Candlelighters Expands Mission To Include Research

by Ruth Hoffman MPH
Source: Fall/Winter 2006 CCCF Newsletter

Executive Summary

Childhood cancer is the most common disease killer of children in America. The 1970s-80s brought the advent of chemotherapy "cocktails" applied to childhood cancer, where toxic compounds that preferentially killed the tumor cells kept many children from immediate death. The quoted cure rates for childhood cancer are oft-touted as proof of principle of the success of academic clinical trials, however 25% of children die within five years of their cancer diagnosis, and 30% of those that survive endure severe side effects from treatment, including cognitive deficits, organ failure, and secondary cancers.

Too often, the perceived success of childhood cancer is portrayed in the media and by leading cancer institutions and organizations in a way that minimizes the on-going severity of the disease. Sadly, this cruel "myth of cure" has contributed to a general lack of concern for childhood cancer mortality and morbidity, which has resulted in a relative lack of public/government funding for cutting edge molecular based research for pediatric cancer, as compared to adult cancers and other childhood diseases.

Newly emerging cancer therapy is focused on drugs that kill only the cancer cells, and are not toxic to the normal cells of the patient. They accomplish this by using molecular genetic approaches to identify the "Achilles heel" of each specific tumor type, then attack this weak spot in a highly specific manner. While pediatric cancer was the proving ground for traditional toxic chemotherapies, adult cancers have largely been the focus for targeted therapeutics. Thus, the young patients that are most vulnerable to life years lost and to longterm side effects from toxic chemotherapy as a result of having growing bodies and developing brains at the time they were exposed to such toxic compounds, this patient population continues to be exposed to these older treatments.

The following grassroots research funding campaign initiated by Candlelighters Childhood Cancer Foundation is designed to address these issues through the following objectives.

  • Develop a cutting-edge science- based plan that would kick-start a targeted therapeutics initiative for childhood cancer, and develop draft legislation to support the plan.
  • Create a broad-based grassroots coalition to support the plan.

The primary goal of this grassroots research funding campaign is, at a minimum to raise $1 million in donations from our membership/constituency, and to leverage a subsequent $20 million ($4 million annually for 5 years) from government appropriations for biomedical research. The overarching goal of the targeted therapeutic research is to improve the long-term survival rates for children and adolescents with cancer through the development of new molecularly targeted drugs, while dramatically reducing the long-term side effects associated with current toxic treatment.

Background

Each year in the United States, approximately 13,000 children under the age of 20 are diagnosed with cancer.1 Standard cancer treatments (without complications such as relapsed disease), lasts from one to three years depending upon the diagnosis. End result - at any given time in the U.S., there are approximately 30,000 to 40,000 children and adolescents on active cancer treatment.

Over the last thirty-six years of Candlelighters' existence, the five-year survival rate for childhood cancer, (the standard set of metrics used to evaluate progress in cancer treatment), has improved dramatically from 10% to 75%. These dramatic improvements in the five-year survival rate, however, have overshadowed other equally important aspects of treating children with toxic cancer therapies, namely:

  • Many types of childhood cancer, including neuroblastoma IV, brainstem gliomas, acute myelogenous leukemia, and metastatic bone cancers (osteosarcoma and Ewing sarcoma) continue to have dismal prospects for even a five year survival.
  • The treatments, which consist of toxic drugs that kill cancer cells have a plethora of severe side effects due to toxicity to normal cells and surrounding tissues. Traditional chemotherapy and radiation treatments are unable to discern between malignant cells and normal tissue. As a result, both cell types are targeted and damaged or destroyed in the process of current cancer therapies. When applied to the developing body of a child, damage to normal tissue can result in life-long chronic health problems that may lead to an early death.
  • Even with improved survival of childhood cancer patients, childhood cancer remains the leading disease killer of our nation's children and teens. In spite of $30 million spent annually on clinical trial research, cancer still claims more children's lives than Cystic Fibrosis, Muscular Dystrophy, AIDS, asthma, and juvenile diabetes combined.
  • The annual death rate from childhood cancer decreased by 2.7 percent per year from 1975 to 1998. This decline in mortality rate reached a plateau however in 1998, and has remained unchanged for the past 8 years despite on-going enrollment into aggressive clinical trials.2

Despite such dismal prospects for healthy long-term survival, childhood cancer is often portrayed as the cancer success story of the twentieth century. Moreover, success with childhood cancer is often touted as "proof of principle" that we can now succeed with adult cancers if we focus our efforts in ways similar to what we have done for children with cancer. Sadly, this myth - that we have largely won the war on childhood cancers, has led to a relative lack of research focused at the existing mortality and morbidity rate of childhood cancer, and the plateau in survival rates over the last decade. While adult cancer is receiving extensive government and private research funding to identify the underlying genetic causes of tumorigenesis (tumor development), and to identify and develop new molecularly based drugs to target adult cancers, comparatively little funding is being made available for such cutting edge scientific research for childhood cancer. Without the development of new drugs to treat children with cancer, we continue to fund clinical trials based upon new combinations of existing toxic therapies. Such investment of tens of millions of dollars each year into clinical trial research without the accompanying basic research to develop new molecular therapies, has led to no improvement in the overall survival of childhood cancer. As mentioned, there has been no improvement in the overall rate of childhood cancer survivorship for almost a decade.

Treatment and long-term late effects for child and adolescent cancer

Treatment for childhood and adolescent cancer is targeted toward destroying cancer cells, typically with a combination of chemotherapy, radiation, and surgery. Children and teens receiving cancer therapy are treated at a time in their life when they have a growing body and developing brain. Such exposure to toxic cancer therapy results in extensive damage to the tissue and organs of the child on active treatment. Recent studies have shown that the majority of survivors (two-thirds) have some late effects resulting from treatment, with approximately 30% of those late sequelae classified as clinically moderate to severe.3 Long term impairments include cognitive deficits (from chemotherapy to the spinal fluid and/or radiation to the brain), endocrine dysfunction, cardiomyopathy, seizures (brain tumor patients), stroke, peripheral nerve dysfunction, chronic fatigue, hearing loss, vision impairment (cataracts), stunted growth, obesity, and secondary malignancies. Depending on the diagnosis and corresponding initial cancer treatments, follow-up care resulting from late complications of the cancer treatment can result in the need for the child to receive extensive healthcare throughout the remainder of their childhood and into adulthood. It is estimated that over 270,000 survivors of childhood cancer are living today in the United States.4 These young people are growing up and finding their way into adult society. The miracle of "cure" however, has overshadowed the price that is often paid by this unique cancer population to survive.

Death as a result of secondary cancers diagnosed greater than 5 years from the original cancer diagnosis has been shown to be 10.8 times that of the general population that is the same age.5 Death due to secondary malignancies was shown to be statistically significantly higher in females; individuals diagnosed with cancer before the age of 5 years; and those with an initial diagnosis of leukemia or a CNS tumor.6 In general, the secondary cancers usually developed more than 10 years after the childhood cancer diagnosis and were most often linked to tissue types that had been previously radiated. The secondary solid tumors include: breast cancer, thyroid carcinoma, skin cancers, lung cancer, and GI cancers. Secondary leukemia (acute myeloid leukemia) is also seen as a secondary cancer caused by initial chemotherapy regimens. Most of these deaths will not be classified in any cancer registry as being caused by a childhood cancer malignancy. With the majority of secondary cancer deaths occurring greater than 10 years after the initial childhood cancer diagnosis, most occur in young adulthood and will be recorded as a young adult malignancy, once again unfavorably skewing the childhood cancer related mortality statistics that could lead to increased research funding for this patient population.

A Potential Solution: Increased Research for "Targeted Therapeutics."

The problem of late-effects of childhood cancer is one of toxicity of the treatments. The drugs currently used to treat pediatric cancer are designed to kill most living and dividing cells - cancer and non-cancer cells alike. Because cancer cells typically grow more quickly than normal cells, the goal of current therapy is to find the right "balance" of toxic drugs, so that the cancer is preferentially killed over the rest of the child's body. This balance is obviously difficult to achieve. If there are any remaining cancer cells left after treatment, then relapse occurs, often with the relapsing cancer resistant and refractory to the toxic treatments. This then leads to even more aggressive treatments. The side effects of learning disabilities, organ failure, and secondary cancers are all the consequence of damage to normal cells.

Is there an alternative approach to current toxic cancer therapeutics? Rapidly emerging genome-enabled technologies currently being utilized for adult cancers permit a detailed molecular understanding of tumors and normal cells. Using genome-wide research approaches, "signatures" of each type of adult cancer tumors are quickly being defined. Critical to these signatures is how a specific tumor is different from all other normal cells. These differences are then targeted to specifically kill the tumor cell. This is the nature of "targeted therapeutics." The goal of targeted therapeutics is to avoid toxic drugs that poorly discern between cancer and normal cells, and instead use drugs that attack a cancer cell's unique genetic "fingerprint."

One of the best examples of this approach is with regards to chronic myelogenous leukemia (CML). This blood cancer typically affects older individuals, and had a poor prognosis up until three years ago. A drug emerged - Gleevec, which specifically targeted a molecular pathway that was hyper-activated in CML cells, but not normal cells (ABL tyrosine kinase). Specifically, most patients with CML show a chromosomal translocation called the "Philadelphia chromosome " (translocation between chromosomes 6 and 9; t(6;9)(p23;q34)). This translocation causes inappropriate hyper-activation of the ABL tyrosine kinase, and this signaling molecule imparts abnormally high cell divisions and resistance from cell death to blood cells. Given that this specific tyrosine kinase drives much of the CML cancer, identification of drugs that specifically inhibit this enzyme was sought. This approach was successful in 2003, when the drug Gleevec was shown to inhibit the ABL tyrosine kinase, and as such, successfully led to remission for the large majority of patients with CML.

While there is considerable research focused on the target identification and drug development for adult cancers including a huge undertaking within the NCI known as caBIG (Cancer Biomedical Informatics Grid), such molecular targeting of therapeutics is largely nonexistent for pediatric cancers. There is a currently a well-established "pipeline" for developing targeted therapeutic drugs for adult cancers. The goal of this campaign would be to generate both awareness and funding sources so that the "pipeline" can be initiated and pursued for most childhood cancers.

A pipeline for pediatric cancer targeted therapeutics consists of the following:

  • Defining the molecular signatures of each pediatric cancer, starting with resistant cancer types such as neuroblastoma IV, brainstem glioma, and AML.
  • Pathways that are specifically induced in each cell type.
  • Identifying drugs that can target these tumor-specific molecular pathways.

A key initial step would be to also create centralized databases of pediatric tumor profiles that would facilitate the identification of signatures and unique molecular pathways.

Once tumor specific protein targets and pathways are identified, one needs to identify drugs that inactivate that target. The typical approach is called "high throughput screening" (HTS). This process involves developing a cell-based assay that is able to signal when the target has been inactivated in that cell. One then grows thousands to millions of small dishes of the cell-based assay, with each dish (0.5 cm) then treated with a specific drug. The "read out" of such assays are automated, so that thousands to millions of drugs can be screened for their effect at inactivating the target protein, with a "hit" signaled to computers when a drug indeed inactivates the target. The drug can then be modified using medicinal chemistry such that the maximum potency against the target protein can be achieved, while minimizing non-specific toxicities to other cells and tissues.

This entire drug discovery pipeline using HTS is very well established in most major pharmaceuticals. One problem is that pediatric cancer is often considered too rare to be of economic interest to major pharmaceuticals. Very recently, the NIH has made a number of new initiatives to create national core facilities for HTS that can be accessed by academic investigators. This, coupled with smaller biotechnology companies willing to apply their specific HTS technologies to a wider range of disorders, sets the stage for major advances in pediatric cancer therapeutics. Essential to meeting the goal of increased government funding for this research initiative, it is essential to have a scientific plan that can be used for language in an associated appropriation or childhood cancer research bill.

Candlelighters' Expands its Mission to Support Targeted Therapeutic Research

Candlelighters' believe that the message of "cure" has overshadowed the devastation that this disease continues to have on our nation's children. In light of the above, it is imperative that a new message be heard by members of government, and the cancer leaders of the U.S., and that this new message dispel the myth that "all is well in the world of childhood cancer." Reality from the families who have lost their child to cancer, the survivors who were treated for this disease, and the families who daily care for them, has shown that "life for kids with cancer isn't always happily ever after!" For most, there is no "cure" that returns their child's health to a pre-cancer state, free of life-long late effects from treatment.

In light of the above research and treatment needs, Candlelighters Childhood Cancer Foundation's Board of Directors voted to expand our mission to support the development of molecular targeted therapeutics for childhood cancer.

We met with leaders from the NCI, and the ACS and initiated a two day workshop in May 2005 focused on the need to develop a targeted therapeutics research initiative for childhood cancer. This past July, we hosted a workshop in conjunction with the UICC during the World Cancer Congress to increase awareness of the need for a targeted therapeutic research initiative for pediatric oncology (see page 4). Such research would be directed towards the identification of the genetic "fingerprints" of specific childhood cancer tumors (neuroblastoma IV, AML, and brainstem glioma), and the subsequent development of molecularly based drugs - targeted therapeutics that will target those genetic changes leading to tumorigenesis.

In November 2006, we will be hosting a workshop for database design experts. It is now technically and financially feasible to generate extensive genomewide data sets on individual human subjects, including extensive clinical and laboratory data, 500k SNP chips for CGH and genetic association studies, mRNA expression and splicing arrays, quantitative proteomic profiling, and re-sequencing data. The participants at this workshop would undertake a discussion of the pros/cons of a publicly accessible, standardized database structure for integrated genomics information.

In order to improve survival for children and adolescents with cancer, while dramatically reducing the long-term side effects associated with current standard treatment, it is essential that a comprehensive research initiative aimed at targeted therapeutics be undertaken. Our nation's children deserve no less than the reality of a "real cure" from this devastating disease.

Through our members' support of this important research need, we CAN move this needed research initiative forward. With a newsletter distribution of 25,000 families, it is possible to immediately raise $250,000 with a donation of $10.00 each. With a $40.00 donation per member, we could raise the necessary $1 million to build a centralized database of pediatric tumor profiles that would facilitate the identification of signatures and unique molecular pathways.

PLEASE support this important research initiative through your year end donations!

In addition, please consider doing a fundraiser for Candlelighters' Targeted Therapeutic Research Initiative.

References

1 Ries L, Smith M, Gurney J. Linet M Tamra T, Young J, Bunin G (eds). SEER Pediatric Monogram, Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995; National Cancer Institute SEER Program;.NIH Pub. No. 99-4649. Bethesda MD 1999; 1

2 Ries, L. A. G., Eisner, M. P., Kosary, C. L., Hankey, B. F., Miller, B. A., Clegg, L., Mariotto, A., Feuer, E. J., and Edwards, B. K. SEER Cancer Statistics Review, 1975-2002. 2005. National Cancer Institute. Bethesda, MD

3 Oeffinger K, Eshelman D, Tomlinson G, Buchanan G, Foster B,.Grading of late effects in young adult survivors of childhood cancer followed in an ambulatory adult setting, Cancer. 2000 Apr 1; 88(7):1687-95.

4 Hewitt M et al, Childhood Cancer Survivorship: Improving Care and Quality of Life, Institute of Medicine, National Research Council. 2003; 1

5 Mertens, Ann C.; Yasui, Yutaka; Neglia, Joseph P.; Potter, John D.; Nesbit, Mark E. Jr,; Ruccione, Kathy; Anthony Smithson, W.; Robison, Leslie L., 2001, Late Mortality Experience in Five-Year Survivors of Childhood and Adolescent Cancer: The Childhood Cancer Survivor Study. J. Clin Oncol, Vol. 19 (13): 3163- 3172

6 Ibid