Rationale for the advancement of PI3K pathway inhibitors for personalized chordoma therapy

Michmerhuizen, Nicole L.; Owen, Jennifer C.; Neal, Molly Heft; Mann, Jacqueline E.; Leonard, Elizabeth; Wang, J; Zhai, Jingyi; Jiang, Hui; McHugh, Jonathan B.; Brenner, J. Chad; Prince, Mark E.

doi:10.1007/s11060-020-03418-7

Cited by 11 publications

(14 citation statements)

References 34 publications

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“…Some recent studies have found that molecular targeting technology has a good prospect in the treatment of chordoma. At present, the research on the molecular mechanism of chordoma mainly includes receptor tyrosine kinase and its downstream signaling pathways, Src/Stat3 signaling pathway and PI3K/AKT/mTOR pathway (40)(41)(42)(43)(44). Many clinical studies on tyrosine kinase inhibitors, such as imatinib and erlotinib, suggested that tyrosine kinase inhibitors may be the breakthrough in the treatment of chordoma (45,46).…”

Section: Discussionmentioning

confidence: 99%

Multivariate Analysis and Validation of the Prognostic Factors for Skull Base Chordoma

et al. 2021

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Background: Skull base chordoma is a rare tumor with low-grade malignancy and a high recurrence rate, the factors affecting the prognosis of patients need to be further studied. For that, we investigated prognostic factors of skull base chordoma through the database of the Surveillance, Epidemiology, and End Results (SEER) program, and validated in an independent data set from the Xiangya Hospital.Methods: Six hundred and forty-three patients diagnosed with skull base chordoma were obtained from the SEER database (606 patients) and the Xiangya Hospital (37 patients). Categorical variables were selected by Chi-square test with a statistical difference. Survival curves were constructed by Kaplan–Meier analysis and compared by log-rank test. Univariate and multivariate Cox regression analyses were used to explore the prognostic factors. Propensity score matching (PSM) analysis was undertaken to reduce the substantial bias between gross total resection (GTR) and subtotal resection (STR) groups. Furthermore, clinical data of 37 patients from the Xiangya Hospital were used as validation cohorts to check the survival impacts of the extent of resection and adjuvant radiotherapy on prognosis.Results: We found that age at diagnosis, primary site, disease stage, surgical treatment, and tumor size was significantly associated with the prognosis of skull base chordoma. PSM analysis revealed that there was no significant difference in the OS between GTR and STR (p = 0.157). Independent data set from the Xiangya Hospital proved no statistical difference in OS between GTR and STR groups (p = 0.16), but the GTR group was superior to the STR group for progression-free survival (PFS) (p = 0.048). Postoperative radiotherapy does not improve OS (p = 0.28), but it can prolong PFS (p = 0.0037). Nomograms predicting 5- and 10-year OS and DSS were constructed based on statistically significant factors identified by multivariate Cox analysis. Age, primary site, tumor size, surgical treatment, and disease stage were included as prognostic predictors in the nomograms with good performance.Conclusions: We identified age, tumor size, surgery, primary site, and tumor stage as main factors affecting the prognosis of the skull base chordoma. Resection of the tumor as much as possible while ensuring safety, combined with postoperative radiotherapy may be the optimum treatment for skull base chordoma.

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Section: Discussionmentioning

confidence: 99%

Multivariate Analysis and Validation of the Prognostic Factors for Skull Base Chordoma

et al. 2021

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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%

“…[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. 14 Histologically, chordomas show positive nuclear staining for brachyury and this biomarker helps to differentiate chordomas from other tumors.…”

Section: Introductionmentioning

confidence: 99%

“…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…”

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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Small molecule profiling to define synergistic EGFR inhibitor combinations in head and neck squamous cell carcinoma

et al. 2022

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Background Head and neck squamous cell carcinoma (HNSCC) is a debilitating disease with poor survival. Although epidermal growth factor receptor (EGFR)‐targeting antibody cetuximab improves survival in some settings, responses are limited suggesting that alternative approaches are needed. Methods We performed a high throughput drug screen to identify EGFR inhibitor‐based synergistic combinations of clinically advanced inhibitors in models resistant to EGFR inhibitor monotherapies, and then performed downstream validation experiments on prioritized synergistic combinations. Results From our screen, we re‐discovered known synergistic EGFR inhibitor combinations with FGFR or IGF‐1R inhibitors that were broadly effective and also discovered novel synergistic combinations with XIAP inhibitor and DNMT inhibitors that were effective in only a subset of models. Conclusions Conceptually, our data identify novel synergistic combinations that warrant evaluation in future studies, and suggest that some combinations, although highly synergistic, will require parallel companion diagnostic development to be effectively advanced in patients.

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Rationale for the advancement of PI3K pathway inhibitors for personalized chordoma therapy

Cited by 11 publications

References 34 publications

Multivariate Analysis and Validation of the Prognostic Factors for Skull Base Chordoma

Multivariate Analysis and Validation of the Prognostic Factors for Skull Base Chordoma

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

Small molecule profiling to define synergistic EGFR inhibitor combinations in head and neck squamous cell carcinoma

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