Clinical Genomic Sequencing of Pediatric and Adult Osteosarcoma Reveals Distinct Molecular Subsets with Potentially Targetable Alterations

Suehara, Yoshiyuki; Alex, Deepu; Bowman, Anita S.; Middha, Sumit; Zehir, Ahmet; Chakravarty, Debyani; Wang, Lu; Jour, George; Nafa, Khédoudja; Hayashi, Takuo; Jungbluth, Achim A.; Frosina, Denise; Slotkin, Emily K.; Shukla, Neerav; Meyers, Paul A.; Healey, John H.; Hameed, Meera; Ladanyi, Marc

doi:10.1158/1078-0432.ccr-18-4032

Cited by 91 publications

(85 citation statements)

References 90 publications

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“…In metastatic/recurrent samples 41.2% had VEGFA whereas the primary site had only 9.7%. 56 Amplification of VEGFA has been shown to be a predictor of poor outcomes. 57 In the whole cohort, they found genetic changes that can be potentially targeted in 21% and in another 40% they found mutually exclusive VEGFA or PDGFR amplification which can be evaluated as targets.…”

Section: Genomic Profiling Next-generation Sequencing and Target-basmentioning

confidence: 99%

“…The authors proposed a genetic algorithm classifying approximately 50% of OGS patients eligible for targeted therapy trials. 56 Despite encouraging results in identification of targets in refractory paediatric sarcoma, genomic profiling and nextgeneration sequencing approaches are still experimental.…”

Section: Genomic Profiling Next-generation Sequencing and Target-basmentioning

confidence: 99%

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<p>Management of Refractory Pediatric Sarcoma: Current Challenges and Future Prospects</p>

Pushpam¹,

Garg²,

Ganguly³

et al. 2020

OTT

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Paediatric sarcomas are a heterogeneous group of disorders constituting bone sarcoma and various soft tissue sarcomas. Almost one-third of these presents with metastasis at baseline and another one-third recur after initial curative treatment. There is a huge unmet need in this cohort in terms of curative options and/or prolongation of survival. In this review, we have discussed the current treatment options, challenges and future strategies of managing relapsed/ refractory paediatric sarcomas. Upfront risk-adapted treatment with multidisciplinary management remains the main strategy to prevent future recurrence or relapse of the disease. In the case of limited local and/or systemic relapse or late relapse, initial multimodality management can be administered. In treatment-refractory cases or where cure is not feasible, the treatment options are limited to novel therapeutics, immunotherapeutic approach, targeted therapies, and metronomic therapies. A better understanding of disease biology, mechanism of treatment refractoriness, identifications of driver mutation, the discovery of novel targeted therapies, cellular vaccine and adapted therapies should be explored in relapsed/refractory cases. Close national and international collaboration for translation research is needed to fulfil the unmet need.

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Section: Genomic Profiling Next-generation Sequencing and Target-basmentioning

confidence: 99%

Section: Genomic Profiling Next-generation Sequencing and Target-basmentioning

confidence: 99%

<p>Management of Refractory Pediatric Sarcoma: Current Challenges and Future Prospects</p>

Pushpam¹,

Garg²,

Ganguly³

et al. 2020

OTT

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“…Advanced unresectable osteosarcoma is still a fatal disease in children and adults [ 34 ]. Even though a complex karyotype and the absence of a clear oncogene addiction [ 1 , 35 , 36 , 37 ] made osteosarcomas hard to tackle with target therapies, after our previous report of sorafenib activity in advanced osteosarcoma [ 38 , 39 ], several other TKIs have been tested and have shown intriguing, but short-lived activity [ 4 , 5 , 6 , 7 , 8 , 9 ]. Moreover, another level of complexity is represented by microenvironment contributions that fuel resistance/rescue pathways [ 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights

Chiabotto

Grignani

Todorovic

et al. 2020

Cancers

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Receptor tyrosine kinases (RTKs) inhibitors’ activity in advanced osteosarcoma is significant but short-lived. To prevent or at least delay drug resistance, we explored a vertical inhibition by combining drugs acting at different levels of the RTK pathways (pazopanib + trametinib). We studied pazopanib + trametinib antitumor activity both in vitro and in vivo (MNNG-HOS and KHOS xenografts in NOD/SCID mice) investigating the molecular mechanisms and potential escapes. The involvement of MAPK-PI3K pathways was validated by Nanostring technology, western blot and by silencing/overexpression experiments. Pazopanib targets were expressed on seven osteosarcoma cell lines and their pathways were activated. Pazopanib + trametinib exhibited synergistic antitumor activity by inducing apoptosis and inhibiting ERK1/2 and Akt. In vivo antitumor activity was shown in osteosarcoma-bearing mice. The drug combination significantly down-modulated RTK Ephrin Type-A Receptor 2 (EphA2) and Interleukin-7 Receptor (IL-7R), whereas induced mitogen-activated protein-kinase kinase (MAPKK) MEK6. EphA2 silencing significantly reduced osteosarcoma cell proliferation and migration, while impeding MEK6 up-regulation in the treated cells significantly increased the antitumor effect of the studied drugs. Moreover, the up-regulation of MEK6 reduced combination activity. Pazopanib + trametinib demonstrated synergistic antitumor effects in osteosarcoma models through ERK and Akt inhibition and EphA2 and IL-7R down-modulation. MEK6 up-regulation might evoke escaping mechanism.

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“…Han et al proposed that Ctsk+ cells serve as a physiologic and pathological precursor in osteogenic tumor[27–29], and we chose it as one of the major indicators. Meanwhile, bone sialoprotein (BSP) is thought to function in the initial mineralization of bone and selectively expresses by differentiated osteoblast[30]. Here, the OS cells were characterized using CDH11, BSP, LUM, DCN and COL1A1 as markers.…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, the genes related to p53 downstream signaling pathways were significantly enriched in the subcluster. As we know, TP53 and Rb1 exhibited the most frequent mutations in OS, which may be the initiating factors for OS tumorigenesis[30]. The OS cells with TP53 mutation exhibit a high chromosomic instability and lead to secondary genetic aberrations in new cancer cell clones that emerged from the initial monoclone [31].…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA-seq reveals identity and heterogeneity of malignant osteoblast cells and TME in osteosarcoma

Zhou

2020

Preprint

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25Osteosarcoma (OS) has high heterogeneity and poor prognosis. In order to explore the 26 molecular mechanism of OS and the tumor micro-environment (TME) on OS, we 27 employed single-cell RNA-sequencing (scRNA-seq) on 110,745 individual cells from 28 65 chromosomal lesions, including structural variations (SVs) and copy number 66 alterations (CNAs); however, few recurrent point mutations in protein-encoding genes 67 have been identified in OS [11][12][13][14][15].Low expression of immune-associated genes is 68 another significant phenotype for OS [16]. How to convert the immunosuppressive 69 microenvironment into the one that favors the induction of antitumor immunity is 70 indispensable for effective cancer immunotherapy. 71Here, we employed single cell transcriptome approach to dissect the 72 heterogeneity of OS cells. We analyzed the transcriptomic profiles of a total of 73 110745 cells from 7 primary tumors, 2 lung metastatic and 2 recurrent OS tissues. We 74 first divided the OS cells into 5 sub-clusters and osteoclast into 3 subtypes. The 75 profiles of OS, OC and immune-system cells were analyzed. We found that the TME 76 of the recurrent and lung metastatic OS exhibited more significant suppressivity than 77 primary tumor tissue. Thus, the results in this study improve the understanding of the 78 immune-suppressivity observed in advanced OS including distant metastasis and 79 recurrence, and are potentially valuable in novel treatment strategy for OS. 80Of importance, we are the first to uncover that Treg cells in OS expressed 81 TIGIT. TIGIT is a coinhibitory receptor expressed on effector T cells, natural killer 82 (NK) cells, T regulatory cells (Treg) and T follicular helper (TFH) cells. It has gained 83 attention as a potential therapeutic target in wide variety of tumors[17-19]. The 84 antibodies of TIGIT, named BGB-A1217, had registered and recruited on August 85 2019. Here we explored the preclinical significance of blocking of TIGIT. 86 Method 87 Patients 88 The eleven patients for scRNA-seq analysis enrolled in this study were hospitalized 89 during the period of The study was approved by Shanghai Sixth People's Hospital Ethics Committee. Each 91 patient was provided a written signed consent. All patients were diagnosed according 92 to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines 93 in Oncology with the terms of Bone Cancer (Version 2.2019). Among 11 patients for 94 scRNA-seq, 7 were derived from the primary sites of patients who received traditional 95 first line combination chemotherapy for OS, including Adriamycin(ADM), 96 cisplatin(DDP), methotrexate(MTX) and Ifosfamide(IFO) and surgical therapy. 2 lung 97 metastatic patients and 2 recurrent patients all received the gemcitabine combined 98 with Docetaxel(GT) chemotherapy treatment. The BC17, one of the lung metastasis 99 patients, had enrolled in clinical trial NCT03676985 and undergone the anti-PD-L1 100 treatment for 6 times. For this clinical trial, all enrolled patients had finished the 101 neoadjuvant...

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Clinical Genomic Sequencing of Pediatric and Adult Osteosarcoma Reveals Distinct Molecular Subsets with Potentially Targetable Alterations

Cited by 91 publications

References 90 publications

<p>Management of Refractory Pediatric Sarcoma: Current Challenges and Future Prospects</p>

<p>Management of Refractory Pediatric Sarcoma: Current Challenges and Future Prospects</p>

Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights

Single-cell RNA-seq reveals identity and heterogeneity of malignant osteoblast cells and TME in osteosarcoma

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