Nanotechnology shows potential as a treatment for pediatric sarcomas

Issue: June 25, 2011

Each year in the United States between 1,500 and 1,700 children are diagnosed with a bone or soft tissue sarcoma, making up about 15% of cancers in youth aged younger than 20 years. However, pediatric cancers themselves are rare and comprise only about 1% of cancer cases.

Pediatric bone cancer has been identified in many forms, including Ewing’s sarcoma, chondrosarcoma and osteosarcoma, the most common form. Osteosarcoma, or osteogenic sarcoma, usually affects the large bones of the arm or leg and occurs most commonly in adolescents and young adults, affecting more males than females. Each year in the United States approximately 450 children and adolescents younger than 20 years old will be diagnosed with osteosarcoma.

Challenges and treatment options

Historically, survival rates of children with osteosarcoma were some of the bleakest of all cancer diagnoses. Treatment options were limited to surgical resection by amputation, and despite these aggressive surgeries, most patients did not survive, instead succumbing to metastatic disease.

In the last 50 years, we’ve seen a dramatic improvement in treatment options for patients with osteosarcoma due in part to advances in chemotherapy regimens. Although surgical removal of all gross and microscopic tumors is required to prevent local tumor recurrence, amputation is no longer the only surgical approach. Currently, 95% of patients with localized osteosarcoma of the extremity can be considered for limb-salvage surgery. Because of the improved treatment options, the 5-year survival rate today is estimated at 65% for patients with osteosarcoma, compared with only 15% in the early 1960s.

Despite the advancements that have been made, patients diagnosed with metastatic, refractory or recurrent osteosarcoma remain the most challenging for physicians. In fact, for patients with localized osteosarcoma, if treated with surgery alone, 80% to 90% of patients will see a recurrence of metastatic disease. This has led many researchers to hypothesize that patients had subclinical metastatic disease at the time of diagnosis, even if overt clinical metastases were not identified. Although advancements have been made in treating patients with localized osteosarcoma, the same improvements have not been seen in these patients, and their prognosis remains grim, with only a 20% to 30% survival at 5 years.

Cancer cells continue to evolve and we, as physicians, must evolve as well. Cytotoxic chemotherapy is administered with the implicit hope that enough of the active agent will percolate into tumor cells to kill them without wreaking irreversible havoc on the rest of the body. Our chemotherapeutic agents are not specifically targeted to sarcomas, and the bystander effects to normal tissues are considerable and potentially lifelong in this young population. Strategies that improve the delivery of a particular anticancer agent to pediatric sarcomas will not only increase the dose effectiveness of chemotherapy, but will also reduce the systemic toxicity to normal cells.

Tumor-specific targeting requires a strategy to distinguish cancer cells from normal cell counterparts. Although cancer cells frequently express unusual cell surface markers, almost invariably these antigens are also expressed on subsets of normal cells. Attempts to develop targeted therapies have focused on using immunoconjugates directed toward cell surface markers on tumor cells. Limitations to such therapies exist because frequently they can only be directed toward a single antigen and are toxic to normal cells that express the same molecules. A strategy simultaneously targeting two tumor-associated markers may improve specificity significantly.

The potential of nanomedicine

Nanomedicine has been around for decades; however, we continue to discover new ways of using this technology in treating patients with a host of diseases. The concept of targeting or programming a nanoparticle to target cancer is relatively recent. There are possibilities that lie within this field to treat children who have been diagnosed with osteosarcoma and currently have few options available for treatment.

Nanotechnology and nanoparticles offer the opportunity to deliver high doses of cytotoxic agents specific to osteosarcoma cells anywhere in the body as well as limit the bystander and dose-limiting effects of our therapies on normal tissues. This will give pediatric patients the opportunity to avoid the damaging side effects that they would otherwise incur during standard chemotherapy treatments.

Research and implications

At UCLA, in collaboration with NanoValent Pharmaceuticals Inc., researchers and I are working to develop polymerized liposomes to target osteosarcoma cells using a novel surface marker. We have shown that this targeting is highly specific and efficient for osteosarcoma cells in an in vitro model (Figure 1). We are now delivering the anthracycline chemotherapeutic agent, doxorubicin, in this manner.

The field of nanotechnology is advancing rapidly and we’re seeing the use of this technology expanding into areas never before realized until now. There are several nanoparticle therapies that are FDA-approved and many currently in phase 1, 2 and 3 clinical trials. We continue to learn more about how this treatment option can be used but still have a lot to discover about the true potential of nanoparticle therapies.

Since the late 1980s, we have seen a plateau in the survival rates among pediatric sarcoma patients. The goal of our research is to harness the power of nanoparticles and nanotechnology to alleviate this stalemate and increase survival rates among these young patients. In the future, we should be able to save a life without the loss of a limb or fear of recurrence and be able to tell our patients and families diagnosed with refractory, recurrent, and/or metastatic osteosarcoma that survival is the rule rather than the exception.

Future applications

Although we are still in the preliminary stages of our research, we are cautiously optimistic based on what we have discovered about targeting nanoparticles in pediatric sarcomas. Our most recent research developments indicate that nanoparticles are able to be specifically programmed to target and deliver higher amounts of toxicity to the osteosarcoma cells. Theoretically, this can one day be applied to many, if not all, therapeutic strategies in pediatric malignancies. Because nanoparticles are a flexible delivery and carrier system, they can be modified relatively easily. We hope that our work will be able to be generalized in some fashion to advance the therapeutics of other pediatric and adult cancers. In fact, our work in pediatric sarcomas has led us to collaborations at UCLA Medical Center targeting cancers such as pancreatic and colorectal carcinomas in adults. While we still have much to learn about nanotechnology and nanoparticles, the success we have already achieved is evidence there is a place for this treatment in not only pediatric sarcomas but also a variety of cancers.

Dr. Federman is director of the Pediatric Bone and Soft Tissue Sarcoma Program at UCLA, part of the UCLA Sarcoma Program and UCLA’s Jonsson Comprehensive Cancer Center. He works with Ronald Reagan UCLA Medical Center and Santa Monica-UCLA Medical Center and Orthopaedic Hospital, specializing in pediatric hematology and oncology. He can be reached at nefederman@mednet.ucla.edu.

For more information:

www.sarcomahelp.org/sarcoma_statistics.html

Bruland, OS, Høifødt, H, Saeter, G, et al. Hematogenous micrometastases in osteosarcoma patients. Clin Cancer Res. 2005; 11:4666.

Disclosure: Dr. Federman is the recipient of a 3-year research grant from the St. Baldrick’s Foundation.