Exploring pharmacotherapeutic options for treating chordoma

CONTENTS

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .575Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .575Conventional cytotoxic chemotherapy . . . . . . . . . . . . . . . . . . . . . .575Molecular targets and therapies . . . . . . . . . . . . . . . . . . . . . . . . . . .577Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .578References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .580

SUMMARY

Chordoma is a rare, primary bone cancer arising along the midline from the skull base to the sacrum. Chordomas appear histologically low-grade but are highly invasive and often recur locally. Management is maximal surgical resection. Radiation therapy using protons and photons is often necessary because complete resection is frequently not possible due to tumor invasion into surrounding critical structures.Cytotoxic chemotherapy is often ineffective. The high rate of recurrence is reflected by a median survival of 6-7 years. The authors present a review of the current and emerging medical treatments for chordoma and the rationale supporting their use.

Key words: Chordoma – Bone cancer – Surgical resection –Chemotherapy – Radiation therapy INTRODUCTION

Chordoma is a rare primary malignancy of the bone arising from the axial skeleton and ranging from the skull base (clivus) to the sacrum.The incidence is approximately 0.1 per 100,000 people per year (1, 2).It commonly presents in the 5th decade of life, with a slight male pre-dominance. The distribution along the axial skeleton is approximate-ly equal for the sacrum, skull base and mobile spine. Chordomas are believed to arise from remnants of the notochord, and supporting this hypothesis is the frequent, if not universal, expression of brachyury, a transcription factor specific for notochord (2, 3).

Patients often present in a delayed fashion, typically with nonspecific symptoms until late stages, when the tumor is locally advanced, or less commonly, metastatic (4-6). Radiographically, chordoma appears as an osteolytic lesion centered in the midline (clivus, verte-bral body or sacrum) and associated with a soft tissue mass (7). They are well-defined extradural masses that compress or encase adja-cent neurovascular structures (8). Intratumoral calcification is pres-ent in many cases (7, 9, 10). On magnetic resonance imaging (MRI),they appear iso- to hypointense on T1-weighted sequences, with areas of hypointensity due to calcification, cystic changes and hem-orrhage. On T2-weighted sequences, they are often hyperintense,with areas of signal heterogeneity and heterogeneous contrast enhancement (Figure 1).

The diagnosis of chordoma can only be established from pathologi-cal examination of surgical specimens. There are three histological subtypes: classical, chondroid and dedifferentiated (8, 11). The clas-sical variant displays the physaliphorous (“soap bubble”) appear-ance microscopically. The chondroid subtype is difficult to differenti-ate from chondrosarcoma without immunostains, such as brachyury.Dedifferentiated chordomas resemble fibrosarcoma or osteosarcoma (8) (Figure 2).

Treatment of chordoma is primarily surgical. En bloc surgical resec-tion is the standard treatment when possible; however, given the location and late presentation of these tumors, complete resection is often not possible (10, 12-14). After surgery, the local control rate is approximately 50%. Traditional fractionated radiotherapy has been largely ineffective at biologically achievable doses, but with the advent of advanced radiation therapy, delivery techniques including radiosurgery, intensity modulated radiotherapy and hadron-based radiation therapy, reasonable tumor control rates have been report-ed, with approximately 50% or higher tumor control at 5 years (15-19). The overall survival for all patients with chordoma is 50% at 10years. When the disease is metastatic, survival decreases to 1-3 years (4, 20-28).

CONVENTIONAL CYTOTOXIC CHEMOTHERAPY

There are no approved medical therapies for chordoma. Because chordoma is a rare cancer, a single phase II trial of 9-nitrocamp-tothecin demonstrated a single objective response from 15 patients and a 33% 6-month survival (29) (Table I). Additionally, anecdotal

FILLING THE GAPS IN DRUG THERAPY

EXPLORING PHARMACOTHERAPEUTIC OPTIONS FOR TREATING CHORDOMA

B.J. Williams 1, B. Gupta 1, J. Sommer 2, M.E. Shaffrey 1and D.M. Park 1

1

Division of Neuro-Oncology, Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia; 2Chordoma Foundation,Durham, North Carolina

THOMSON REUTERS

Drugs of the Future 2013, 38(8): 575-582

Copyright ? 2013 Prous Science, S.A.U. or its licensors. All rights https://www.360docs.net/doc/462359319.html,C: 0377-8282/2013

DOI: 10.1358/dof.2013.38.8.1970870

Neurological Surgery, University of Virginia, Charlottesville, Virginia 22908, USA; E-mail: DMP3J@https://www.360docs.net/doc/462359319.html,.

CHORDOMA PHARMACOTHERAPY B.J. Williams et al.

T1 Sagittal pre-contrast T2 Sagittal

T1 Sagittal post-contrast T1 Axial post-contrast

T1 Axial pre-contrast T1 Sagittal pre-contrast

T2 Axial T2 Sagittal T2 Sagittal STIR

Figure 1.MRI of clival and sacral chordoma.

responses have been reported with anthracyclines, vinca alkaloids, platinum-based agents, alkylating agents and etoposide (30-35). The underlying reason for resistance to cytotoxic chemotherapeutics remains unclear (36, 37).

MOLECULAR TARGETS AND THERAPIES

Tyrosine-protein kinases

Platelet-derived growth factor receptor beta

Platelet-derived growth factor receptor beta (PDGFRβ) is a tyrosine-protein kinase expressed and activated in most chordomas (38-40). This signaling pathway regulates proliferation, differentiation, sur-vival, angiogenesis and growth, primarily via PI3K/Akt/mTOR and Ras/MAPK signaling.

Based on this observation, the clinical activity of imatinib mesylate, a small-molecule inhibitor of PDGFRα, PDGFRβand proto-onco-gene c-Kit, was evaluated. The initial series published in 2004 included six patients with PDGFRβexpression and four with activa-tion of the receptor. Responses were evaluated based on computed tomography (CT), magnetic resonance imaging (MRI) and flourodeoxyglucose (FDG) positron emission tomography (PET). Four of the six patients were continued on treatment for at least 1 year (41). A multicenter phase II trial was then performed on advanced and progressive PDGFRβexpressing chordoma. The response rate was 1 of 50 (2%), which occurred at 6 months accord-ing to Response Evaluation Criteria in Solid Tumors (RECIST) (42). Thirty-five (70%) patients had stable disease and median progres-sion-free survival was 9 months (43).

Han et al. demonstrated hyperactivation of mTORC1 signaling due to complete or partial loss of phosphatase and tensin homolog (PTEN) in 10 sporadic sacral chordomas (44). They further demonstrated that chordoma cell lines are sensitive to the mammalian target of

B.J. Williams et al.CHORDOMA PHARMACOTHERAPY

A B

Figure 2.Hematoxylin and eosin (H&E) and brachyury stain for chordoma.

PFS, progression-free survival; N/A, not applicable.

rapamycin (mTOR) inhibitor, rapamycin, and PI3K/Akt inhibitor, but not to ERK/MAPK inhibition. Other groups have corroborated these findings, demonstrating activation of mTOR and its effectors S6 and 4E-BP1 (40, 45-47). Translating this work, a pilot study of imatinib and the mTOR inhibitor sirolimus was performed on nine patients with advanced progressive chordoma. According to RECIST criteria, one patient had a partial response and seven stable disease. These data suggest that patients who fail imatinib treatment may benefit from dual treatment with a rapalog (mTOR inhibitor) (48). Based on this evidence, a phase II trial for advanced chordoma is under way based in Milan, Italy, using imatinib combined with the mTOR inhibitor everolimus (Figure 3).

Epidermal growth factor receptor

Epidermal growth factor receptor (EGFR) and related family mem-bers are believed to play a critical role in the pathogenesis and pro-gression of a variety of cancers. In a molecular analysis of 22 untreated chordomas, approximately 70% of chordomas expressed EGFR, with activation of the receptor (40, 49, 50). Subsequently, a separate group demonstrated cytostatic activity for EGFR inhibition in vitro (40, 49).

There have been two case reports of the use of the EGFR inhibitors gefitinib and cetuximab, which have suggested activity in EGF-posi-tive chordomas (51, 52). Another report demonstrated an imaging response to erlotinib, a small-molecule EGFR inhibitor, in an advanced case of imatinib-resistant chordoma (53). Along this line of evidence, a phase II trial of lapatinib, a small-molecule inhibitor of EGFR and receptor tyrosine-protein kinase erbB2, was completed in Italy for advanced EGFR-positive chordoma (54). This trial demon-strated modest activity, with 11 of 16 patients demonstrating RECIST stable disease. Interestingly, EGFR status was not a predictor of treatment response.

Insulin-like growth factor 1 receptor

Insulin-like growth factor 1 receptor (IGF1R) and its ligand are also consistently expressed in chordoma (55, 56). Expounding on this, a group from Vanderbilt University demonstrated activation of the IGF1R and downstream effectors in 41% of 30 chordomas, while also showing lack of activation in benign tissues from fetal notochord (57).

Hepatocyte growth factor receptor

Tissue studies have demonstrated overexpression of hepatocyte growth factor receptor (c-Met) and hepatocyte growth factor (HGF), its ligand, in most chordomas (22, 58, 59). This has been shown to correlate with aggressiveness of these lesions. Additionally, cytogenetic analysis supports a role for c-Met, as chromosome 7 is often abnormal in chordomas, which is where the c-Met locus resides (60-62).

Hypoxia signaling

Intratumoral hypoxia and its adaptive responses play a critical role in the progression and treatment resistance of many cancers (63-69). There is evidence suggesting that hypoxia inducible factor 1-alpha (HIF1-alpha) is active in the pathological evaluation of chordomas and a chordoma cell line (37). Additionally, we have observed that inhibition of HIF1-alpha using a histone deacetylase inhibitor (LBH-589, panobinostat) in concert with imatinib is able to over-come PTEN loss of heterozygosity in vitro (unpublished data; see Figure 2). These data provided the basis of an ongoing phase I trial of imatinib with concurrent LBH-589 for chordoma (NCT01175109). STAT3

Recently, an analysis of 70 chordoma specimens demonstrated acti-vation of signal transducer and activator of transcription 3 (STAT3) (70). These data corroborate other reports that STAT3 inhibitors have in vitro activity against chordoma (71).

Brachyury

During the 1890’s when Ribbert coined the term “chordoma”, a pop-ular theory suggested a notochordal origin for these tumors based primarily on their anatomical location and histological appearance (72). However, it was not until the 21st century that direct evidence emerged supporting this claim. Evidence from pathological evalua-tion of human fetuses and cell fate tracking experiments support the notochord hypothesis (73, 74). Moreover, brachyury is a transcription factor expressed by the notochord and chordoma (3, 75), and has emerged as an integral biomarker distinguishing chordoma from other chondroid lesions. Tissue microarray analysis of 103 chondroid tumors from the skull base and head and neck demonstrated that brachyury combined with cytokeratin staining had a sensitivity and specificity for detecting chordoma approaching 100% (3).

Finally, brachyury may not only be a marker for chordoma, but also a driver of their pathogenesis as well. Transient genetic knockdown of brachyury in chordoma cells was found to induce differentiation and senescence (76). Furthermore, brachyury has been shown in experimental models of human carcinomas to contribute to epithelial?mesenchymal transition, control metastatic potential and regulate expression of several stem cell markers (77). Immunotherapeutic strategies targeting brachyury may be useful for chordoma and other cancers that demonstrate ectopic expression of this protein.

CONCLUSION

Performing research in the chordoma field has been challenging due to limited cell line availability and lack of a faithful model system. Recent reports on the feasibility of establishing xenograft models are encouraging (78-80). Additionally, the Chordoma Foundation (https://www.360docs.net/doc/462359319.html,) is supporting disease-specific research and development of research tools, including patient-derived xenografts and cell lines, which it makes available to aca-demic and industry investigators through a centralized repository. Efforts are also under way to develop transgenic mouse and zebrafish models of chordoma. Increased availability of cell lines and model systems should allow rigorous preclinical screening of medical therapies for chordoma and the development of promising novel treatments.

ACKNOWLEDGMENTS

This work was funded by ASCO CDA to DMP.

CHORDOMA PHARMACOTHERAPY B.J. Williams et al.

B.J. Williams et al.CHORDOMA PHARMACOTHERAPY

Figure 3.Diagram of tyrosine-protein kinase, e.g., A) PDGF/EGF/IGF/c-Met signaling pathway. and B) HIF signaling pathway.

DISCLOSURES

Deric M. Park has received research support from Novartis. The other authors state no conflicts of interest.

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