The use of whole exome sequencing and murine patient derived xenografts as a method of chemosensitivity testing in sarcoma

Calvert, Nicholas; Wu, Jiansha; Sneddon, Sophie; Woodhouse, Jennifer; Carey-Smith, Richard; Wood, David; Ingley, Evan

doi:10.1186/s13569-018-0090-1

Cited by 5 publications

(4 citation statements)

References 32 publications

(27 reference statements)

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“…These findings support the notion that the serial transplantation of PDX models may enhance drug sensitivity, which in turn may contribute to the observations of variable clinical responses. Because of proven discrepancies in drug sensitivity in later passage PDXs, subsequent studies have modified the experimental design to use early passage PDX models . A recent study in head and neck squamous cell carcinoma showed genomic SMAD family member 4 (SMAD4) alterations in PDX .…”

Section: Aggressive Phenotypes and Variable Drug Sensitivitymentioning

confidence: 99%

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

Shi

Jia

et al. 2019

Intl Journal of Cancer

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Patient‐derived xenograft (PDX) models are widely used as preclinical cancer models and are considered better than cell culture models in recapitulating the histological features, molecular characteristics and intratumoral heterogeneity (ITH) of human tumors. While the PDX model is commonly accepted for use in drug discovery and other translational studies, a growing body of evidence has suggested its limitations. Recently, the fidelity of cancer cells within a PDX has been questioned, which may impede the future application of these models. In this review, we will focus the variable phenotypes of xenograft tumors and the genomic instability and molecular inconsistency of PDX tumors after serial transplantation. Next, we will discuss the underlying mechanism of ITH and its clinical relevance. Stochastic selection bias in the sampling process and/or deterministic clonal dynamics due to murine selective pressure may have detrimental effects on the results of personalized medicine and drug screening studies. In addition, we aim to identify a possible solution for the issue of fidelity in current PDX models and to discuss emerging next‐generation preclinical models.

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Section: Aggressive Phenotypes and Variable Drug Sensitivitymentioning

confidence: 99%

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

Shi

Jia

et al. 2019

Intl Journal of Cancer

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“…With the advances in genetic testing, whole exome sequencing (WES) of fresh tumor specimens via a bioinformatics pipeline may help identify potential actionable chemotherapy agents for angiosarcomas and may lead to developing personalized cancer therapy in the future. A pilot, prospective, nonrandomized control experimental study by Calvert et al analyzed 12 patients with metastatic bone or soft tissue sarcoma who had failed first-line chemotherapy treatment [ 49 ]. One part of the surgical tumor biopsy material was used for WES, and the remaining part was implanted subcutaneously in immunodeficient mice.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, WES identified potential actionable therapeutics in all 12 patients with successfully established PDX tumor models in 7 patients. Significant variation in predicted therapeutics was demonstrated between three PDX samples and their matched tumor samples [ 49 ]. This trial is an example of a bright glimpse into modern personalized cancer management as genetic testing gets more available every year [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Paraneoplastic Phenomena of Disseminated Intravascular Coagulopathy in Hepatic Angiosarcoma – Rare, Challenging and Fatal. Case Report and Literature Review

Strainiene

Jauniškis

Savlan

et al. 2021

AML

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Background. Hepatic angiosarcoma is an uncommon, malignant, primary liver tumor, comprising 2% of liver cancers and accounting for < 1% of all sarcomas. Patients usually present with nonspecific symptoms, such as fatigue, weight loss, right upper quadrant pain, anemia, which leads to late diagnosis of an advanced stage tumor. The median life expectancy after the diagnosis of hepatic angiosarcoma is about 6 months, with only 3% of patients surviving more than 2 years. Liver failure and hemoperitoneum are the leading causes of death in patients with liver angiosarcoma. In rarer cases, it might cause paraneoplastic syndromes such as disseminated intravascular coagulopathy. The treatment of angiosarcomas is complicated as there are no established and effective treatment guidelines due to the tumor’s low frequency and aggressive nature.Case summary. We present the case of a 68-year old woman who was admitted to the hospital due to fatigueand severe anemia (hemoglobin 65 g/l). Laboratory results also revealed high-grade thrombocytopenia(8 × 109/l). The abdominal ultrasound and computed tomography scan showed multiple lesions throughout with hepatic angiosarcoma. The treatment with first-line chemotherapy (doxorubicin) was initiated despiteongoing paraneoplastic syndrome – disseminative intravascular coagulopathy. However, the disease was terminal, and the patient died 2 months since diagnosed.Conclusions. Hepatic angiosarcoma is a rare and terminal tumor. Therefore, knowledge about its manifestations and effective treatment methods is lacking. Disseminative intravascular coagulopathy is a unique clinical characteristic of angiosarcoma seen in a subset of patients.

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“…However, current OS therapeutic agents have been limited to cytotoxic drugs interfering with DNA replication (Lamplot et al, 2013; S. Y. Wang, Hu, Qing, Zhang, & Shao, 2020), with a lack of targeted therapies, due to the fact that OSs can have unique underlying genetic drivers in addition to their near‐ubiquitous disruption of the TP53 and Rb tumour suppressors, resulting in their varied protein expression patterns (Krzyszczyk et al, 2018). Personalised medicine approaches have developed using whole exome or genome sequencing to identify targetable drivers including tyrosine kinases that can be involved in OS progression (Calvert et al, 2018). Our current knowledge of the molecular mechanisms and pathways involved in OS progression have the potential to uncover novel therapeutics for OS by targeted small molecule anticancer drugs.…”

Section: Molecular Pathology Of Osmentioning

confidence: 99%

The Hippo in the room: Targeting the Hippo signalling pathway for osteosarcoma therapies

Rothzerg

Ingley

Mullin

et al. 2020

Journal Cellular Physiology

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Osteosarcoma (OS) is a primary malignant bone tumour which usually occurs in children and adolescents. OS is primarily a result of chromosomal aberrations, a combination of acquired genetic changes and, hereditary, resulting in the dysregulation of cellular functions. The Hippo signalling pathway regulates cell and tissue growth by modulating cell proliferation, differentiation, and migration in developing organs. Mammalian STE20-like 1/2 (MST1/2) protein kinases are activated by neurofibromatosis type 2, Ras association domain family member 2, kidney and brain protein, or other factors. Interactions between MST1/2 and salvador family WW domain-containing protein 1 activate large tumour suppressor kinase 1/2 proteins, which in turn phosphorylate the downstream Yes-associated protein 1/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). Moreover, dysregulation of this pathway can lead to aberrant cell growth, resulting in tumorigenesis. Interestingly, small molecules targeting the Hippo signalling pathways, through affecting YAP/TAZ cellular localisation and their interaction with members of the TEA/ATTS domain family of transcriptional enhancers are being developed and hold promise for the treatment of OS. This review discusses the existing knowledge about the involvement of the Hippo signalling cascade in OS and highlights several small molecule inhibitors as potential novel therapeutics.

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The use of whole exome sequencing and murine patient derived xenografts as a method of chemosensitivity testing in sarcoma

Cited by 5 publications

References 32 publications

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

Paraneoplastic Phenomena of Disseminated Intravascular Coagulopathy in Hepatic Angiosarcoma – Rare, Challenging and Fatal. Case Report and Literature Review

The Hippo in the room: Targeting the Hippo signalling pathway for osteosarcoma therapies

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