Trabectedin and irinotecan combination regresses a cisplatinum-resistant osteosarcoma in a patient-derived orthotopic xenograft nude-mouse model

https://doi.org/10.1016/j.bbrc.2019.03.191Get rights and content

Highlights

  • Osteosarcoma is the most common primary malignant bone tumor.

  • Osteosarcoma shows resistance to mainly available drugs.

  • Trabectedin (TRAB) and irinotecan (IRT) combination can regress osteosarcoma PDOX.

  • First study shows TRAB-IRT combination is active in osteosarcoma.

Abstract

Recurrent osteosarcoma is a chemotherapy-resistant disease. Individualized precision therapy is needed for this disease. Toward this goal, we have developed the patient-derived othotopic xenograft (PDOX) mouse model of all major cancer types including osteosarcoma. Synergistic efficacy of trabectedin (TRAB) and irinotecan (IRT) has been reported in Ewing's sarcoma, soft-tissue sarcoma, and ovarian cancer. However, the efficacy of this combination on osteosarcoma is not known. The goal of present study was to determine the efficacy of the TRAB and IRT combination on cisplatinum (CDDP)-resistant osteosarcoma PDOX. The osteosarcoma PDOX models were randomized into five treatment groups of six mice: Untreated control; CDDP alone; TRAB alone; IRT alone; and TRAB and the IRT combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was regressed only by the TRAB-IRT combination. Tumors treated with the TRAB-IRT combination had the most tumor necrosis with degenerative change. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the TRAB and IRT combination for chemotherapy-resistant osteosarcoma.

Introduction

Osteosarcoma is the most common primary malignant bone tumor which occurs mainly in children and adolescents [1,2]. Current therapeutic options for osteosarcoma include chemotherapy, surgery, and radiation therapy [3,4]. Cisplatinum (CDDP), doxorubicin (DOX), and high-dose methotrexate (MTX) are usually used either alone or in combination for first-line treatment of osteosarcoma [1,2,5]. However, resistance to these drugs is commonly seen, leading to a recurrence of the tumor which is often fatal to the patient [6]. This suggests that novel strategies are needed to overcome resistance to these drugs.

Trabectedin (TRAB) is an alkylating agent which covalently binds to the minor groove of DNA, disrupting transcription, blocking the cell cycle in late S/G2 phase, leading to apoptosis [7]. TRAB has been used as a single agent for the treatment of patients with soft-tissue sarcoma after failure of DOX or ifosfamide [7].

Irinotecan (IRT), a derivative of camptothecin, is an inhibitor of topoisomerase-1 and prevents DNA replication by binding to the topoisomerase-1-DNA complex, leading cell death in S-phase [8,9]. IRT has been widely used in the treatment of colorectal cancer with limited efficacy and better results have been achieved with IRT in combination with other cytotoxic drugs [10].

A strong synergism of TRAB and IRT has been shown in preclinical reports of several cancers such as Ewing's sarcoma, rhabdomyosarcoma, and ovarian cancer [8,[11], [12], [13]]. However, the efficacy of this combination for osteosarcoma is not known.

In the present study, we determined if the TRAB-IRT combination could overcome CDDP-resistance in a patient-derived orthotopic xenograft (PDOX) models of osteosarcoma.

Section snippets

Mice

Athymic nu/nu nude mice (AntiCancer, Inc., San Diego, CA, USA), 4–6 weeks old, were used. To minimize any suffering of the animals, anesthesia and analgesics were used for all surgical experiments [14]. The mouse investigations presented here were carried out using an AntiCancer, Inc. Institutional Animal Care and Use Committee (IACUC) protocol specifically approved for this study as previously described [14] and as per as the principles and procedures provided in the National Institute of

Efficacy of tested drugs on the osteosarcoma-PDOX

We tested the efficacy of CDDP, TRAB, IRT alone or in combination with TRAB on the CDDP-resistant osteosarcoma in a PDOX mouse model. TRAB alone or IRT alone significantly, but moderately, inhibited osteosarcoma PDOX growth compared with the untreated control (p = 0.04 and p = 0.007, respectively). On the other hand, the TRAB and IRT combination regressed the osteosarcoma PDOX tumor (p < 0.001). Only the TRAB-IRT combination had a significant increased efficacy compared to CDDP (p = 0.02).

Discussion

In the present study, we found the TRAB-IRT combination regressed a chemotherapy-resistant osteosarcoma tumor in a PDOX model (Fig. 4B). This is the first study which shows that the TRAB-IRT combination is active in osteosarcoma.

TRAB exhibited a favorable toxicity profile in the treatment of unrespectable liposarcomas or leiomyosarcomas in the clinic [7]. TRAB inhibited the growth and metastatis of the cutaneous melanoma [17]. TRAB resensitized recurrent ovarian cancer to platinum-based therapy

Declaration of interest statement

AntiCancer Inc. uses PDOX models for contract research. TK, KM, HO, NS, KH, HK, SM, KI and RMH are or were unsalaried associates of AntiCancer Inc. There are no other competing financial interests.

Acknowledgements

This paper is dedicated to the memory of Reese Imhoff.

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