Cancer trees are growing in China.
Camptotheca acuminata is a fast-growing deciduous tree called xi shu in Chinese, which literally translates to the happy tree. This leafy plant is otherwise referred to as the Tree of Life or more notably the Cancer Tree, as extracts from Camptotheca are used as anti cancer treatments.
Western researchers from the U.S. Department of Agriculture and the National Cancer Institute first discovered the happy tree’s anti-cancer properties in 1958. In the early 1990s Japanese scientists introduced irinotecan, a semi-synthetic derivative of a plant alkaloid obtained from the “happy tree.”
In 1994, irinotecan received accelerated Food and Drug Administration (FDA) approval in the United States where it is now marketed as Camptosar® by the pharmaceutical company, Pfizer, for the treatment of lung, cervical, ovarian and recurrent colon cancers. One year prior to FDA approval, Peter Houghton, PhD, and colleagues examined the effect of irinotecan against a panel of human tumor models derived from adult and pediatric cancers. They saw that the models of rhabdomyosarcoma, a fast growing malignant soft tissue tumor seen most often in children, were highly responsive to the drug, even rhabdomyosarcomas that were resistant to existing cancer-drugs.
One year passed, then two years, then three. It wasn’t until 1999 that the first clinical study of irinotecan involving children occurred. During this time lapse, an average 350 U.S. children were diagnosed with rhabdomyosarcoma each year.
“It takes too long for cancer drugs to reach children,” said Dr. Houghton, director of the Center for Childhood Cancer at The Research Institute at Nationwide Children’s Hospital. “There are more than 600 drug therapies being developed for cancer and virtually none of them are developed for pediatric cancer specifically.” How can we more rapidly develop drugs for kids? How can we ensure that discoveries like that from the happy tree are transformed into treatments for children worldwide?
An answer is coming from Dr. Houghton’s work. Over the last 30 years, Dr. Houghton’s team has developed mouse models of childhood cancer that mimic human disease. They have established 47 models of eight tumor types (neuroblastoma, acute lymphoblastic leukemia, glioblastoma, ependymoma, medulloblastoma, Wilms tumor, rhabdoid tumor, and sarcoma – including rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma). About half of the mice represent models of relapse; many others are chemo-resistant tumors, representing childhood cancers that are in desperate need of new therapies. “The models that we’ve created really do look very much like childhood cancer,” said Dr. Houghton.
The pre-clinical models also respond to drug therapies much like human cancers do. Using models of rhabdomyosarcoma and neuroblastoma, Dr. Houghton’s preclinical testing has been able to predict activity of new agents in children with these cancers. “We’ve found that if we use these models intelligently, then they can be quite predictable,” said Dr. Houghton. “We have determined drug levels achievable in mice that cause tumor regression and correlate them to drug levels you can safely use in humans. This seems like common sense, but the reality is that no one has ever done this before.”
This preclinical testing concept led to the now four-year-old Pediatric Preclinical Testing Program (PPTP), a multi-center initiative supported by the U.S. National Cancer Institute and led by Dr. Houghton.
Through the PPTP, scientists systematically evaluate new agents against the molecularly characterized childhood solid tumor and leukemia models. The primary goal is to identify new agents that have the potential for being clinically effective. “Scores of new agents are in development as cancer therapeutics,” said Dr. Houghton. “Only a fraction of these new agents can be systematically evaluated in children, largely because of the limited number of children eligible for early phase clinical trials. Logistically, the Children’s Oncology Group, which is the National Cancer Institute’s worldwide clinical trial cooperative, can perform fewer than 20 Phase I clinical trials each year and from four to eight Phase II clinical trials,” said Dr. Houghton. “Through the PPTP, we can evaluate available agents and prioritize them for pediatric testing.”
The PPTP systematically tests 10 to 12 agents or combinations of agents each year. They seek to test these agents near the time they are entering Phase I evaluation in adults with cancer. Testing for different tumor panels occurs at Nationwide Children’s and five additional sites: Children’s Hospital of Philadelphia, Children’s Cancer Institute Australia, Duke University, Albert Einstein Medical Center and Texas Tech University.
To identify which new drugs could have significant anti-tumor activity against one of the pediatric cancer models, the drug is evaluated using the 47 established models, ensuring that it is tested against multiple tumor panels, each encompassing some of the genetic diversity of the disease. The drugs that look promising after this first stage are then advanced to a second stage to determine how different doses of the drug affect anti-tumor activity. When appropriate, second-stage testing may also involve models of pediatric cancer that has spread to other areas of the body as sometimes seen in children. (View a graphic of the PPTP process).
Over the last four years, 47 new drugs have been tested and the group has identified three that perform very well in the models of pediatric cancer. One of their studied drugs, MLN8237, showed dramatic activity in relapsed neuroblastoma and within 10 months of presenting the data, the drug was being used in a pediatric clinical trial.
Dr. Houghton expects that Nationwide Children’s connection to The Ohio State University Comprehensive Cancer Center will provide an additional catalyst for the PPTP through collaborations with the program leader of Experimental Therapeutics Michael Grever, MD, and other cancer researchers. “I consider Dr. Michael Grever’s program at The Ohio State University to be the best in the United States,” he said. “I think we can build from OSU’s strengths in terms of having access to some of the compounds that might be restricted in pediatrics. This gives Nationwide Children’s an edge in developing a Phase I and Phase II clinical trials program that is ahead of the curve.”
Parallel to prioritizing pediatric cancer drugs for study through the PPTP, Dr. Houghton also focuses his laboratory work on developing treatment approaches that are less traumatic on patients’ bodies than existing cytotoxic treatments, like chemotherapy.
Early in his career, Dr. Houghton identified a chromosomal translocation in rhabdomyoscarcomas, which are extremely fast growing childhood tumors. This mutation leads to the overexpression of insulin-like growth factor 2 (IGF2), a protein that is critical in tumor survival. Since then, he and his team have focused on therapeutic approaches to block IGF signaling, a strategy that could apply to multiple tumor types. “The real focus has been on trying to interrupt the signaling pathway,” said Dr. Houghton.
In the early 1990s Dr. Houghton’s team discovered that the drug rapamycin blocks a very specific kinase that is downstream of the IGF1 receptor. “Rapamycin is a terrific inhibitor, as it hits a watershed kinase that is absolutely critical for many processes in tumors, including relating cell cycle progression and transcription,” said Dr. Houghton.
Dr. Houghton’s lab is studying how rapamycin can impact processes critical in tumor survival and evaluating the effect of combining rapamycin with IGF inhibitors. They are also investigating how the tumor suppressor gene, p53, impacts cell survival in the tumor environment, all while determining which strategies would be best matched with specific c tumor types.
Dr. Houghton says that these studies provide evidence that chemotherapy and other current cytotoxic therapies may not be the first-line of defense against childhood cancer in the future. “In the next five years, I believe things are going to look radically different. I don’t think we’re going to completely get away from cytotoxic drugs, but we’ve seen that combining two non-cytotoxic drugs, like rapamycin and an IGF-inhibitor, can cause complete regression in models of cancer. We’ve seen that there could be a light at the end of the tunnel.”
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