-
cation machinery, so that the HIV-1 viruses are pushed into
latency, instead of eradication. In a solid tumor, an inter-
esting idea has been proposed to use a tumor-associated
macrophage (TAM) as delivery vehicle for the vector [37,
62] . TAM migrates into a solid tumor cluster and upregu-
lates HIF-1, which facilitates angiogenesis and metastasis.
If TAM can be used to retake control, robustness may be
well controlled and self-extending symbiosis in cancer
evolution may be aborted.
Sixth, it is critically important that therapeutic inter-
ventions specifically target tumor cells, but not normal
cells. Simply identifying causative genes is not enough, as
most disease-causative genes also bear important functions
for the operation of normal cells. The difference between
target and off-target cells has to be identified. Recently, the
author's team created a novel biological assay method
called 'gTOW'
e
genetic Tug-of-War
that enables us to
e
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