A patient-derived orthotopic xenograft (PDOX) nude-mouse model precisely identifies effective and ineffective therapies for recurrent leiomyosarcoma

Abstract

Leiomyosarcoma is a rare and recalcitrant disease. Doxorubicin (DOX) is usually considered first-line treatment for this disease, but frequently is ineffective. In order to individualize therapy for this and other cancers, we have developed the patient-derived orthotopic xenograft (PDOX) mouse model. In the present study, we implanted a recurrent leiomyosarcoma from a resected tumor from the patient’s thigh into the femoral muscle of nude mice. The following drugs were tested on the leiomyosarcoma PDOX model: DOX, the combination of gemcitabine (GEM) and docetaxel (DOC), trabectedin (TRA), temozolomide (TEM), pazopanib (PAZ) and olaratumab (OLA). Of these agents GEM/DOC, TRA and TEM were highly effective in the leiomyosarcoma PDOX model, the other agents, including first-line therapy DOX, were ineffective. Thus the leiomyosarcoma PDOX model could precisely distinguish effective and ineffective drugs, demonstrating the potential of the PDOX model for leiomyosarcoma treatment.

Introduction

Leiomyosarcoma is one of the most frequent soft tissue sarcomas (STS), accounting for 10% of all STS. It occurs often in the thigh [1,2] and other places in the body including the retroperitoneum, uterus, breast, pulmonary vein, intracranial and thyroid [[3], [4], [5], [6]]. Patients with leiomyosarcoma have a poor prognosis, frequent recurrence and very low response to currently available chemotherapies. Pathophysiology of leiomyosarcoma is poorly defined. Recent genomic and transcriptomic analysis showed that leiomyosarcoma is characterized by high chromosomal instability, mutational heterogeneity and activation of genes that induce cell proliferation and anti-apoptotic pathways [7,8].

Surgical resection is the best option of treating leiomyosarcoma. Several chemotherapy drugs have been reported for the treatment of leiomyosarcoma in the last 30 years with variable response [[9], [10], [11], [12]]. Doxorubicin (DOX) is first-line therapy for leiomyosarcoma, but the responsive rate is low [13]. The combination of gemcitabine (GEM) and docetaxel (DOC) (GEM/DOC) is also used for leiomyosarcoma with limited efficacy [13]. Trabectedin (TRA) has also been used in advanced leiomyosarcoma, and its efficacy may be better than dacarbazine [14,15]. Temozolomide (TEM) is an oral alkylating agent with well-tolerance and promising efficacy in metastatic unresectable leiomyosarcoma [16,17]. The multitarget tyrosine kinase inhibitor pazopanib (PAZ) has shown some efficacy for recurrent leiomyosarcoma [18]. Olaratumab (OLA), a monoclonal antibody that blocks the platelet-derived growth factor receptor alpha (PDGFRα) has shown efficacy against leiomyosarcoma in combination with DOX [19,20].

Our laboratory developed the patient-derived orthotopic xenograft (PDOX) mouse model of cancer in which tumor fragments are implanted directly into the corresponding anatomic location in the mouse. Using surgical orthotopic implantation (SOI) techniques, we have developed PDOX models of all major cancer [[21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]]. We also demonstrated that the PDOX model is more patient-like than the subcutaneous patient-derived xenograft (PDX) model [32,33]. Our previous studies suggest that PDOX model retain the original histological and molecular characters after xenograft in mice [27,29,30]. We previously developed a PDOX model of gastric leiomyosarcoma, and we found that GEM/DOC could regress the PDOX leiomyosarcoma and was significantly more effective than DOX [31].

In the present study, we established a PDOX model of an advanced leiomyosarcoma originating from the left medial high to evaluate the efficacy of 7 different treatments groups, in order to provide a precise individualized treatment data.