- Division of Neurosurgery, McGill University, Jewish General Hospital, Montreal, QC, Canada
- Department of Pathology and Laboratory Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
- Department of Neurological Surgery, University of Washington, University of Washington Medical Center, Seattle, Washington, USA
Salvatore Di Maio
Department of Neurological Surgery, University of Washington, University of Washington Medical Center, Seattle, Washington, USA
DOI:10.4103/2152-7806.112822Copyright: © 2013 Di Maio S This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Maio SD, Kong E, Yip S, Rostomily R. Converging paths to progress for skull base chordoma: Review of current therapy and future molecular targets. Surg Neurol Int 01-Jun-2013;4:72
How to cite this URL: Maio SD, Kong E, Yip S, Rostomily R. Converging paths to progress for skull base chordoma: Review of current therapy and future molecular targets. Surg Neurol Int 01-Jun-2013;4:72. Available from: http://sni.wpengine.com/surgicalint_articles/converging-paths-to-progress-for-skull-base-chordoma-review-of-current-therapy-and-future-molecular-targets-2/
Background:Chordomas of the skull base are rare locally aggressive neoplasms with a predilection for encapsulating critical neurovascular structures, bony destruction and irregular growth patterns, and from which patients succumb to recurrence and treatment failures.
Methods:A review of the medical literature is performed, using standard search engines and identifying articles related to skull base chordomas, surgery, radiation therapy, chemotherapy, molecular genetics, and prospective trials.
Results:A synthesis of the literature is presented, including sections on pathology, treatment, molecular genetics, challenges, and future directions.
Conclusion:Beyond an understanding of the current treatment paradigms for skull base chordomas, the reader gains insight into the collaborative approach applied to orphan diseases, of which chordomas is a prime exemplar.
Keywords: Chordomas, cell lines, radiation therapy, review, skull base neoplasms, surgery
Chordomas are rare, locally aggressive neoplasms thought to arise from notochordal remnants in the axial skeleton. In the skull base, they destroy bone, encapsulate critical neurovascular structures, and have irregular patterns of growth, rendering safe maximal surgical removal and effective radiation therapy challenging. In many ways, however, skull base chordomas are a paradigm for advancing progress in orphan diseases due to multi-institutional collaboration. In this article, we review the current treatment paradigms for cranial base chordomas, outline the molecular biology and potential therapeutic targets, and discuss future directions for such collaboration and research.
Chordomas occur with an annual age-adjusted rate of 0.02/100,000 person years and account for 0.1% of all reported brain tumors in the United States, 2004-2007.[
Virchow in 1846 is credited with first describing the physaliphorous cell, however, he believed these tumors were derived from a cartilaginous overgrowth at the base of the skull, and termed them “ecchondrosis physaliphora spheno-occipitalis”.[
Histologically, three types of chordoma are recognized by the World Health Organization: Classic chordoma, chondroid chordoma, and dedifferentiated chordoma.[
Systemic metastases may occur in as many as 30% of patients,[
There is compelling evidence that en bloc surgical excision of chordomas confers long-term recurrence-free survival, based on experience with spinal column tumors.[
The vast majority of cranial base chordomas are not amenable to strict en bloc oncologic resection; instead an intralesional resection toward normal appearing bony margins is typically performed in order to avoid neurovascular complications. Nevertheless, maximal safe resection of skull base chordomas is generally advocated, although there has been limited evidence supporting this practice. In a recent meta-analysis of the literature over the past 10 years, 23 studies incorporating 807 patients were combined to analyze the effect of complete resection on 5-year overall and PFS.[
Achieving aggressive removal of chordomas largely provided the impetus for pioneers in skull base surgery to develop and refine open approaches to the central skull base.[
Recently a number of centers have published short-term data regarding endoscopic endonasal resection of cranial base chordomas.[
Despite an apparent benefit to maximal surgical removal of skull base chordomas, recurrence without adjuvant therapy remains high.[
Chordomas are radiosensitive tumors, with a clearly established dose-response relationship and effective dose above 65 Gy.[
Proton and/or carbon ion therapy, however, remains considerably more expensive than photon treatment, particularly in terms of investment cost,[
With advances in molecular biology and sequencing capability, the field of molecularly targeted therapeutics has expanded with the development of drugs inhibiting pathways necessary for uncontrolled cell proliferation [
Epidermal growth factor receptor and platelet-derived growth factor receptor signaling pathways in chordoma mediated by tyrosine kinases and downstream effectors. These molecules are potential therapeutic targets of targeted inhibition by cetuximab, erlotinib, gefitinib, imatinib, PI-103, and rapamycin analogs
One such potential therapeutic target is the brachyury (T) gene, which codes for a transcription factor that is uniquely expressed in chordoma cells. Brachyury plays an important role during the development of the notochord in embryos but later remains unexpressed in normal tissue.[
A number of different mechanisms have been suggested to be the cause of brachyury expression in chordoma. It was demonstrated, in a familial chordoma study involving four families, to be due to duplication of a region in 6q27 containing the T gene.[
In addition to being an identifying marker for chordoma, brachyury also plays an important role in its pathogenesis. It was observed that when the brachyury gene was silenced in chordoma cell line JHC7, cells became more differentiated, displaying senescence and complete growth arrest and were unable to be passaged in vitro, indicating that without brachyury expression, they lose their tumorigenic capabilities. Similarly, brachyury knockdown in chordoma cell line UCH-1 resulted in decreased cell proliferation and senescent appearance.[
Since silencing of brachyury results in the interruption of cell growth in vitro, it presents itself as an ideal candidate as a molecular target for therapy. Moreover, targeted silencing of brachyury expression results in the abrogation of transcriptional activation of numerous downstream genes. What makes it an attractive target is that it is only expressed in tumor cells, meaning if it is targeted, the cancer cells will be preferentially affected while leaving the normal cells with little to no adverse side effects. With the lower chance of toxicity to normal cells in combination with the antitumourigenic qualities from its inhibition, brachyury targeting has great potential for the development of a molecular therapy for chordoma patients.
Receptor tyrosine kinases
Receptor tyrosine kinase (RTK) inhibitory drugs for cancer have experienced much advancement in recent years, with the sharp increase in our ability to sequence, and thus detect mutations in, RTK genes in tumor DNA. RTKs are proteins on the cell surface that interact with extracellular ligands to become activated and dimerize, which triggers phosphorylation of a downstream signaling protein and initiates a signaling pathway ultimately leading to a transcriptional change. In cancer cells, the transcriptional change most often gives rise to angiogenesis, cell proliferation or antiapoptosis, which all contribute to tumorigenesis. When an RTK is hyperactivated, its associated pathway also becomes constitutively active as well, leading to loss of control over cell proliferation and cancerous cell growth. The RTK can become hyperactive as a result of autocrine/paracrine loops, ligand or receptor overexpression, or gain of gene mutations.
One commonly targeted RTK in many cancers is the epidermal growth factor receptor (EGFR), which binds a number of ligands including EGF and transforming growth factor alpha (TGF-α). A significant portion of chordomas have EGFR overexpression that causes increased initiation of cell proliferation, leading to higher degree of aggressive behavior of the tumor. This has been evidenced in a study where 69% of cases expressed EGFR and close to 40% of the chordomas tested had amplification of the gene.[
Targeting EGFR in chordoma has only just begun, with four studies conducted thus far. The first (Hof et al.[
Another promising target therapy involves the platelet-derived growth factor receptor (PDGFR). Similar to EGFR, this RTK can display oncogenic properties when hyperactivated, initiating cell proliferation and growth via the PI3K/AKT, RAS/ERK, or STAT pathways. Of the two different types of PDGFR, α and β, overexpression of the β variant is particularly common in chordomas[
Trials of imatinib treatment, a PDGFR inhibitor, on chordoma patients first began in 2004 with a compassionate trial for six patients, of whom four were positive for PDGFR expression.[
From the results observed in the imatinib trials, patients’ disease progression halted for a period of approximately 9 months, accompanied with symptomatic improvement even in cases with no volumetric response. Particularly in the very advanced chordoma cases, where survival was predicted to be less than 1 year, the benefit of imatinib is evident. However, the limitations of this treatment are also exhibited clearly. Only a minority of cases showed decrease in tumor size, indicating that it does little in terms of dimensional response, reflecting on its inability to decrease cell numbers. This may be due to the preferential overexpression of PDGFR in stromal cells, thereby reducing the variety of tumor cells that are affected by the treatment. Nevertheless, benefits have been observed in patient cases thus far, demonstrating the effectiveness of imatinib overall as an antitumor therapy. Further study of imatinib in vivo will help in determining the extent of its efficacy in chordoma.
While RTK inhibitors have proven to be useful target therapies, the immense diversity of receptors in a cell makes it difficult to control cell growth through the inhibition of a single RTK. Many cancers possess multiple oncogenic mutated RTKs. If a particular RTK is inhibited, its function can be replaced by the increased activity of a different RTK able to activate the same downstream signaling pathway, thus leading to the onset of resistance to the RTK inhibitor. This drug resistance has been observed in various cancers and likewise in chordoma. Targeting signaling structures downstream in the pathway can overcome the problem of one RTK making up for the inhibition of another due to the fact that many of the RTK activated pathways converge into a common one downstream.
One such pathway that receives signals from a variety of different RTKs is the phosphoinositide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. This pathway is often found to be constitutively activated in cancers because it is a mechanism that cells use to control proliferation, differentiation, and apoptosis. Ungoverned activation of the pathway is caused by an amalgamation of various mutations, including down regulation of normally present suppressor proteins, hyperactivity of its associated RTKs, or an inability to deactivate constituents via the proper feedback loop. As a result of deregulation of this pathway, cells undergo unrestrained growth, leading to cancer and tumor formation.
In human chordoma, activation of this pathway has been observed. The majority of a 13 chordoma sample study had unusually high levels of activated AKT and mTOR,[
The PI3K/AKT/mTOR pathway has been targeted mainly through the inhibition of mTOR with rapamycin and its analogs. mTOR is targeted by rapamycin, as is apparent in its name, causing growth arrest in the early G1 phase and inhibiting translation initiation.[
The historical lack of major progress in improving outcomes for chordoma patients stems both from its rarity and difficulties in adapting standard paradigms to its basic scientific investigation. Chordoma is a recognized rare (or orphan) disease,[
In response to the needs of orphan diseases such as chordoma, the National Institutes of Health (NIH) created the Office of Rare Diseases Research (ORDR)[
As a result of their relative rarity and unfavorable location, the management of cranial base chordomas remains challenging. Refinements in open and endoscopic skull base approaches and improvements in stereotactic radiotherapy and radiosurgery techniques have facilitated local control and survival for new cases as well as at the time of recurrence. Nevertheless, many patients with chordoma ultimately recur and succumb to the disease. Through an increasing knowledge of tumor genetics and molecular biology, advances in laboratory techniques, new in vitro cell lines and xenograft models, preclinical screening for potential therapeutic agents, and collaboration between centers, an improved understanding of chordoma biology that can be translated into treatment paradigms will hopefully occur.
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