Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

CANCER PREVENTION AND TREATMENT: PRESENT AND FUTURE
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or more—far beyond expectations for comparable patients without this treatment.
Even more promising are recent clinical trials using a combination of two
antibodies, one against CTLA4 and the other against PD1, a second cell-surface
receptor on T cells that normally restrains their activity.
In clinical trials using such techniques, a substantial fraction of the patients
can respond in a dramatic way, with their cancer being driven into remission
for years, while the treatment fails to help others with the same type of cancer.
One possible explanation is that, while most tumors express proteins that protect
them from T-cell attack, these proteins are different for different tumors. Thus,
while some tumors will respond dramatically when treated with an antibody that
blocks a particular immunosuppressive agent, many others will not. If true, one
can foresee an era of personalized immunotherapy, in which each patient’s tumor
is molecularly analyzed to determine its particular mechanisms of immunosuppression.
The patient would then be treated with a specific cocktail of antibodies
designed to remove these blocks (see Figure 20–45).
Cancers Evolve Resistance to Therapies
High hopes have to be tempered with sobering realities. We have seen that genetic
instability can provide an Achilles heel that cancer therapies can exploit, but at the
same time it can make eradicating the disease more difficult by allowing the cancer
cells to evolve resistance to therapeutic drugs, often at an alarming rate. This
applies even to the drugs that target genetic instability itself. Thus, PARP inhibitors
give valuable remission of illness, but in the long term the disease generally comes
back. For example, Brca-deficient cancers can sometimes develop resistance to
PARP inhibitors by undergoing a second mutation in an affected Brca gene that
restores its function. By then, the cancer is already out of control and it may be too
late to affect the course of the disease with additional treatments.
There are many different strategies by which cancers can evolve resistance to
anticancer drugs. Often, a cancer will be dramatically reduced in size by an initial
drug treatment, with all of the detectable tumor cells seeming to disappear. But
months or years later the cancer will reappear in an altered form that is resistant
to the drug that was at first so successful. In such cases, the initial drug treatment
has evidently failed to destroy some tiny fraction of cells in the original tumorcell
population. These cells have escaped death because they carry a protective
mutation or epigenetic change, or perhaps simply because they were lurking in
a protected environment. They eventually regenerate the cancer by continuing to
proliferate, mutating and evolving still further as they do so.
In some cases, cells that are exposed to one anticancer drug evolve a resistance
not only to that drug but also to other drugs to which they have never been
exposed. This phenomenon of multidrug resistance frequently correlates with
amplification of a part of the genome that contains a gene called Mdr1 or Abcb1.
This gene encodes a plasma-membrane-bound transport ATPase of the ABC
transporter superfamily (discussed in Chapter 11), which pumps lipophilic drugs
out of the cell (see Movie 11.5). The overproduction of this protein (or some of its
other family members) by a cancer cell can prevent the intracellular accumulation
of many cytotoxic drugs, making the cell insensitive to them.
In the to-and-fro struggle between advanced metastatic cancer and the therapist,
as current practice stands, the cancer usually wins in the end. Does it have
to be so? As we discuss below, there is reason to think that by attacking a cancer
with many weapons at once—instead of using them one after another, each until
it fails—it may be possible to do much better.
Combination Therapies May Succeed Where Treatments with
One Drug at a Time Fail
Nowadays, cancers caught at an early stage can often be cured, by surgery, radiation,
or drugs. For most cancers that have progressed and metastasized widely,
however, cure is still beyond us. Treatments such as those described above can