Rational, "Personalized" Strategy and a Chemotherapeutic One-Two Punch Reverse Resistance of Tumors to Treatment
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®.