Alexander J. Chou

Chemotherapy resistance in osteosarcoma: current challenges and future directions

For patients with osteosarcoma, the use of chemotherapy has improved survival from 11% with surgical resection alone in the 1960s, to 70% by the mid-1980s. However, survival has since plateaued, despite advances in anticancer therapy. Elucidation of the mechanisms of chemoresistance and implementation of strategies to overcome chemoresistance will likely be pivotal to improving survival. In this review, the focus is on the current understanding of the mechanisms of resistance to the most commonly used agents in the treatment of osteosarcoma and the methods employed to overcome chemotherapy resistance.

Therapy for osteosarcoma: where do we go from here?

Osteosarcoma is the most common malignant primary bone tumor in children and adolescents. Current optimal treatment for osteosarcoma consists of multi-agent chemotherapy and aggressive surgical resection of all sites of disease involvement. The current national and international cooperative trial for patients with newly diagnosed osteosarcoma builds upon the backbone of cisplatin, doxorubicin, and methotrexate. This protocol is designed to clarify whether (i) the addition of ifosfamide and etoposide to postoperative chemotherapy with cisplatin, doxorubicin, and methotrexate improves the event-free survival and overall survival for patients with resectable osteosarcoma and a poor histologic response to 10 weeks of preoperative chemotherapy; and (ii) the addition of pegylated interferon-α-2b as maintenance therapy after postoperative chemotherapy with cisplatin, doxorubicin, and methotrexate improves the event-free survival and overall survival for patients with resectable osteosarcoma and a good histologic response to 10 weeks of preoperative chemotherapy. However, the optimal treatment strategy (or strategies) for patients with relapsed or metastatic disease has yet to be defined. This remains one of the persistent challenges in the treatment of osteosarcoma.Recent therapeutic advances have focused on circumventing chemotherapy resistance mechanisms, incorporation of non-classical agents into upfront therapy, targeting of the tumor micro-environment, and investigating the role of novel delivery mechanisms.In patients with localized disease the 5-year survival rate is at least 70%; patients with metastatic or recurrent disease have <20% chance of long-term survival despite aggressive therapies. These figures have changed little in the past 2 decades. This review focuses on the current therapy for osteosarcoma, and highlights emerging strategies that will hopefully change the outlook for patients with this disease.

Addition of Muramyl Tripeptide to Chemotherapy for Patients with Newly Diagnosed Metastatic Osteosarcoma: a Report from the Children's Oncology Group

The addition of liposomal muramyl tripeptide phosphatidylethanolamine (MTP‐PE) to chemotherapy has been shown to improve overall survival in patients with nonmetastatic osteosarcoma (OS). The authors report the results of addition of liposomal MTP‐PE to chemotherapy for patients with metastatic OS.

Irinotecan and temozolomide for Ewing sarcoma: The Memorial Sloan‐Kettering experience

The prognosis for recurrent/progressive Ewing sarcoma (ES) remains poor. Pre‐clinical, adult phase I and II trials have demonstrated the combination of irinotecan and temozolomide to have schedule‐dependent synergy and significant antitumor activity. A pediatric phase I trial has shown this regimen to be safe and active in advanced ES.

Treatment of osteosarcoma at first recurrence after contemporary therapy: the Memorial Sloan-Kettering Cancer Center experience.

Overall survival after recurrence of osteosarcoma (OS) is < 30%. The authors reported their experience treating recurrent OS at the time of first recurrence (R1).

Addition of pamidronate to chemotherapy for the treatment of osteosarcoma

This study evaluated the safety and feasibility of the addition of pamidronate to chemotherapy for treatment of osteosarcoma.

Phase I Trial and Pharmacokinetic Study of Lexatumumab in Pediatric Patients With Solid Tumors

PURPOSE Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. PATIENTS AND METHODS This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age≤21 years with recurrent or progressive solid tumors. RESULTS Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response. CONCLUSION Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects.

Over-expression of parathyroid hormone Type 1 receptor confers an aggressive phenotype in osteosarcoma.

Osteosarcoma is the most common primary bone malignancy in children and is associated with rapid bone growth. Parathyroid hormone‐related peptide (PTHrP) signaling via parathyroid hormone Type 1 receptor (PTHR1) is important for skeletal development and is involved in bone metastases in other tumors. The aim of this study was to investigate the status of PTHrP/PTHR1 and its possible role in osteosarcoma. In a preliminary screening, a higher level of PTHR1 mRNA, but not PTHrP, was found in 4 osteosarcoma xenografts as compared with 4 standard cell lines, or 5 patient derived cell lines (p < 0.05) using quantitative RT‐PCR. It was therefore extended to 55 patient specimens, in which a significantly higher level of PTHR1 mRNA was detected in metastatic or relapsed samples than those from primary sites (p < 0.01). Cell behavior caused by PTHR1 overexpression was further studied in vitro using PTHR1 transfected HOS cell line as a model. Over‐expression of PHTR1 resulted in increased proliferation, motility and Matrigel invasion without addition of exogenous PTHrP suggesting an autocrine effect. Importantly, the aggressiveness in PTHR1‐expressing cells was completely reversed by RNAi mediated gene knockdown. In addition, PTHR1 over‐expression led to delayed osteoblastic differentiation and upregulation of genes involved in extracellular matrix production, such as TGF‐β1 and connective tissue growth factor. When cocultured with bone marrow derived monocytes, PTHR1 transfected HOS cells induced a greater number of osteoclasts. This study suggests that PTHR1 over‐expression may promote osteosarcoma progression by conferring a more aggressive phenotype, and forming a more favorable microenvironment.

Mifamurtide in Metastatic and Recurrent Osteosarcoma: A Patient Access Study with Pharmacokinetic, Pharmacodynamic, and Safety Assessments

This non‐randomized, patient‐access protocol, assessed both safety and efficacy outcomes following liposomal muramyl‐tripeptide‐phosphatidylethanolamine (L‐MTP‐PE; mifamurtide) in patients with high‐risk, recurrent and/or metastatic osteosarcoma.

Expression of granulocyte-colony-stimulating factor and its receptor in human Ewing sarcoma cells and patient tumor specimens: potential consequences of granulocyte-colony-stimulating factor administration.

Ewing sarcoma (ES) is a highly vascular malignancy. It has been demonstrated that both angiogenesis and vasculogenesis contribute to the growth of ES tumors. Granulocyte‐colony‐stimulating factor (G‐CSF), a cytokine known to stimulate bone marrow (BM) stem cell production and angiogenesis, is routinely administered to ES patients after chemotherapy. Whether ES cells and patient tumor samples express G‐CSF and its receptor (G‐CSFR) and whether treatment with this factor enhances tumor growth was examined.