Patient's response was predicted by test for mutant protein in tumor cells
Geoffrey Shapiro, MD, PhD
A new oral drug caused dramatic shrinkage of a patient's rare,
aggressive form of soft-tissue cancer that was driven by an abnormally
activated protein, physician-scientists from Dana-Farber Cancer
Institute report in the Oct. 28 issue of the New England Journal of Medicine.
A second patient who had a similar tumor that was not fueled by the
mutant protein, called ALK (named for the first disease in which it was
found, anaplastic lymphoma kinase), failed to respond to the drug, said
the researchers, confirming the inhibitor's specificity for the abnormal
protein. The findings also highlight the value of "personalized
medicine" gene-testing strategies to predict the best drug treatment for
an individual's particular, genetically defined cancer.
The patient described in the NEJM Brief Report is a
44-year-old man diagnosed in 2007 with inflammatory myofibroblastic
tumor (IMT), a type of sarcoma that typically develops in the chest or
abdomen in children and young adults.
In approximately half the cases of IMT, ALK is fused to a different
protein in the patients' cancer cells, spurring cancer development. The
patient had been treated with standard chemotherapy drugs followed by
the targeted compound Gleevec, but the cancer returned in the form of
James Butrynski, MD and Geoffrey Shapiro, MD, PhD,
Dana-Farber oncologists and the first and senior authors of the report,
respectively, offered the patient participation in a Phase 1 trial of
an experimental drug, crizotinib, which blocks ALK activity, as well as
that of another oncogene, MET, that is abnormally activated in a number
Crizotinib treatment shrank the tumors by more than 50 percent —
technically called a "partial response." After several months of
crizotinib, in December 2008, some of the tumors became resistant to the
drug and started growing again. These tumors, as well as tumors still
responsive to crizotinib, were removed surgically. Crizotinib was
resumed after the surgery, and the patient remains without evidence of
disease as of September 2010, according to the investigators.
The activity of crizotinib goes beyond this rare sarcoma. The current
report accompanies a paper in the same journal describing striking
activity of crizotinib in a group of patients with non-small cell lung
cancers (NSCLC) containing the abnormal ALK protein. Researchers from
Massachusetts General Hospital, Dana-Farber/Brigham and Women's Cancer
Center, and other hospitals gave crizotinib to 82 patients after
standard drugs failed to halt the tumors' growth. As part of the
personalized medicine effort ongoing in the Dana-Farber/Brigham and
Women's Cancer Center Thoracic Oncology Program, patients with abnormal
ALK were identified for the trial, underscoring the importance of tumor
profiling to match drug with patient.
Results showed that 47 patients had tumor shrinkage (complete
disappearance in one patient) and the cancer stopped growing in 27
patients. The ALK rearrangements are found in a small subset, about 5
percent, of patients with NSCLC, but scientists are searching for other
cancers that may also be susceptible to the ALK inhibitor.
Shapiro noted that even highly successful targeted drugs like
crizotinib are vulnerable to tumors' developing resistance against them.
In fact, the IMT patient's tumors that developed resistance to
crizotinib and were removed surgically have been studied by one of the
reports co-authors, Pasi Jänne, MD, PhD, also of Dana-Farber.
In a paper appearing simultaneously in Cancer Research,
Jänne and his colleagues have identified a secondary mutation in ALK in
the patient's tumor that conferred resistance to crizotinib.
Furthermore, in work recently published by Jänne, Shapiro and their
Dana-Farber colleague, Kwok-Kin Wong, MD, PhD, the abnormal ALK
proteins, including the protein with the secondary mutation that was
resistant to crizotinib, were found to depend on a cellular chaperone,
called Hsp90, for their stability. Inhibitors of Hsp90 are currently
under clinical evaluation and have been shown to cause destruction of
the aberrant ALK proteins.
Crizotinib is one of many targeted agents currently being evaluated
by the Early Drug Development Center within the Experimental
Therapeutics Program at Dana-Farber, with the aim of translating the
best science into effective new therapies for patients with many forms
of cancer that can be defined by sophisticated new molecular profiling
Authors of the NEJM Brief Report, in addition to Shapiro,
Butrynski, and Jänne, include co-senior author George Demetri, MD, and
Marzia Capelletti, PhD, Dana-Farber; Nikhil Ramaiya, MD,
Dana-Farber/Brigham and Women's; and Jason Hornick, MD, PhD, Paola Dal
Sin, PhD, and Scott Rodig, MD, PhD, Brigham and Women's, as well as
researchers from other hospitals and Pfizer Global Research and
The work was supported in part by Pfizer as well as the National Institutes of Health.