pazopanib and Osteosarcoma

Due to the rarity and heterogeneity of bone and soft-tissue sarcomas, investigation into molecular targets and new treatments has been particularly challenging. Although intensive chemotherapy and establishment of surgical procedures have improved the outcomes of patients with sarcoma, the curative rate of recurrent and metastatic sarcomas is still not satisfactory. Recent basic science research has revealed some of the mechanisms of progression and metastasis of malignancies including proliferation, apoptosis, angiogenesis, tumor microenvironment, migration, invasion, and regulation of antitumor immune systems. Based on these basic studies, new anticancer drugs, including pazopanib, trabectedin, eribulin, and immune checkpoint inhibitors have been developed and the efficacies and safety of the new drugs have been assessed by clinical trials. This review summarizes new molecular therapeutic targets and advances in the treatment for bone and soft tissue sarcomas.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bone Neoplasms; Drug Therapy; Furans; Humans; Immunotherapy, Adoptive; Indazoles; Ipilimumab; Ketones; Nivolumab; Osteosarcoma; Progression-Free Survival; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sorafenib; Sulfonamides; Trabectedin

Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma.. This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort.. 57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet the primary endpoint of the study (66%). The exploratory osteosarcoma cohort exceeded previously established phase II trial comparator data benchmark of 12% with a PFR at 12 weeks of 69.55%. Treatment with the combination of pazopanib and topotecan was accompanied by a grade 3 or 4 toxicities in most patients.. In this prospective trial in refractory metastatic or unresectable STS and osteosarcoma, the combination of pazopanib with topotecan did not meet its primary endpoint of progression-free rate at 12 weeks. The combination of pazopanib with topotecan was associated with a high degree of toxicity.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Administration Schedule; Humans; Indazoles; Male; Middle Aged; Neoplasm Metastasis; Osteosarcoma; Prospective Studies; Pyrimidines; Sarcoma; Sulfonamides; Topotecan; Treatment Outcome; Young Adult

In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p < 0.05). There was no significant body-weight loss in any group. Only the EVE-PAZ combination caused tumor necrosis. The present study demonstrates that a combination of an mTOR-VEGF inhibitor and a VEGFR inhibitor was effective for a DOX-resistant lung-metastatic osteosarcoma PDOX mouse model, at least in part due to strong anti-angiogenesis efficacy of the combination.

Topics: Adolescent; Animals; Antibiotics, Antineoplastic; Bone Neoplasms; Disease Models, Animal; Doxorubicin; Drug Resistance, Neoplasm; Drug Therapy, Combination; Everolimus; Female; Humans; Indazoles; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Osteosarcoma; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; TOR Serine-Threonine Kinases

Topics: Humans; Indazoles; Myositis; Osteosarcoma; Pyrimidines; Sulfonamides

Axial skeleton primary tumor, metastatic disease at presentation, incomplete surgical resection, and <90% tumor necrosis have all been known to influence prognosis adversely in osteosarcoma. Relapse of osteosarcoma, typically occurring within the first 18 months of therapy, with an incidence rate of 50% is treated with surgery, chemotherapy, and targeted therapy. Here, we discuss 2 patients treated with pazopanib, a multi-tyrosine kinase inhibitor presently approved to treat renal cell carcinoma and soft tissue sarcomas. Case 1 achieved positive response and remains on pazopanib. Case 2 sustained gastrointestinal toxicity requiring suspension of drug, despite achieving stable disease.

Topics: Adult; Bone Neoplasms; Female; Humans; Indazoles; Male; Neoplasm Recurrence, Local; Osteosarcoma; Pyrimidines; Sulfonamides

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Bone Neoplasms; Child; Female; Humans; Indazoles; Male; Middle Aged; Neoplasm Recurrence, Local; Osteosarcoma; Progression-Free Survival; Pyrimidines; Salvage Therapy; Sulfonamides; Young Adult

Topics: Adolescent; Angiogenesis Inhibitors; Bone Neoplasms; Child; Female; Humans; Indazoles; Liver Neoplasms; Lung Neoplasms; Male; Osteosarcoma; Pyrimidines; Sulfonamides

Topics: Adolescent; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Female; Humans; Humerus; Indazoles; Lung Neoplasms; Male; Neoplasms, Radiation-Induced; Osteosarcoma; Pyrimidines; Skull Neoplasms; Sulfonamides; Young Adult

Osteosarcoma (OS) is the most common malignant bone tumor and the prognosis depends on pulmonary metastases, which arise from multi-step progression of malignant tumors. We herein aimed to clarify the critical step of pulmonary metastasis using the syngeneic mouse spontaneous highly metastatic OS LM8 and parental Dunn cell lines, to identify new candidate molecules to suppress pulmonary metastasis. We first investigated the chronological detection of circulating tumor cells (CTCs) from mice with either cell line. LM8 CTCs appeared faster, at a higher rate and with a greater number compared to Dunn CTCs. Cultured cells from CTCs of LM8 showed higher proliferative ability than cells from the primary site in suspension culture, which mimicked the environment of the bloodstream for CTCs. The proliferative ability of LM8 cells was also higher than that of Dunn cells in 3D collagen culture with low stiffness (-150 Pa; close to conditions in the lung). We next focused on the extravasation step. LM8 showed higher migration ability compared to Dunn with transendothelial migration assay. We also found a disruption in endothelial barrier function throughout co-culture with LM8 using time-lapse imaging. In addition, LM8 secreted high levels of vascular endothelial growth factor (VEGF), while VEGF signal inhibition with a small molecule tyrosine kinase inhibitor (pazopanib) decreased disruption of the vascular barrier and transendothelial migration of LM8. Finally, daily oral administration of pazopanib reduced the rate and size of pulmonary metastasis in vivo. Collectively, these results show anti-VEGF therapy as a candidate for pulmonary metastasis of OS.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Blotting, Western; Bone Neoplasms; Cell Movement; Cell Proliferation; Coculture Techniques; Immunoenzyme Techniques; Indazoles; Lung Neoplasms; Mice; Mice, Inbred C3H; Osteosarcoma; Pyrimidines; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Low dose metronomic (LDM) chemotherapy, combined with VEGF signaling pathway inhibitors, is a highly effective strategy to coordinately inhibit angiogenesis and tumor growth in many adult preclinical cancer models. We have tested the efficacies of daily oral LDM topotecan alone and in combination with pazopanib, a VEGF receptor inhibitor, in three pediatric extracranial solid tumor mouse models.. In vitro dose-response study of topotecan and pazopanib was conducted on several neuroblastoma, osteosarcoma, and rhabdomyosarcoma cell lines. In vivo antitumor efficacies of the LDM topotecan and pazopanib as single agents and in combination were tested on 4 subcutaneous xenograft models and on 2 neuroblastoma metastatic models. Circulating angiogenic factors such as circulating endothelial cells (CEC), circulating endothelial pro genitor cells (CEP), and microvessel densities were used as surrogate biomarker markers of antiangiogenic activity.. In vitro, topotecan caused a dose-dependent decrease in viabilities of all cell lines, while pazopanib did not. In vivo, combination of topotecan + pazopanib (TP + PZ) showed significant antitumor activity and significant enhancement in survival compared with the respective single agents in all models. Reductions in viable CEP and/or CEC levels and tumor microvessel density were correlated with tumor response and therefore confirmed the antiangiogenic activity of the regimens. Pharmacokinetic studies of both drugs did not reveal any drug-drug interaction.. Metronomic administration of TP + PZ showed a statistically significant antitumor activity compared with respective single agents in pediatric tumor mouse models and represent a valid option as a maintenance therapy in aggressive pediatric solid tumors.

Topics: Administration, Metronomic; Administration, Oral; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cell Line, Tumor; Endothelial Cells; Humans; Indazoles; Mice; Mice, Inbred NOD; Mice, SCID; Microvessels; Neoplasms; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Neuroblastoma; Osteosarcoma; Pyrimidines; Random Allocation; Rhabdomyosarcoma; Stem Cells; Sulfonamides; Topoisomerase I Inhibitors; Topotecan; Xenograft Model Antitumor Assays