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Case Reports
. 2018 Aug 20;18(1):840.
doi: 10.1186/s12885-018-4703-0.

Trabectedin arrests a doxorubicin-resistant PDGFRA-activated liposarcoma patient-derived orthotopic xenograft (PDOX) nude mouse model

Tasuku Kiyuna  1   2   3 , Yasunori Tome  4 , Takashi Murakami  1   2 , Kei Kawaguchi  1   2 , Kentaro Igarashi  1   2 , Kentaro Miyake  1   2 , Masuyo Miyake  1   2 , Yunfeng Li  5 , Scott D Nelson  5 , Sarah M Dry  5 , Arun S Singh  6 , Tara A Russell  7 , Irmina Elliott  7 , Shree Ram Singh  8 , Fuminori Kanaya  3 , Fritz C Eilber  9 , Robert M Hoffman  10   11
Affiliations
Case Reports

Trabectedin arrests a doxorubicin-resistant PDGFRA-activated liposarcoma patient-derived orthotopic xenograft (PDOX) nude mouse model

Tasuku Kiyuna et al. BMC Cancer. .

Abstract

Background: Pleomorphic liposarcoma (PLPS) is a rare, heterogeneous and an aggressive variant of liposarcoma. Therefore, individualized therapy is urgently needed. Our recent reports suggest that trabectedin (TRAB) is effective against several patient-derived orthotopic xenograft (PDOX) mouse models. Here, we compared the efficacy of first-line therapy, doxorubicin (DOX), and TRAB in a platelet-derived growth factor receptor-α (PDGFRA)-amplified PLPS.

Methods: We used a fresh sample of PLPS tumor derived from a 68-year-old male patient diagnosed with a recurrent PLPS. Subcutaneous implantation of tumor tissue was performed in a nude mouse. After three weeks of implantation, tumor tissues were isolated and cut into small pieces. To match the patient a PDGFRA-amplified PLPS PDOX was created in the biceps femoris of nude mice. Mice were randomized into three groups: Group 1 (G1), control (untreated); Group 2 (G2), DOX-treated; Group 3 (G3), TRAB-treated. Measurement was done twice a week for tumor width, length, and mouse body weight.

Results: The PLPS PDOX showed resistance towards DOX. However, TRAB could arrest the PLPS (p < 0.05 compared to control; p < 0.05 compared to DOX) without any significant changes in body-weight.

Conclusions: The data presented here suggest that for the individual patient the PLPS PDOX model could specifically distinguish both effective and ineffective drugs. This is especially crucial for PLPS because effective first-line therapy is harder to establish if it is not individualized.

Keywords: Liposarcoma; PDGFRA amplification; PDOX; Patient-derived orthotopic xenograft; Precision medicine; Trabectedin.

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Conflict of interest statement

Ethics approval and consent to participate

Written informed consent was obtained from the patient as part of a University of California, Los Angeles (UCLA) Institutional Review Board (IRB#10–001857) approved protocol. Written informed consent was obtained from the patient for publication of the study. All mice investigations were done with an AntiCancer, Inc. Institutional Animal Care and Use Committee (IACUC)-protocol mainly approved for this study and in correspondence with the principals and procedures outlined in the National Institute of Health (NIH) Guide for the Care and Use of Animals under Assurance Number A3873–1.

Consent for publication

Written informed consent was obtained from the patient for publication of the study.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Treatment protocol and quantitative drug efficacy. Treatment protocol. G1: untreated control (n = 7); G2: treated with doxorubicin (DOX) (3 mg/kg, i.v., weekly, 2 weeks, n = 7); Group 3, treated with trabectedin (TRAB) (0.15 mg/kg, i.v., weekly, 2 weeks, n = 7). All treated mice were sacrificed on termination day-15, and tumors were resected for further histological evaluation
Fig. 2
Fig. 2
Line graphs show relative tumor volume (tumor at any time point relative to day 0). *p < 0.05, **p < 0.01, Error bars: ±SD
Fig. 3
Fig. 3
a Tumor volumes at the end of the experiment (day-15). b: Macro tumor images after treatment. All treated mice were sacrificed on day-15, and tumors were resected for further histological evaluation. Images are representative of tumors harvested after orthotopic growth in the biceps femoris. Scale bar: 10 mm
Fig. 4
Fig. 4
Mouse body weight. Bar graphs show body weight of mice treated with each compound as well as the untreated control. Error bars: ± SD. n.s.: not significant
Fig. 5
Fig. 5
Tumor histology. Hematoxylin and eosin (H&E), a stained sections of tumors. a: original patient tumor; b: untreated control PDOX tumor; c: DOX-treated PDOX tumor; d: TRAB- treated PDOX tumor. Scale bars: 100 μm
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References

    1. Manji GA, Schwartz GK. Managing Liposarcomas: cutting through the fat. J Oncol Pract. 2016;12(3):221–227. - PubMed
    1. Agarwal J, Kadakia S, Agaimy A, Ogadzanov A, Khorsandi A, Chai RL. Pleomorphic liposarcoma of the head and neck: presentation of two cases and literature review. Am J Otolaryngol. 2017;38(4):505–507. - PubMed
    1. Tiemeier GL, Brown JM, Pratap SE, McCarthy C, Kastrenopoulou A, Bradley K, Wilson S, Orosz Z, Gibbons CLMH, Oppermann U, Athanasou NA. Pleomorphic liposarcoma of bone: a rare primary malignant bone tumour. Clin Sarcoma Res. 2018;8:2. - PMC - PubMed
    1. Ahmed Z, Shah HU, Yaqoob N, et al. Pleomorphic liposarcoma in a ten year old child. J Pak Med Assoc. 2004;54:533–534. - PubMed
    1. Saeed M, Plett S, Kim GE, et al. Radiological-pathological correlation of pleomorphic liposarcoma of the anterior mediastinum in a 17-year-old girl. Pediatr Radiol. 2010;40(suppl 1):S68–S70. - PMC - PubMed

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