Combination Therapy Drives Cancer into Remission:
Rational, "Personalized" Strategy and a Chemotherapeutic
One-Two
Punch
Reverse Resistance of Tumors to Treatment
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Cold Spring Harbor, NY, March 17 — Researchers
have achieved an experimental breakthrough in the simultaneous
use of two or more agents for treating cancer, known as combination
therapy. If it is shown to be safe and effective in humans, the
therapy outlined by the new study is a promising general strategy
for treating many cancers that do not respond to current therapies.
A two-drug combination therapy, published in tomorrow's issue
of the journal Nature, led to the complete remission of a mouse
model of B-cell lymphoma in all of the treated animals. In contrast,
animals treated with either drug alone (rapamycin or doxorubicin)
rarely experienced complete remission.
The study, led by Dr. Scott Lowe of Cold Spring Harbor Laboratory,
establishes a new paradigm for overcoming chemotherapy resistance
in many forms of cancer.
Rational Target Selection and an Off-the-Shelf
Chemotherapeutic "One-Two Punch" for Lymphoma and Other
Cancers
Pre-cancerous cells can be eliminated from the body by a natural
self-destruct mechanism—normally active in many types of cells—called
programmed cell death. Unfortunately, a hallmark of most cancers
is a defect in programmed cell death that enables pre-cancerous
cells to survive, proliferate out of control, and form a tumor.
Because most traditional chemotherapy agents act by triggering
programmed cell death, such agents are frequently ineffective
against tumors that lack a functional programmed cell death mechanism.
Such tumors are said to be chemotherapy-resistant. The evasion
of treatment-induced programmed cell death by chemotherapy-resistant
tumors has been a major impediment to successful therapeutic
outcomes for human cancer.
Lowe and his colleagues reasoned that—like a one-two knockout
punch in boxing—using one drug to restore the programmed cell
death mechanism and a second drug to trigger the process might
reduce or eliminate chemotherapy-resistance and be an effective
strategy for treating cancer.
Based on their familiarity with the programmed cell death mechanism,
and on their knowledge of which existing drugs target which components
of the mechanism, the researchers were able to take two existing
drugs "off-the-shelf" in a rational way and show that
they worked extraordinarily well, when combined, for treating "Akt-positive" lymphomas
(Lymphomas in which the hyperactivity of a protein called Akt
inactivates the programmed cell death mechanism).
Genetic lesions that aberrantly activate the Akt protein or other
components of the Akt-mediated growth control pathway (e.g. mTOR
or another protein called PI3 kinase) are common in leukemia,
lymphoma, and in a variety of solid tumors. Therefore, the combination
therapy outlined by the new study is a promising general strategy
for treating many cancers that are refractory to current therapies.
The drug chosen to restore the programmed cell death mechanism
was the antibiotic rapamycin. Rapamycin treatment blocks the
action of an Akt "effector" protein called mTOR and
thereby restores the programmed cell death mechanism in Akt-positive
lymphomas.
The drug chosen to trigger the programmed cell death mechanism
was a different antibiotic called doxorubicin. Like many traditional
chemotherapy drugs, doxorubicin triggers programmed cell death
by damaging DNA.
With the programmed cell death mechanism restored by rapamycin
treatment, triggering the mechanism by doxorubicin treatment
delivered the decisive, knockout blow to Akt-positive lymphomas.
The researchers observed massive death of lymphoma cells when
the animals were treated with both rapamcyin and doxorubicin.
The animals rapidly became tumor-free, and their period of tumor-free
survival was greatly extended compared to that of mice bearing
genetically different, non-responsive "Bcl2-positive" lymphomas,
and when compared to mice bearing Akt-positive lymphomas that
were either untreated or treated with rapamycin or doxorubicin
alone. (A copy of the study and a variety of images and illustrations
are available on request.)
In studies of cancer therapy with mice, weight loss is the most
reliable marker for whether a particular treatment is tolerable
or unacceptably toxic. The mice in the new study tolerated the
rapamycin plus doxorubicin combination therapy well, experiencing
loss of less than 10% of their body weight.
The Importance of "Personalized" Cancer Therapies
Based on the Molecular Profiling of Tumors
Personalized cancer therapy, still in its infancy, involves profiling
the genetic lesions within a patient's tumor cells at the level
of DNA or protein and using the resulting profile to select the
best drug or drug combination for treatment. The new study demonstrates
that determining the status of pivotal growth-controlling proteins
within a particular tumor can be a crucial step in selecting
a treatment regimen that is most likely to succeed.
The researchers, including the lead author of the study—Dr.
Hans-Guido Wendel—showed that upon biopsy and examination
of tumor pathology, lymphomas that resulted from transplanted
cells producing hyperactive Akt protein were pathologically indistinguishable
from lymphomas that resulted from transplanted cells producing
excess Bcl2 protein.
However, despite the superficial resemblance of these lymphoma
types to one another, only the Akt-positive lymphomas responded
to the rapamycin plus doxorubicin combination therapy. The Bcl2-positive
lymphomas were completely resistant to the therapy. As a result,
all nineteen of the treated Akt-positive lymphomas were driven
into remission, whereas none of six Bcl2-positive lymphomas responded
to the treatment.
Drs. Lowe and Wendel of Cold Spring Harbor Laboratory were joined
in the study by Dr. Jerry Pelletier of McGill University and
their colleagues.
By demonstrating that the success or failure of a therapeutic
strategy depends on the molecular profile of a particular cancer,
the study indicates that treatment decisions are best guided
by the molecular diagnosis of which gene products are hyperactive
or inactive in a particular tumor.
Moreover, the study indicates that existing drugs believed to
be ineffective against a particular class of cancer can in fact
be used with success through rational, personalized target validation
and the use of one drug to sensitize cancer cells to the effects
of another drug.
Background Information About the Drugs Used in the Study
Rapamycin was isolated in the early 1970s from cultures of the
fungus Streptomyces hygroscopicus sampled on Easter Island (“Rapa
Nui”) and is also known by the brand name Rapamune (sirolimus).
Rapamycin analogs include CCI-779 (Wyeth), RAD001 (Novartis),
and AP23573 (Ariad Pharmaceuticals).
Doxorubicin was isolated in 1967 from cultures of the fungus
Streptomyces peucetius sampled near the Adriatic Sea (hence its
alternative name, "adriamycin") and is also known by
the brand name Adriamycin®.
To obtain a copy of the study and/or representative illustrations,
or to arrange to interview the Principle Investigator and/or
the Lead Author, contact:
Jeff Picarello
Director of Public Affairs
Cold Spring Harbor Laboratory
e-mail: picarell@cshl.edu
tel: 516-367-8486
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