Review: Precise sarcoma patient-derived orthotopic xenograft (PDOX) mouse models enable identification of novel effective combination therapies with the cyclin-dependent kinase inhibitor palbociclib: A strategy for clinical application

Abstract

Introduction: Sarcomas are rare heterogeneous malignant tumors that originate and develop in soft tissue or bone. Effective treatment for sarcomas is still limited to traditional chemotherapy and surgery that are often ineffective for recurrent disease. Cyclin-dependent kinases (CDKs) promote abnormal cell cycling and cell division in many cancers including sarcomas. Therefore, our hypothesis was that CDK inhibitors may be useful candidates for sarcoma treatment. Patient-derived orthotopic xenograft (PDOX) mouse models mimic the clinical disease for all major cancer types and have identified effective treatments that hold much clinical promise. The present report reviews sarcoma PDOX models that we have established for their potential to discover effective combination treatments based on CDK inhibitors for recalcitrant sarcoma.

Methods: We have previously reported six sarcoma PDOX studies evaluating the CDK inhibitor palbociclib on sarcoma, including osteosarcoma, Ewing sarcoma, de-differentiated liposarcoma, and peritoneal metastatic leiomyosarcoma.

Results: Palbociclib monotherapy significantly inhibited, but not regressed, the PDOX growth of osteosarcoma, Ewing sarcoma, de-differentiated liposarcoma, and peritoneal metastatic leiomyosarcoma. A combination of palbociclib and a mammalian target of rapamycin (mTOR) inhibitor, everolimus, significantly inhibited, but did not regress, the PDOX growth of osteosarcoma. Combinations of palbociclib with a multikinase inhibitor, sorafenib, and palbociclib combined with recombinant methioninase were effective and regressed the osteosarcoma and de-differentiated liposarcoma PDOX models, respectively.

Conclusions: Novel effective drug combinations using the CDK inhibitor palbociclib were identified in PDOX models of the major types of sarcomas. Methionine restriction effected by methioninase increased the efficacy of palbociclib. Combination therapy with palbociclib is a promising future strategy for improved sarcoma therapy in the clinic.

Keywords: CDK4/6 inhibitor; combination therapy; methioninase; osteosarcoma; palbociblib; patient-derived orthotopic xenograft (PDOX); sarcoma; soft-tissue sarcoma.

Figure 1

Establishment of a patient-derived orthotopic xenograft (PDOX) models of sarcoma. (A) Chest-wall Ewing sarcoma PDOX model. (B) Peritoneum and retroperitoneum soft-tissue sarcoma PDOX models. (C) Osteosarcoma PDOX model.

Figure 2

A representative osteosarcoma patient-derived orthotopic xenograft (PDOX) study identifying effective combination treatment with palbociclib. (A) The line graphs indicate the tumor volume at each time point after treatment start relative to the initial tumor volume for each group. *p < 0.05; ***p < 0.001. Error bar: ± standard error of the mean. (B) Representative photographs of the control, palbociclib-treated, or palbociclib–sorafenib combination-treated osteosarcoma PDOX models. Arrows indicate the tumor margins. (C) Hematoxylin and eosin-stained sections of control, palbociclib-treated, or palbociclib–sorafenib combination-treated tumors. Scale bar: 100 µm. Modified after Higuchi et al. (35).