State of the Fight: Childhood Cancer by Kimberly Stegmaier, M.D.


Though pediatric cancer is perceived as rare, it is the second most common cause of death in children 5 to 14 years of age in the United States. With a growing number of childhood cancer survivors, the impact of toxic therapies on long-term health is even more palpable. One in 250 people in the United States were childhood cancer survivors in 2010. While great progress has been made in treating children with cancer, there is still much more work to do. Morbidity from our current treatments is significant, and new approaches to treating children suffering from these diseases are still sorely needed. My hope is that targeted therapy, a promising new avenue of research, will offer improved efficacy and decreased toxicity compared to current chemotherapy treatments currently used to treat most pediatric cancers.

The most frequent type of cancer affecting children is leukemia, which accounts for 27 percent of all cancers in children younger than 20 years of age and 32 percent of all cancers in children under 15. Approximately 3,540 children younger than 20 years old are diagnosed with leukemia in the United States each year. There are different types of childhood leukemia with ALL being the most common, accounting for 73 percent, acute myeloid leukemia (AML) accounting for 18 percent and chronic myeloid leukemia (CML) accounting for less than 4 percent. Malignant lymphomas are the third most commonly diagnosed group of malignancies in children after leukemia and brain tumors, accounting for 4 percent of cancer diagnoses in children under age 5 and up to 15.5 percent in children under 20 years in the United States.

Central nervous system (CNS) tumors account for 25 percent of pediatric cancers. Each year, there are approximately 2,820 new diagnoses of CNS tumors in U.S. children younger than 15 years old. These tumors of the brain and spinal cord are second behind the leukemias in incidence but are the number one cause of cancer-related mortality in children. Here, the presence of the blood-brain barrier makes drug delivery to the tumor difficult, and the need to modify therapies to spare neuro-cognitive development has further compounded the challenge of therapy development for this class of pediatric cancers. This is one area where the need for improved therapy is all too apparent.

While brain tumors are the most common form of solid tumors in children, there are many other types of solid tumors afflicting children. The most common extra-cranial solid tumor in children is neuroblastoma, accounting for 7.5 percent of cancer diagnoses in children younger than 15 years old, with approximately 650 new U.S. cases diagnosed each year. Neuroblastoma is a very heterogeneous disease as seen in the biological and genetic features of the tumor itself, as well as in the variable prognosis. For example, prognosis can vary from over 90 percent long-term survival to less than 50 percent long-term survival depending on a complexity of tumor and patient features. In parallel, treatment can range from observation only for those with the most favorable prognosis to a combination of high-dose chemotherapy, surgery, radiation, double autologous stem cell transplantation, and biological agents for those with the most unfavorable disease.

Other common solid tumors of childhood include Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma, and Ewing sarcoma (EWS), each generally treated with a combination of systemic chemotherapy and either surgery or radiation therapy for local control of the primary site of disease. Again, prognosis for each of these diseases varies depending on many features, such as the stage of disease and the molecular characteristics of the tumor.

The specifics of therapy for childhood cancer vary from one type to another. However, a common theme is that of combination chemotherapy using cytotoxic drugs and, in the case of the solid tumors, surgery and/or radiation therapy. The notion of combination chemotherapy began with the treatment of children with ALL in the 1960’s and marked the first success story in cancer-directed therapies. What then followed was the identification of effective combinations and doses of cytotoxic drugs for the majority of pediatric malignancies. Dose intensification and the addition of newer cytotoxic drugs have improved tumor response in many pediatric cancers. Moreover, with advances in supportive care, such as growth factor support to improve normal white blood cell count recovery, antibiotic prophylaxis to prevent infection, and drugs to protect against cardiac toxicity, there has been a reduction in chemotherapy-related mortality and morbidity. With improved predictors of response to therapy, we have also been able to reduce the intensity of therapy for good prognosis patient populations in some diseases.

Even with this progress in treatment, for many high-risk disease subtypes, and even for a well-treated disease such as childhood ALL, survival curves have reached a plateau, suggesting that novel, out-of-the-box approaches beyond the current armamentarium are needed to continue to make progress and minimize children’s suffering. One of the major challenges we as researchers face is in identifying new targeted treatments for pediatric and other cancers stems from the very nature of the cancer-promoting proteins responsible for these diseases. Sometimes genetic mutations driving cancer create abnormal proteins that are specific to the cancer cells but are not present in normal cells. This raises the possibility of developing drugs that kill only the cancer cells by targeting these cancer-promoting proteins. However, many of these cancer-promoting proteins have been difficult to target with standard approaches to drug discovery.

The primary goal of our SU2C project is to develop and apply new drug discovery approaches to target these cancer-promoting proteins previously considered “undruggable.” To overcome this challenge, we developed a gene expression fingerprint approach for discovering potential new cancer therapies, called Gene Expression-based High-throughput Screening (GE-HTS). Like a fingerprint, which provides uniquely identifying information beyond a simple measurement, GE-HTS provides a complex, unique measurement of a cellular response.

We are applying GE-HTS to the cancer-promoting protein EWS/FLI in the pediatric solid tumor Ewing sarcoma, the second most common primary tumor of the bone diagnosed in U.S. children. Because genetic inactivation of the EWS/FLI protein leads to impairment of Ewing sarcoma growth in the laboratory, we hypothesize that chemicals that inactivate the EWS/FLI gene expression signature will also impair cell growth.

We have already identified very interesting chemicals that inactivate the EWS/FLI signature, including several drugs FDA-approved for another indication. We will now use these chemicals as tools in the laboratory to further dissect the molecular origins of Ewing sarcoma and the role of EWS/FLI in this disease. This research should shed light on the molecular origins of pediatric cancers and may also lead to new therapies, reaching beyond Ewing sarcoma and impacting other types of pediatric and adult cancers.

For my laboratory, the SU2C Innovative Research Grant funding has been transformative, facilitating the collaborative development of our generic approach to drug discovery that can be applied broadly to cancer. On a very personal level, it has welcomed me into a passionate community of researchers and advocates united in the fight against cancer. And as a pediatric oncologist who sees firsthand the losses and the limitations of our current therapies, it has empowered this painfully obvious notion that we need to speed up the pace of discovery for the countless children and adults afflicted with cancer.

In contrast to our thinking about adult malignancies, we do not yet know of strategies to prevent pediatric cancers. There are unfortunately not preventative screening tests that exist for children as they do for some adult cancers. With this being said, one of the things I encourage parents to remember is that habits learned in childhood are frequently carried forward into adulthood. Though we may not be able to prevent childhood cancers, the prevention of adult cancers begins in childhood. Early teaching of the importance of smoking prevention, exercise, maintenance of an ideal body weight, sunscreen, and routine medical examinations can go a long way in the prevention of cancer in adulthood.

In terms of “what to look out for,” I tend to believe that parents know their children best and often have a sixth sense when something is simply just not right. Listening to this gut feeling and bringing the concern to the attention of the child’s pediatrician is very important. Though there generally may not be a “catching the cancer early” in pediatrics, starting treatment in a timely manner before the cancer injures normal organs is important.

Funding opportunities for pediatric cancer research are very limited, but we must keep this kind of research going for a multitude of reasons. Research involving pediatric cancer has also helped to inform research on adult cancers. This is because pediatric cancers tend to be less genetically complex than adult malignancies making it easier to distinguish the real cancer-promoting, driver events from the passengers. Moreover, as the adult cancers are subdivided into finer and finer categories based on molecular features, even “lung cancer” can become a rare disease if defined by a specific genetic lesion. There is a lot to be learned from the pediatric history of treating “rare” cancers. Most importantly, though, the loss of a life of a child is an utter tragedy.

Despite the battle we were engaged in, children have an uncanny resiliency. I am often asked, “How can you do this?” I would answer, “How can you not!” The last 20 years have seen steady, progress in the treatment and survival of children diagnosed with cancer, but there is still much work to be done. Though our fight to defeat childhood cancer against is still raging, this is an incredibly exciting time in cancer research. I look to the future with great hope and cherish each success that I see.


By Kimberly Stegmaier, M.D.

Kimberly Stegmaier, M.D., is an assistant professor in the department of pediatrics at Harvard Medical School, an independent investigator in pediatric oncology at the Dana-Farber Cancer Institute, and an attending physician in pediatric hematology-oncology at the Children’s Hospital Boston and the Dana-Farber Cancer Institute. She is also an associate member of the Broad Institute of MIT and Harvard. Stegmaier was awarded a SU2C Innovative Research Grant for her work on “Modulating Transcription Factor Abnormalities in Pediatric Cancer.”