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.
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.
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.
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.
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.