Biochem Biophys Res Commun. 2007 Jun 29;358(2):399-403. Epub 2007 Apr 30.
Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer.
Perez-Pinera P,
Chang Y,
Astudillo A,
Mortimer J,
Deuel TF.
Source
The Scripps Research Institute, La Jolla, CA 92037, USA.
FREE TEXT
Abstract
Pleiotrophin (PTN, Ptn) is an 18kDa cytokine expressed in human breast cancers. Since inappropriate expression of Ptn stimulates progression of breast cancer in transgenic mice and a dominant negative PTN reverses the transformed phenotype of human breast cancer cells that inappropriately express Ptn,
it is suggested that constitutive PTN signaling in breast cancer cells that inappropriately express Ptn activates pathways that promote a more aggressive breast cancer phenotype. Pleiotrophin signals by inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP)beta/zeta, and, recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTPbeta/zeta signaling pathway in PTN-stimulated cells, not through a direct interaction of PTN with ALK and thus not through the PTN-enforced dimerization of ALK. Since full-length ALK is activated in different malignant cancers and activated ALK is a potent oncogenic protein, we examined human breast cancers to test the possibility that ALK may be expressed in breast cancers and potentially activated through the PTN/RPTPbeta/zeta signaling pathway; we now demonstrate that
ALK is strongly expressed in different histological subtypes of human breast cancer; furthermore, ALK is expressed in both nuclei and cytoplasm and, in the ;;dotted" pattern characteristic of ALK fusion proteins in anaplastic large cell lymphoma. This study thus supports the possibility that activated ALK may be important in human breast cancers and potentially activated either through the PTN/RPTPbeta/zeta signaling pathway, or, alternatively, as an activated fusion protein to stimulate progression of breast cancer in humans.
- PMID:
- 17490616
- [PubMed - indexed for MEDLINE]
- PMCID: PMC1945107
results demonstrated that 75% of the infiltrating ductal carcinomas, 50% of the infiltrating lobular carcinomas, 50% of the medullary carcinomas, 100% of the mucinous carcinomas, and 50% of the intraductal carcinomas express high levels of ALK immunoreactivity. Interestingly, 100% of the cases of Paget’s disease were found to express high levels of ALK as well (
Figure 3). In contrast, the single sample of comedocarcinoma of the breast only weakly expressed ALK.
Figure 3Levels of expression of ALK in different human breast cancers
Clin Cancer Res. 2011 Apr 15;17(8):2081-6. Epub 2011 Feb 2.
Targeting anaplastic lymphoma kinase in lung cancer.
Shaw AT,
Solomon B.
LINK
Source
Thoracic Oncology Center, Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
ashaw1@partners.org
Abstract
Several decades of cancer research have revealed a pivotal role for tyrosine kinases as key regulators of signaling pathways, controlling cell growth and differentiation.
Deregulation of tyrosine kinase-mediated signaling occurs frequently in cancer and is believed to drive the initiation and progression of disease. Chromosomal rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) occur in a variety of human malignancies including non-small cell lung cancer (NSCLC), anaplastic large cell lymphomas, and inflammatory myofibroblastic tumors. The
aberrant activation of ALK signaling leads to "oncogene addiction" and marked sensitivity to ALK inhibitors such as crizotinib (PF-02341066). This review focuses on ALK rearrangements in NSCLC, starting with the discovery of the EML4-ALK fusion oncogene, and culminating in the recent validation of ALK as a therapeutic target in patients with ALK-rearranged NSCLC. Current efforts seek to expand the role of ALK kinase inhibition in lung and other cancers and to address the molecular basis for the development of resistance.
©2011 AACR.
ASCO 2011: Crizotinib Continues to Show Responses in Lung Cancer Patients
By Anna Azvolinsky, PhD | June 15, 2011
An ongoing Phase II trial of patients with non-small cell lung cancer (NSCLC) that harbor a specific mutation in the anaplastic lymphoma kinase (ALK) gene reported at ASCO that ~80% of trial participants have responded to crizotinib. A second presentation at ASCO showed that 61% of NSCLC patients showed a response in an expansion of the Phase I crizotinib study.
Crizotinib is an oral, selective, small-molecule inhibitor developed by Pfizer. Recall that we reported on the publication of a portion of this Phase I trial in the New England Journal of Medicine (NEJM) ("
Targeted Lung Cancer Drug, Crizotinib Shows Promise in Typically Unresponsive Non-Small-Cell Lung Cancer" Feb. 24, 2011).
Quote:
Targeted Therapeutic Test
Pfizer is currently collaborating with Abbott Molecular on a standardized test that will utilize FISH to detect patient tumors that are ALK-positive. The company is also exploring other options including a PCR test and immunohistochemistry in order to identify all eligible patients and allow easier testing in community settings.
Atypically Fast Progression from Clinical Trials to NDA Filing
Oncology drugs normally take at least 10 years to make it to commercial filing status, however, crizotinib has managed to do this in 5 years: Initial clinical trials began in 2006. Pfizer has stated that the filed NDA is based on early-stage trials and that they will not need to wait for completion of the currently ongoing Phase 3 crizotinib trials.
Current ongoing trials include a Phase 1b trial in tumor patients positive for the ALK mutation excluding NSCLC patients; a Phase II NSCLC single-arm 400 patient trial; and a randomized Phase 3 trial that compares crizotinib to the standard of care, docetaxel and pemetrexed in patients with advanced NSCLC. Additionally, the Memorial Sloan Kettering Cancer Center is running a trial to determine the mechanism of resistance in NSCLC patients with the ALK fusion gene by examining tumors from 40 patients to determine the genetic changes that occur that faciliate resistance to crizotinib.
All of this is good news for NSCLC patients as well as for the oncology field as a whole as it moves towards real personalized therapies based on the biology of a patient's tumor.
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ONCOLOGY. Vol. 25 No. 7 2011
REVIEW ARTICLE
ALK-Targeted Therapy for Lung Cancer: Ready for Prime Time
By Hatim Husain, MD
1, Charles M. Rudin, MD, PhD
1 | June 14, 2011
1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
ABSTRACT: Lung cancer remains the leading cause of cancer-related death in the United States. Ongoing research into the molecular basis of lung cancer has yielded insight into various critical pathways that are deregulated in lung tumorigenesis, and in particular key driver mutations integral to cancer cell survival and proliferation. One of the most recent examples of this has been definition of translocations and functional dysregulation of the anaplastic lymphoma kinase (ALK) gene in a subset of patients with non–small-cell lung cancer. The pace of research progress in this area has been remarkable: chromosomal rearrangements involving this gene in lung cancer were first reported in 2007 by a team of investigators in Japan. Less than 3 years later, an early-phase clinical trial of a targeted ALK inhibitor has yielded impressive responses in patients with advanced lung cancer containing ALK rearrangements, and mechanisms of acquired resistance to ALK-targeted therapy are being reported. A definitive study randomizing patients with ALK-mutant lung cancer to crizotinib (also known as PF-02341066 or 1066) versus standard therapy has recently completed enrollment. Taken together, these data describe a trajectory of research progress from basic discovery science to real-world implementation that should serve as a model for future integration of preclinical and clinical therapeutic research.
From
commentary on above
(Note: ALK may be more common in breast cancers?)
Quote:
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It is estimated that ALK translocations occur in approximately 4% of all lung cancer cases.[15] Patients harboring this molecular abnormality almost always have adenocarcinoma histology and are never or former light smokers.[16] With rare exception,[17] ALK translocations appear to be mutually exclusive of the more common KRAS and EGFR mutations. The use of certain clinical enrichment factors (histology, smoking status) as well as molecular factors (KRAS and EGFR wild type [wt] status) will alter the frequency of finding ALK translocations. Given the activity of crizotinib in this setting, however, no patient with an ALK translocation should be denied exposure to this agent. Routine consideration of testing for an ALK translocation should be the standard of care and will increase our knowledge about the clinical spectrum of ALK-positive lung cancer.
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