Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study

Gaspar, Nathalie; Occean, Bob-valery; Pacquement, Hélène; Bompas, Emmanuelle; Bouvier, C; Brisse, H.; Castex, Marie‐Pierre; Cheurfa, Nadir; Corradini, Nadège; Delaye, Jessy; Entz‐Werlé, Natacha; Gentet, Jean‐Claude; Italiano, Antoîne; Lervat, Cyril; Marec‐Bérard, Perrine; Mascard, Éric; Rédini, Françoise; Saumet, L.; Schmitt, Claudine; Tabone, Marie‐Dominique; Verite-Goulard, Cécile; Deley, Marie-Cécile Le; Piperno‐Neumann, Sophie; Brugières, Laurence

doi:10.1016/j.ejca.2017.09.036

Cited by 90 publications

(85 citation statements)

References 23 publications

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“…Therapeutic outcomes have remained essentially unchanged in osteosarcoma patients since the introduction of doxorubicin, methotrexate, and cisplatin in the late 1970s, with the 5‐year overall survival of osteosarcoma patients remaining relatively stagnant . Recent cooperative international clinical trials have attempted to intensify treatments or modulate immune responses, but this has been met with limited success, with no marked improvement in drug efficacy or toxicity . Therefore, considering the current limitations in the optimal treatment of osteosarcoma patients, there is an urgent need to identify novel cellular targets for the development of new therapeutic regimens.…”

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confidence: 99%

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Tang

Seebacher

et al. 2019

Journal Orthopaedic Research

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Mutant TP53 is a promising therapeutic target in cancers. Considering the current challenges facing the clinical treatment of cancer, as well as the urgent need to identify novel therapeutic targets in osteosarcomas, we aimed to evaluate the clinical significance of mutant TP53 in osteosarcoma patients and to explore the therapeutic effect of targeting mutant TP53 in osteosarcomas. We performed a meta‐analysis to investigate the relationship between mutant TP53 and the overall survival of patients with osteosarcoma. A CRISPR‐Cas9 system and a TP53 inhibitor, NSC59984, were also used to specifically knock‐out and inhibit mutant TP53 in the human osteosarcoma cell lines, KHOS, and KHOSR2. The meta‐analysis demonstrated that mutations in the TP53 gene could be used to predict a poor 2‐year survival in osteosarcoma patients. We also demonstrated that the expression of mutant TP53 in human osteosarcoma cell lines can be efficiently knocked‐out using CRISPR‐Cas9, and this decreased the proliferation, migration, and tumor formation activity of these osteosarcoma cells. Moreover, drug sensitivity to doxorubicin was increased in these TP53 knock‐out osteosarcoma cells. NSC59984 also showed similar anti‐tumor effects as CRISPR‐Cas9 targeted TP53 in the osteosarcoma cells in vitro. We have also demonstrated that the knock‐out or inhibition of mutant TP53 decreased the expression of the oncogene IGF‐1R, anti‐apoptotic proteins Bcl‐2, and Survivin in osteosarcoma cells. Collectively, these results suggest that mutant TP53 is a promising therapeutic target in osteosarcomas. Therefore, further studies exploring novel strategies to target mutant TP53 may help improve the treatment outcomes of osteosarcoma patients in the clinic. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

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confidence: 99%

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Tang

Seebacher

et al. 2019

Journal Orthopaedic Research

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“…The median treatment duration from the start of preoperative chemotherapy was 31 weeks (IQR 28–37) in the API–AI protocol, and 37.4 weeks (IQR 34.7–39.9) for patients treated with the MTX‐based regimen . This was expected since the postoperative schedule with the MTX‐based regimen was longer for both good and poor responders.…”

Section: Discussionmentioning

confidence: 97%

“…The toxicities observed were mainly haematological with no significant difference in acute toxicities observed between patients younger than 25 years and those older than 25 years. Major modifications of the preoperative chemotherapy were less frequent (6%) than in patients treated with the MTX‐based regimen (15%), from which five patients died from adverse events …”

Section: Discussionmentioning

confidence: 99%

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Results of API–AI based regimen in osteosarcoma adult patients included in the French OS2006/Sarcome‐09 study

Piperno‐Neumann

Ray‐Coquard

Occean

et al. 2019

Intl Journal of Cancer

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In the OS2006 study, patients younger than 18 years were treated with a methotrexate‐based regimen (MTX), patients older than 25 years with a doxorubicin–cisplatin–ifosfamide‐based regimen (API–AI), whereas patients aged 18–25 years received either API–AI or MTX. We herein report the prespecified subgroup analysis of the outcome of 106 patients treated with API–AI. Preoperative chemotherapy combined three doxorubicin–ifosfamide–cisplatin (API) and two doxorubicin–ifosfamide (AI) courses. Postoperative chemotherapy was assigned by risk group: localised patients with a good histological response (<10% viable cells) received two AI and two cisplatin–ifosfamide (PI) courses; patients with synchronous metastases, poor histological response or unresectable primary received five cycles of etoposide–ifosfamide (EI). Of the 106 patients, 61 were randomised to receive or not zoledronate. Median age was 30 years (range 18–67), 66 (62%) patients were >25 years. The primary tumours were axial in 28 patients (26%), and 28 (26%) presented with metastases. Ninety‐six patients (91%) had surgery, conservative in 82 (85%); 36 patients (38%, 95% CI 28–48%) were good responders. Toxicity was manageable, with no significant difference in severe acute toxicity between patients aged >25 years and those younger. With a median follow‐up of 4.8 years, the 5‐year event‐free survival and overall survival rates were 46% (95% CI 36–56) and 57% (95% CI 47–67), respectively. The primary tumour size and initial metastases correlated with a higher risk of event. In these 106 osteosarcoma adult patients, API–AI proved feasible with no excess of toxicity, and favourable activity despite poor‐prognosis factors.

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“…Transactivation and upregulation of FPGS have been reported to promote the cytotoxicity of MTX in many cancer cell lines and vice versa. Treatment with histone deacetylase inhibitors (HDA-Cis) resulted in increased FPGS expression and higher intracellular accumulation of long-chain MTX-PG [3][4][5][6][7] in the relevant all models through epigenetic mechanisms involving histone modifications and chromatin remodelling and NFY-B-and Sp1-mediated recruitment of HDAC1 to the FPGS promoter [41]. Some fusion proteins, such as TEL-AML1 and E2A-PBX1, suppress FPGS transcription by recruiting co-repressors (mSin3A, Rb) and HDAC1 to the FPGS promoter region [42].…”

Section: Discussionmentioning

confidence: 99%

SKA1 induces de novo MTX‐resistance in osteosarcoma through inhibiting FPGS transcription

Min²,

Lin

et al. 2019

The FEBS Journal

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De novo methotrexate (MTX)‐resistance, whose underlying mechanism remains largely unknown, usually leads to very poor prognosis in patients with osteosarcoma (OS). In this study, we established the de novo MTX‐resistant OS cell line SF‐86 and identified the candidate gene spindle and kinetochore associated complex subunit 1 (SKA1) as potentially related to de novo MTX‐resistance. Analysis of a cohort of 95 OS patients demonstrated that SKA1 overexpression significantly correlated with de novo MTX‐resistance and poor 5‐year survival. Mechanistically, SKA1 overexpression lead to a downregulation of folylpoly‐γ‐glutamate synthetase (FPGS), a key enzyme that converts MTX into its active form, MTX‐PG. We further demonstrated that SKA1 interacts with DNA‐directed RNA polymerase II subunit RPB3. ChIP analysis revealed that RPB3 binds the promoter region of the FPGS gene and triggers FPGS transcription upon MTX treatment in SW1353, a MTX‐sensitive OS cell line lacking endogenous SKA1 expression. On the contrary, this process is blocked in SF‐86 cells due to the formation of an inhibitory SKA1‐RPB3 complex. Furthermore, downregulation of SKA1 levels restores MTX sensitivity in SF‐86. Collectively, our study has established the de novo MTX‐resistant cell line SF‐86 and identified SKA1 as a novel regulator of FPGS, playing a key role in the development of de novo MTX‐resistance in OS.

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Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study

Cited by 90 publications

References 23 publications

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Results of API–AI based regimen in osteosarcoma adult patients included in the French OS2006/Sarcome‐09 study

SKA1 induces de novo MTX‐resistance in osteosarcoma through inhibiting FPGS transcription

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