scholarly journals A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies

Sarcoma ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Jody E. Hooper ◽  
Emma L. Cantor ◽  
Macgregor S. Ehlen ◽  
Avirup Banerjee ◽  
Suman Malempati ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Single Agent ◽  
Xenograft Model ◽  
Soft Tissue Sarcomas ◽  
Preclinical Study ◽  
Embryonal Rhabdomyosarcoma ◽  
Rapid Weight Loss ◽  
Primary Tumor Site ◽  
Immunodeficient Mice ◽  
Patient Derived Xenograft

Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

A phase I trial of doxorubicin and flavopiridol in soft tissue sarcoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9523-9523 ◽  
Author(s):  
D. R. D’Adamo ◽  
K. Scheu ◽  
S. Singer ◽  
G. K. Schwartz ◽  
R. G. Maki
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Phase I ◽  
Stable Disease ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Xenograft Model ◽  
Fixed Dose ◽  
Preclinical Model ◽  
Combination Methods

9523 Background: Flavopiridol, a potent cyclin dependent kinase inhibitor, has been shown in vitro to enhance doxorubicin induced apoptosis. Using the BWH dediffentiated liposarcoma xenograft model we have shown that sequential therapy with doxorubicin (D) followed 1 hour later by flavopiridol (F) is superior to doxorubicin alone (p=0.006). Single agent flavopiridol was also active in this xenograft model, but less so than the combination. Methods: We have commenced an ongoing phase I study of the combination of D and F on the basis of this preclinical data in soft tissue sarcoma with fixed dose D (60 mg/m2), followed 1 hour later by escalating doses of F (40–70 mg/m2) administered over one hour, every 3 weeks. Standard phase I eligibility criteria apply. No prior anthracycline therapy is allowed. At 300 mg/m2 D, dexrazoxane is added to D F. Patients with responsive or stable disease after cumulative D dose of 600mg/m2 can receive single agent flavopiridol. Results: Median characteristics of 7 evaluable patients: age 52 (31–65), KPS 80% (70–90), 3 males / 4 females, 0 prior regimens (range 0–2). The combination has been well-tolerated, with no dose limiting toxicity (DLT) yet. There has been 1 grade 3 bleed in the setting of progressive disease and 1 grade 4 neutropenia without fever. Grade 1 and 2 diarrhea, related to flavopiridol have been observed. Pharmacokinetic (PK) studies are ongoing. We have observed no partial responses (PR). Prolonged stable disease (SD) has been seen in 3 patients for 6, 6 and 11 months. Two patients with SD have liposarcoma. One patient with liposarcoma continues on single agent flavopiridol with stable disease after having reached the prescribed limit of D of 600 mg/m2. Conclusions: The combination of doxorubicin and flavopiridol is safe, with no unexpected toxicities. Disease stabilization in STS has been observed. This appears to be an encouraging combination in liposarcoma and is consistent with our preclinical model. Flavopiridol dose escalation is continuing. No significant financial relationships to disclose.

Pazopanib for metastatic soft-tissue sarcoma: A multicenter retrospective study

2020 ◽  
pp. 107815522092407
Author(s):  
Sinan Koca ◽  
Mehmet Beşiroğlu ◽  
Melike Özçelik ◽  
Mustafa Karaca ◽  
Mehmet Bilici ◽  
...  
Keyword(s):  
Overall Survival ◽  
Weight Loss ◽  
Retrospective Study ◽  
Soft Tissue ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Real Life ◽  
Soft Tissue Sarcomas ◽  
Progression Free Survival ◽  
Free Survival

Purpose Soft tissue sarcomas are associated with a poor prognosis and low chemotherapeutic efficiency. Pazopanib is an orally available multi-tyrosine kinase inhibitor that was explored in patients with non-adipocytic advanced soft tissue sarcomas. The aim of this retrospective study was to evaluate the real life data of single-agent pazopanib efficacy and safety for soft tissue sarcomas in the Turkish population. Materials and methods We evaluated a total of 103 patients (41 males, 62 females) who received pazopanib for advanced non-adipocytic soft tissue sarcomas diagnosis in eight centers of Turkey, retrospectively. The pazopanib dose was 800 mg once daily. Progression-free survival, overall survival, and adverse events were analyzed. Results The median age was 50 years (range, 38–58). Majority of the patients had leimyosarcoma (41%). Median progression-free survival was 4.3 months, and the median overall survival was 10.1 months. The main common toxicities were fatigue, anorexia, weight loss, nausea, hypertension, and grade ≥3 toxicities were fatigue, anorexia, weight loss, and liver disorder. Conclusion Pazopanib is an efficient and tolerable agent and is well tolerated in good performance status patients with relapsed, advanced non-adipocytic soft tissue sarcomas.

scholarly journals Combination of sorafenib and everolimus impacts therapeutically on adrenocortical tumor models

2012 ◽  
Vol 19 (4) ◽  
pp. 527-539 ◽  
Author(s):  
Barbara Mariniello ◽  
Antonio Rosato ◽  
Gaia Zuccolotto ◽  
Beatrice Rubin ◽  
Maria Verena Cicala ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Cell Viability ◽  
Kinase Inhibitor ◽  
Xenograft Model ◽  
Tumor Cell Line ◽  
Tumor Growth Inhibition ◽  
Adrenocortical Cancer ◽  
Antitumor Effects ◽  
Immunodeficient Mice

Treatment options are insufficient in patients with adrenocortical carcinoma (ACC). Based on the efficacy of sorafenib, a tyrosine kinase inhibitor, and everolimus, an inhibitor of the mammalian target of rapamycin in tumors of different histotype, we aimed at testing these drugs in adrenocortical cancer models. The expression of vascular endothelial growth factor and its receptors (VEGFR1–2) was studied in 18 ACCs, 33 aldosterone-producing adenomas, 12 cortisol-producing adenomas, and six normal adrenal cortex by real-time PCR and immunohistochemistry and by immunoblotting in SW13 and H295R cancer cell lines. The effects of sorafenib and everolimus, alone or in combination, were tested on primary adrenocortical cultures and SW13 and H295R cells by evaluating cell viability and apoptosis in vitro and tumor growth inhibition of tumor cell line xenografts in immunodeficient mice in vivo. VEGF and VEGFR1–2 were detected in all samples and appeared over-expressed in two-thirds of ACC specimens. Dose-dependent inhibition of cell viability was observed particularly in SW13 cells after 24 h treatment with either drug; drug combination produced markedly synergistic growth inhibition. Increasing apoptosis was observed in tumor cells treated with the drugs, particularly with sorafenib. Finally, a significant mass reduction and increased survival were observed in SW13 xenograft model undergoing treatment with the drugs in combination. Our data suggest that an autocrine VEGF loop may exist within ACC. Furthermore, a combination of molecularly targeted agents may have both antiangiogenic and direct antitumor effects and thus could represent a new therapeutic tool for the treatment of ACC.

scholarly journals DIPG-50. A NOVEL ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODEL OF RADIATION-INDUCED GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii296-iii296
Author(s):  
Jacqueline Whitehouse ◽  
Meegan Howlett ◽  
Jason Stanley ◽  
Hilary Hii ◽  
Santosh Valvi ◽  
...  
Keyword(s):  
Primary Tumour ◽  
Xenograft Model ◽  
Methylation Array ◽  
Immunodeficient Mice ◽  
Variants Of Unknown Significance ◽  
Patient Derived Xenograft ◽  
Pdx Model ◽  
Unknown Significance ◽  
Dna Methylation Array

Abstract Diffuse midline glioma (DMG) can arise as a primary tumour but also as a consequence of radiation therapy (RT) in survivors of other paediatric brain tumours. Radiation-associated gliomas are molecularly distinct from primary gliomas and have poorer overall survival. We report a case of radiation-associated DMG following treatment for medulloblastoma, and the development of a matched patient-derived xenograft (PDX) model. A four-year-old boy diagnosed with medulloblastoma was treated with surgical resection, RT and chemotherapy (COG:CCG-99701-Arm B). Eleven years post-diagnosis, the patient relapsed with radiation-associated DMG, participated in a Phase I clinical trial (COG:ACNS0927), and passed away eight months later. Tumour tissue collected at autopsy was intracranially implanted into immunodeficient mice and serially transplanted in vivo. Immunohistochemistry demonstrated both the primary DMG and PDXs expressed PDGFR-alpha and PTEN, were H3K27me3-positive, and had undetectable levels of p53. Sequencing revealed an activating mutation in PI3-kinase (H1047L) and variants of unknown significance in GRK4, FLG, BAZ2A, and CRTC3. DNA methylation array of the PDX demonstrated 1p loss, which is not typically associated with primary DMG, and broad deletion within 9p including CDKN2A/B, MTAP and multiple interferon genes. The methylation profile did not significantly classify with other tumours in the Molecular Neuropathology database (molecularneuropathology.org/mnp). We describe the first reported PDX model of radiation-associated DMG following medulloblastoma, which recapitulates the patient disease and is molecularly distinct from primary DMG. Interrogation of this model through RNA and whole genome sequencing presents a valuable opportunity to better understand and identify novel therapeutic vulnerabilities against this currently incurable disease.

Evaluation of combined BCL-2/MCL-1 inhibition as a therapeutic approach for synovial sarcoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e23561-e23561 ◽  
Author(s):  
Carter Kent Fairchild ◽  
Konstantinos Floros ◽  
Sheeba Jacob ◽  
Colin Coon ◽  
Madhavi Puchalapalli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Synovial Sarcoma ◽  
Cell Lines ◽  
Fusion Gene ◽  
Single Agent ◽  
Xenograft Model ◽  
Patient Derived Xenograft ◽  
Hematological Cancers ◽  
Rational Combination

e23561 Background: While Synovial Sarcoma (SS) only accounts for about 10% of soft tissue sarcomas (STS), or ~10,000 cases/year, ~4,000 of these will be fatal. Little benefit has been seen with newer combination chemotherapies and immune checkpoint inhibitors. SS is a transcription factor-driven cancer characterized by an t(X;18) chromosomal translocation resulting in the SS18-SSX fusion gene. SS is also known to overexpress the anti-apoptotic protein BCL-2, which has been used as a diagnostic marker for SS. Venetoclax, the FDA approved BH3 mimetic which specifically inhibits BCL-2, has been used to treat BCL-2-driven hematological cancers. Yet, preclinical studies of venetoclax, currently in clinical use for BCL-2 related hematologic malignancies, have failed in SS, raising the possibility of other BCL-2 family members playing a role in resistance. Methods: Publicly available gene expression databases of SS were queried for expression of BCL-2 family member expression, including the endogenous MCL-1 inhibitor, NOXA. Six SS cell lines, including ASKA, HS-SY-II, Yamato, SW982, SYO.1, and an ex vivo line from a SS patient-derived xenograft (PDX) were tested in vitro with combinations of venetoclax and the MCL-1 inhibitor S63845, using cell viability assays. In vivo testing employed both a patient-derived xenograft (PDX) model of SS and a cell line derived (SYO.1) xenograft model. Results: Queries of published gene expression data for SS demonstrated that SS expresses low levels of the endogenous MCL-1 inhibitor, NOXA, nominating a mechanism for intrinsic venetoclax resistance in these tumors, and suggesting rational combination of venetoclax and the MCL-1 inhibitor, S63845. In vitro, SS all cell lines possessing the SS18-SSX fusion gene demonstrated synergistic sensitivity to combined S63845 and venetoclax, despite generally insensitivity to either drug as monotherapy. Importantly, in an SS PDX, we demonstrated S63845 and venetoclax synergize to induce tumor regression. In the SYO.1 xenograft model, combination therapy significantly reduced tumor growth compared to no treatment or single agent groups. Conclusions: These findings provide the preclinical rationale for translation of the rational combination of BCL-2 and MCL-1 inhibitors into clinical trials for SS.

scholarly journals Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma

2021 ◽  
Author(s):  
Yu-bo Zhou ◽  
Yang-ming Zhang ◽  
Hong-hui Huang ◽  
Li-jing Shen ◽  
Xiao-feng Han ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Targets ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Preclinical Study ◽  
Parp Cleavage ◽  
Rpmi 8226 ◽  
Ongoing Phase

AbstractHDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%–35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

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