Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma

Otani, Ryohei; Mukasa, Akitake; Shin, Masahiro; Omata, Mayu; Takayanagi, Shunsaku; Tanaka, Shota; Ueki, Keisuke; Saito, Nobuhito

doi:10.3171/2016.12.jns161444

Cited by 42 publications

(34 citation statements)

References 35 publications

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“…Through molecular studies and a highthroughput monotherapy drug screen, we and others have previously shown that the PI3K/AKT/mTOR pathway provides a promising therapeutic target in preclinical models. 6,[9][10][11][12] However, limited response to PI3K inhibition in several of our models suggest the presence of resistance mechanisms prompting the development of combination therapies. Here, we aimed to identify potential synergistic combinations with PI3K pathway inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Through targeted exome sequencing and a high-throughput drug screen, our laboratory and others have identified alterations within the PI3 kinase (PI3K)/AKT/mTOR pathway in both chordoma tumors and patient-derived cell lines (including UM-Chor1 and UM-Chor2), and demonstrated the effectiveness of PI3K inhibitor monotherapies in vitro. [6][7][8][9][10][11][12] Subsequent work between our laboratory and the Chordoma Foundation using patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) models showed reduction in tumor growth with PI3K inhibitor, BKM-120 in some, but not all models suggesting that there may be a role for alternative pathways in developing resistance to these drugs. 12,13 In addition to the PI3K signaling pathway, T which encodes the brachyury protein (a nuclear transcription factor responsible for notochord development) is frequently disrupted in chordoma and provides another promising target.…”

Section: Introductionmentioning

confidence: 99%

“…A study by Otani et al revealed that overexpression of brachyury correlated with increased expression of PI3K pathway genes in 26 tumor samples and that inhibition of PI3K resulted in decreased brachyury protein expression in the U-CH2 cell line. 9 In UM-Chor1, brachyury has been shown to be highly expressed at the RNA and protein level, while whole exome sequencing data reveal normal copy number status. 14 Here, we advance our recent high-throughput single agent drug screens by testing the hypothesis that combining PI3K inhibitors with a small molecule inhibitor library or with knockdown of T (brachyury) may provide a more robust and therapeutic effect in a patient-derived cell line, UM-Chor1.…”

Section: Introductionmentioning

confidence: 99%

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Advancement of PI3 Kinase Inhibitor Combination Therapies for PI3K-Aberrant Chordoma

Neal

Michmerhuizen

Prince

et al. 2020

J Neurol Surg B Skull Base

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Objectives Targeted inhibitors of the PI3 kinase (PI3K) pathway have shown promising but incomplete antitumor activity in preclinical chordoma models. The aim of this study is to advance methodology for a high-throughput drug screen using chordoma models to identify new combination therapies for chordoma. Study Design Present work is an in vitro study. Setting The study conducted at an academic research laboratory. Materials and Methods An in vitro study on automated high-throughput screening of chordoma cells was performed using a library of 1,406 drugs as both mono- and combination therapies with PI3K inhibitors. Combination indices were determined for dual therapies and synergistic outliers were identified as potential therapeutic agents. T (brachyury) siRNA knockdown in combination with PI3K pathway inhibition was also assessed. Results Fifty-nine combination therapies were identified as having potential therapeutic efficacy. Effective combinations included PI3K inhibitors with GSK1838705A (ALK/IGF-1R inhibitor), LY2874455 (VEGFR/FGFR inhibitor), El1 (selective Ezh2 inhibitor), and (-)-p-bromotetramisole oxalate (alkaline phosphatase inhibitor). The top ranking targets identified included ALK, PDGFR, VEGFR, aurora kinase, and BCL-2. T (brachyury) inhibition produced significant reduction in cell viability and growth; however PI3K inhibition in combination with T (brachyury) knockdown did not result in further reduction in growth and viability in vitro. Conclusion High throughput with in vitro combination screening is feasible with chordoma cells and allows for rapid identification of synergistic dual-therapies. Potential combination therapies and targetable pathways were identified. T (brachyury) knockdown produced significant reduction in cell viability, but did not show additional benefit with PI3K pathway inhibition in this model. Further in vitro and in vivo validation of these therapeutic combinations is warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Advancement of PI3 Kinase Inhibitor Combination Therapies for PI3K-Aberrant Chordoma

Neal

Michmerhuizen

Prince

et al. 2020

J Neurol Surg B Skull Base

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“…Analysis of chordoma cell lines not associated with TSC also revealed a correlation between PI3K/AKT pathway upregulation and brachyury expression ( 66 ). Cells from skull-base chordomas with high brachyury expression had significant upregulation of PI3K/AKT pathway genes compared to low-brachyury tumors ( 66 ). Treatment with PI3K/AKT pathway inhibitors resulted in decreased brachyury expression that corresponded with impaired cell growth ( 66 ).…”

Section: Growth Factor Signalingmentioning

confidence: 99%

Translational Windows in Chordoma: A Target Appraisal

et al. 2020

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Chordomas are rare tumors that are notoriously refractory to chemotherapy and radiotherapy when radical surgical resection is not achieved or upon recurrence after maximally aggressive treatment. The study of chordomas has been complicated by small patient cohorts and few available model systems due to the rarity of these tumors. Emerging next-generation sequencing technologies have broadened understanding of this disease by implicating novel pathways for possible targeted therapy. Mutations in cell-cycle regulation and chromatin remodeling genes have been identified in chordomas, but their significance remains unknown. Investigation of the immune microenvironment of these tumors suggests that checkpoint protein expression may influence prognosis, and adjuvant immunotherapy may improve patient outcome. Finally, growing evidence supports aberrant growth factor signaling as potential pathogenic mechanisms in chordoma. In this review, we characterize the impact on treatment opportunities offered by the genomic and immunologic landscape of this tumor.

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“…Otani et al found that brachyury was expressed in all (23) chordomas patients (n=27), albeit with variable levels of expression. Patients with tumors expressing high levels of brachyury were found to have significantly shorter progression free survival compared to those with lower brachyury expression tumors (23). The molecular findings in a chordoma may change how we think about a patient's prognosis.…”

Section: Managementmentioning

confidence: 99%

Chordoma of the mobile spine and sacrum: clinical management and prognosis

D’Amore

Mesfin

2018

J Spine Surg

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Background: Chordomas are rare malignant tumors of the spinal column often afflicting the upper cervical spine and sacrum. There are few large single center series on chordomas due to its rarity. The purpose of this study is to report a single center's experience with the operative and non-operative management of chordomas. Methods: We evaluated our institution's pathology database from 1994 to 2016 to identify patients diagnosed with chordomas. Inclusion criteria were chordomas of the mobile spine and sacrum. Exclusion criteria were chordomas of the clivus and resection performed at another institution. We collected patient demographics as well as the type of resection performed, intra-operative complications, wound complications and recurrence/prognosis. Results: We identified 18 patients diagnosed with chordomas at our institution, and 12 met our inclusion criteria. There were four females and eight males with an average age of 64 [32-87] years. All patients were Caucasian and 10 of the 12 had surgery. Of the two patients with sacral chordomas that did not have surgery, one received chemotherapy and the other did not elect for any treatment. One is alive 161 months following diagnosis and the second died 96 months following diagnosis. Five of the lesions were in the mobile spine (one cervical, two thoracic, two lumbar) and seven were in the sacrum. Six patients underwent an en bloc resection [two via total en bloc spondylectomy (TES)]. Average length of follow up is 60 [3-161] months and eight of 12 patients are alive at latest follow up. Intraoperative complications included cardiac arrest, pleural tear, and excessive blood loss (8 L). Two patients, with sacral chordomas, had wound complications. Recurrence occurred in one patient with piecemeal resection and one patient with incomplete resection had postoperative metastatic lesions to the liver and lung. Conclusions: We found less recurrence in patients managed with an en bloc resection as opposed to piece meal or intralesional resections. Sacral chordoma patients had higher wound complication rates as compared to chordomas of the mobile spine. The long life expectancy of non-surgically managed patients underscores the indolent nature of chordomas.

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Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma

Cited by 42 publications

References 35 publications

Advancement of PI3 Kinase Inhibitor Combination Therapies for PI3K-Aberrant Chordoma

Advancement of PI3 Kinase Inhibitor Combination Therapies for PI3K-Aberrant Chordoma

Translational Windows in Chordoma: A Target Appraisal

Chordoma of the mobile spine and sacrum: clinical management and prognosis

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