Outsmarting Osteosarcoma

Joy Fulbright, MD, and Tomoo Iwakuma, MD, PhD

Researchers at The University of Kansas Cancer Center and Children’s Mercy Kansas City are joining forces to fight a cancer with a long history of low survival rates.

Osteosarcoma is the most common type of bone cancer found in children and teens. Nine out of 10 patients have “micro-metastasis,” meaning a small amount of the cancerous cells have spread from the original tumor site. Despite intensive chemotherapy, the survival rate for osteosarcoma has been stuck between 60 and 70 percent for the past four decades. Metastasized osteosarcoma reduces survival to less than 30 percent.

Through two projects, Tomoo Iwakuma, MD, PhD, KU Cancer Center researcher and director of the Translational Laboratory Oncology Research program at Children’s Mercy, is working closely with Children’s Mercy medical oncologist Joy Fulbright, MD, and other KU Cancer Center members to identify a therapy to inhibit osteosarcoma growth specifically for patients who have not responded well to other therapies.

Children’s Mercy, an official National Cancer Institute Consortium partner of KU Cancer Center, lends robust clinical expertise that dovetails with KU Cancer Center’s strengths in basic research and drug discovery – a “dream” partnership, according to Iwakuma.

“Working together, we see both sides of research processes. I help ensure that what Dr. Iwakuma is doing in the lab translates to the clinic,” Fulbright adds.

Leveraging Drug Discovery Tools

Current treatment for osteosarcoma involves up-front chemotherapy for 12 weeks, then surgery, followed by more chemotherapy. The team’s goal is to discover and develop an effective new drug to improve treatment outcomes.

“Tumor cells are smart and become resistant to a single drug treatment very quickly. We need to discover and develop new drugs that attack osteosarcoma cells without affecting normal cells,” Fulbright says.

To filter through the hundreds of thousands of compounds in existence and identify which ones may specifically kill osteosarcoma cells, the team uses High-Throughput Screening (HTS), a robotic sifting system. The results provide starting points for discovering novel, new drug candidates. KU Cancer Center’s Lead Development and Optimization Shared Resource lends unique, fully integrated drug discovery capabilities including HTS, medicinal chemistry and drug synthesis to support researchers through the discovery process.

“We screened more than 150,000 compounds for activity against our osteosarcoma target, identifying ‘hits,’ or a focused set of potential active compounds,” Iwakuma says.

From there, the team conducted further tests and honed in on a single, novel compound that killed a particularly aggressive line of canine and human osteosarcoma cells. Compound activity in canine osteosarcoma cell lines were evaluated in parallel with human osteosarcoma cell lines. Biologically, the characteristics of the disease in dogs is remarkably like the disease in humans. Iwakuma explains that dogs are 15 times more likely to develop the disease, and studying the efficacy and safety of promising new treatments in already-sick dogs provides valuable insight into how humans may respond.

Iwakuma’s drug target is mutant forms of the p53 protein. In its normal state, the p53 protein, known as the “guardian of the genome,” regulates cell growth. When mutated, it can contribute to metastasis, drug resistance and cell growth.

“We all have active p53 in our genes. However, cancer cells can lose p53 activity. One of the active compounds we’ve identified only kills the cancer cells that lack p53 or contain mutated p53,” Iwakuma says. “In other words, this compound specifically targets cancer cells and does not affect normal cells. At that moment, I knew we had a promising drug discovery project.”

Initially supported by a grant from the Masonic Cancer Alliance and propelled forward with a follow-on grant from Braden’s Hope, a local nonprofit organization, the team is now studying the compound’s mechanisms of action in killing canine and human osteosarcoma cells.

“The loss of p53 protein makes cancer cells more sensitive to the compound. But why and how? So far, we know this compound somehow causes DNA damage that is not efficiently repaired in cells lacking p53. The damage accumulates over time, leading to death of cancer cells,” Iwakuma says.

Although the team is optimistic about the compound currently being studied, parallel efforts are focused on discovering and developing improved drug candidates.

“We have a strong starting point for discovering novel, new agents that target mutant p53 proteins,” Iwakuma says. “It’s a unique advantage to have a team encompassing so many skills, including drug discovery experts who bridge the critical gap between the lab and the clinic. I couldn’t be more excited.”

From the earliest nugget of an idea at the bench to drug development and clinical trials, the collaboration between KU Cancer Center and Children’s Mercy convenes the best from each institution, including biologists, oncologists and translational scientists.

“Working together, we see both sides of the research process,” Fulbright says. “It’s a good back-and-forth partnership that we hope will result in new treatment options for osteosarcoma patients.”