Richard Gorlick

The pediatric preclinical testing program: description of models and early testing results.

The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenografts and cell lines to be used for in vivo and in vitro testing. These include panels for Wilms tumor, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), rhabdoid tumors (CNS and renal), and acute lymphoblastic leukemia (ALL). Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide.

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.

Initial Testing of the Aurora Kinase A Inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP)

MLN8237 is a small molecule inhibitor of Aurora Kinase A (AURKA) that is currently in early phase clinical testing. AURKA plays a pivotal role in centrosome maturation and spindle formation during mitosis.

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.

Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program

Rapamycin is a highly specific inhibitor of mTOR, a serine/threonine kinase that controls cap‐dependent translation. Here we report the activity of rapamycin against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP).

EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

This manuscript describes the experience from registration until randomisation for a cohort of 2260 patients with osteosarcoma who joined the EURAMOS-1 trial. This includes pre-operative chemotherapy and surgery. It sets out the practical issues in collaboration and in achieving randomisation.

Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program.

ABT‐263 is a potent (Ki < 1 nM) small‐molecule BH3 mimetic that inhibits the antiapoptotic proteins Bcl‐2, Bcl‐xL and Bcl‐w. The structurally related Bcl‐2 inhibitor ABT‐737 exhibits single‐agent preclinical activity against lymphoma, small‐cell lung carcinoma, and chronic lymphocytic leukemia and displays synergistic cytotoxicity with chemotherapeutics and radiation.

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).

Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the pediatric preclinical testing program†

Many childhood malignancies including sarcomas, neuroblastoma, and Wilms tumor show the presence of both, active, type‐1‐insulin‐like growth factor receptor (IGF‐1R), and the autocrine production of its ligands IGF‐1/IGF‐2. IMC‐A12 is a fully human IgG1 antibody that prevents ligand binding to the IGF‐1R.

Initial testing of dasatinib by the pediatric preclinical testing program

Dasatinib, a dual inhibitor of the src and abl tyrosine kinases, was recently approved by the Federal Drug Administration for the treatment of imatinib mesylate‐resistant chronic myeloid leukemia.