The Next Step: Innovative Molecular Targeted Therapies for Treatment of Intracranial Chordoma Patients

Barry, Jeffrey J.; Jian, Brian J.; Sughrue, Michael E.; Kane, Ari J.; Mills, Steven A.; Tihan, Tarık; Parsa, Andrew T.

doi:10.1227/neu.0b013e3181fd2ac5

Cited by 25 publications

(17 citation statements)

References 81 publications

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“…Several studies have been published, but they are mostly small series of CHs that recurred after other treatments (surgery and radiotherapy). [41][42][43][44][45] Until now, the benefit of such targeted therapies remains limited with at least 2 main explanations. One is the activation of other RTKs when one RTK is blocked by an inhibitor; another explanation in case of mTOR inhibition is a negative feedback with activation of the upstream factors and the deviation toward another chain of factors.…”

Section: Treatment Modalitiesmentioning

confidence: 99%

Chordomas

George

Bresson

Herman

et al. 2015

Neurosurgery Clinics of North America

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Section: Treatment Modalitiesmentioning

confidence: 99%

Chordomas

George

Bresson

Herman

et al. 2015

Neurosurgery Clinics of North America

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“…Daunorubicin and idarubicin had a 10-fold more potent effect in U-CH1 (IC 50 = 4.14 µM for daunorubicin and 3.05 µM for idarubicin) and C25 (IC 50 = 2.32 µM for daunorubicin and 1.50 µM for idarubicin) cells than in U-CH2 (IC 50 = 21.83 µM for daunorubicin and 56.45 µM for idarubicin), C24 (IC 50 = 20.18 µM for daunorubicin and 65.65 µM for idarubicin) and C32 (IC 50 = 55.27 µM for daunorubicin and 21.26 µM for idarubicin) cells. Receptor tyrosine kinases (RTKs) and their downstream signaling cascades have been implicated as possible targets involved in chordoma 6 . In this study, we found that a group of tyrosine kinase inhibitors including erlotinib, gefitinib, imatinib, sunitinib, and vandetanib had modest growth inhibitor activity in most of these cells, except in C24 cells where erlotinib and vandetanib had significant inhibitory effect with IC 50 of 5.26 µM and 5.05 µM, respectively.…”

Section: Resultsmentioning

confidence: 84%

“…Recent research efforts have begun to focus on the molecular targets and signaling pathways of chordoma in order to efficiently find anti-chordoma therapies 6 . The primary possible targets involved in chordoma are receptor tyrosine kinases (RTKs) and their downstream signaling cascades including the PI3K/AKT/mTOR pathway 6 .…”

Section: Discussionmentioning

confidence: 99%

“…The primary possible targets involved in chordoma are receptor tyrosine kinases (RTKs) and their downstream signaling cascades including the PI3K/AKT/mTOR pathway 6 . In this study we tested several RTK inhibitors including imatinib, sunitnib, vandetanib, erlotinib, and gefitinib, PI3K/mTOR inhibitors, BEZ-235 and rapamycin, and p38 MAP kinase inhibitors including SB 202190 and SB 203580 on chordoma cell lines and primary chordoma cell cultures.…”

Section: Discussionmentioning

confidence: 99%

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Identification of repurposed small molecule drugs for chordoma therapy

Xia

Huang

Sakamuru

et al. 2013

Cancer Biology & Therapy

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Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan, and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potently in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine, and bortezomib showed similar inhibitory effect on cell lines and 3 primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy.

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“…Currently, no newly emerging cancer therapies such as targeted therapy and immunotherapy have been approved for chordoma treatment [3]. It is urgent to explore the biological characteristics of chordoma cells and find new therapeutic schemes.…”

Section: Introductionmentioning

confidence: 99%

Neu-p11 induces NLRP3 inflammasome-induced pyroptosis via provoking NOX4-mediated mitochondrial oxidative injury in chordoma cells

Zhang

2020

Preprint

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Chordoma is a rarely malignant bone tumor with highly resistance to radiotherapy and chemotherapy. Melatonin has been shown to inhibit tumor cell invasion, metastasis and induce apoptosis in several types of cancer. Activation of melatonin receptor inhibit cancer stemness of chordoma, which suggesting that melatonin receptor agonists have potential therapeutic value for the clinical treatment of chordoma. The present study aimed to investigate the anticancer action and molecular mechanism of Piromelatine (Neu-P11) in chordoma cells, a high-efficacy agonist of melatonin receptor-1/melatonin receptor-2 (MT1/MT2). We used Neu-p11 (1, 10, 100, 1000 μM) or vehicle to treat chordoma cell lines U-CH1 and MUG-Chor for 36 hours. CCK-8 assay and LDH activity assay showed that Neu-p11 had dose-dependent cytotoxic effect on chordoma cells. Neu-p11 induced NLRP3 and Cleaved-Caspase-1 expression, while Caspase-1 specific inhibitor Z-YVAD-FMK and NLRP3 specific inhibitor MCC950 independently blocked the cytotoxic effect of Neu-p11 on chordoma cells, indicating that Neu-p11 induced a NLRP3-dependent cell pyroptosis. Neu-p11 promoted NADPH oxidase 4 (NOX4) translocation to mitochondria, resulting in a significant increase in mitochondria-derived ROS and decreased expressions of mitochondrial antioxidant proteins (MnSOD, Sirt3) and mitochondrial DNA replication factor (Tfam), which could be attenuated by NOX4 specific inhibitor GKT137831. Further investigation revealed that Neu-p11 resulted in decreased copy number of mtDNA and increased mtDNA releasing in cytoplasm. Decreased oxygen consumption, reduced membrane potential and ultrastructural damage of mitochondrial were detected in Neu-p11 treated chordoma cells, which could be attenuated by GKT137831. GKT137831 inhibited mitochondria-translocation of NLRP3 and attenuated activation of NLRP3 inflammasome caused by Neu-p11 treatment. Collectively, we demonstrated that Neu-p11 induces mitochondrial translocation of NOX4 leads to oxidative damage of mitochondria, mediating chordoma cells NLRP3-dependent pyroptosis. Neu-p11 may be a a new strategy for chordoma treatment. Graphic abstractAbbreviations Neu-p11, Piromelatine; NOX4, NADPH oxidase 4; NLRP3, NLR Family Pyrin Domain Containing 3; MnSOD, Manganese superoxide dismutase; Sirt3, NADdependent deacetylase sirtuin-3; Tfam, mitochondrial transcription factor A; mtROS, mitochondria-derived reactive oxygen species; mitochondrial membrane potential (MMP, ΔΨm); mtDNA, mitochondrial DNA.

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The Next Step: Innovative Molecular Targeted Therapies for Treatment of Intracranial Chordoma Patients

Cited by 25 publications

References 81 publications

Chordomas

Chordomas

Identification of repurposed small molecule drugs for chordoma therapy

Neu-p11 induces NLRP3 inflammasome-induced pyroptosis via provoking NOX4-mediated mitochondrial oxidative injury in chordoma cells

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