Pediatric Cancer: Major Advances, Major Challenges – Notes from the 5th Annual Childhood Cancer Caucus

The Congressional Childhood Cancer Caucus Presents

Pediatric Cancer: Major Advances, Major Challenges

5th Annual Childhood Cancer Caucus

Friday, September 19, 2014 9:00 – 10:30 a.m.

Congressional Auditorium, US Capitol Visitors Center


Congressman Michael T. McCaul (R-TX)
Congressman Chris Van Hollen (D-MD)

Keynote speaker:

Dr. Francis Collins, Director, National Institutes of Health (NIH)


Dr. Ronald DePinho, President, MD Anderson Cancer Center
Dr. Amrit Ray, Chief Medical Officer, Johnson & Johnson – Janssen Pharmaceuticals


by CAC2 Member Laurie Orloski

Opening remarks

Vickie Buenger, President of the Coalition of Childhood Cancer (CAC2)

Vickie Buenger kicked off the Caucus by welcoming and extending thanks to the Congressional Co-Chairs, distinguished speakers, and attendees. She noted that the first Childhood Cancer Summit was held in 2009 to raise awareness, funding, and support for children and adolescents with cancer, emphasizing that it is critically important that we continue to advocate in support of these various areas in an effort to eliminate cancer as a threat to all children.

Congressmen Michael T. McCaul and Chris Van Hollen, Co-Chairs

The Congressmen Co-Chairs also gave some opening remarks prior to the introduction of the keynote speaker. Congressman Michael McCaul opened by acknowledging the important steps that have been taken from a legislative standpoint, highlighting both the Creating Hope Act and the Caroline Pryce Walker Conquer Childhood Cancer Act. He noted that children with cancer do not have lobbyists in Washington and that a platform like the Caucus is important for giving children a voice. He has a personal connection to a child with cancer, having lost his best friend in grade school from leukemia. The Congressman extended thanks to some selected individuals, including Annette Leslie (for her efforts surrounding the Caucus), Timothy and Donna Culliver (for bringing the problem of pediatric cancer research to his attention), and Nancy Goodwin (for spearheading the Creating Hope Act). According to Congressman McCaul, the Creating Hope Act is already working to incentivize the marketplace, with the first voucher changing hands for almost $70 million. Another voucher is expected to be granted in December 2014, marking the first drug to be specifically approved for childhood cancer since the 1980s.


Importantly, as noted by the Congressman, childhood cancer is not a Democrat or Republican issue—it is an American issue.
From Congressman McCaul’s perspective, he wants to ensure that the Creating Hope Act is made permanent, and that the policies of compassionate use are revised for both children and adults, noting the experience of Andrea Sloan who had recently passed away from ovarian cancer in her 40s. He believes that compassionate use needs to be looked at legislatively and revised using transformative measures, and he sees Johnson & Johnson as being a leader is starting the conversation with industry.
Congressman McCaul then introduced Congressman Chris Van Hollen, who says that he is motivated by 2 groups 1) parents and family members of children who have fought under difficult circumstances, through pain and tragedy to ensure that others are helped and 2) families and children who have battled, survived, and are now contributing to society, such as Matt Grossman who is a childhood cancer survivor working with children with autism.
“Kids say that if we keep fighting with research, we will win the fight”, said Congressman Van Hollen. As a representative of the District that is home to the NIH, he feels an obligation for ensuring that continued investment. At the same time, however, it is well appreciated that NIH funding has fallen in real terms in recent years, irrespective of inflation.
Congressman Van Hollen introduced the keynote speaker, Dr. Francis Collins, a physician-geneticist. His work includes the Human Genome Project, conducted from 1993-2008, that led to the sequencing of 3 billion letters in DNA destruction and represents a significant undertaking of our time. As a scientist and leader at the NIH, Dr. Collins is driven by how research will help patients like children with cancer.

Keynote Presentation – Dr. Francis Collins

Dr. Francis Collins started off by highlighting some of his key areas of research, including the identification of the genes associated with cystic fibrosis, neurofibromatosis, and advanced aging—which have led to clinical trials and better treatments for children. He feels that we need to pull out every possible stop when it comes to biomedical research and is exhilarated by the science being explored at the NIH, with new developments emerging every single day. While the total number of human diseases exceeds 7,000, treatments are available for only about 500 diseases.
Advances in basic discovery are accelerating the pace of translational research. The National Center for Advancing Translational Sciences (NCATS)—has been implemented to help address the so-called Valley of Death of clinical drug development. Dr. Collins also explained the complexity of the NIH, which includes not only the National Cancer Institute but also 27 other institutes and centers.
The focus then shifted to childhood cancer, with Dr. Collins showing a slide illustrating that cancer is the #1 cause of disease-related death for children. Although gradual improvements in therapeutic efficacy are being seen in all age groups when comparing 1977 versus 2010, progress in certain areas like soft tissue sarcomas and brain tumors has fallen short.


Dr. Collins highlighted some data from the Childhood Cancer Survivor Study, in which an NCI-funded network is studying the long-term effects of cancer and cancer therapy in ~35,000 survivors diagnosed between 1970 and 1999. Treatment-related cardiomyopathy has been identified as one of the common long-term effects, with possible genetic risk factors being examined. This research has found that an inherited genetic variation (involving CBR3, a gene for an enzyme involved in anthracycline metabolism) is associated with a 10-fold greater risk of cardiomyopathy after anthracycline-based chemotherapy, as carriers of this genetic variant metabolize anthracycline agents in a distinct way.
Dr. Collins explained the basis of cancer, how it is a disease of the genome that arises from mutations in DNA. The evolution of a normal cell to a tumor involves a multi-step process that is characterized by an accumulation of misspellings in DNA. Oncogenes are regarded as “the accelerators” of malignancy. Whereas normal genes help cells to grow when they should, mutations in oncogenes promote continued cell growth in settings where it is undesirable. These oncogenes are now being recognized and studied as drug targets. Conversely, tumor suppressor genes are regarded as “the breaks”. Tumor suppressor genes normally function to appropriately slow down cell growth, whereas an initial mutation makes an individual a “susceptible carrier” in terms of cancer risk.
Importantly, because of these contributions of an individual’s own oncogenes and tumor suppressor genes, every cancer has a different biology—meaning that every treatment should be individualized.
Dr. Collins showed the plunging cost of sequencing a human genome, which was approximately $100,000,000 in September 2001 versus a few thousand dollars in January 2014, during which time the equipment required has been reduced from the size of a phone booth to that of a postage stamp. These advances in technology are allowing for comparisons between a patient’s cancer cells relative to normal cells, to identify DNA misspellings that can be targeted by drug therapies.
This led into a discussion of The Cancer Genome Atlas (TCGA), a coordinated effort to accelerate our understanding of cancer through genomic analysis, as a means of improving diagnosis, treatment, and prevention. Over 20 types of cancer were the focus on TCGA, including leukemia and solid tumors of the breast, colon, uterus, brain, lung, ovary, and bladder.
A similar initiative, termed TARGET (Therapeutically Applicable Research to Generate Effective Treatments), focuses on pediatric cancer. TARGET involves a collaborative network on pediatric cancer, using a comprehensive genomic approach to identify molecular targets to improve both diagnosis and treatment.
Another project is expanding upon the TCGA and TARGET: the Pediatric Cancer Genome Project (PCGP) that was set forth to discover the genetic origins of select pediatric cancers. PCGP is being co-led by St. Jude Children’s Research Hospital and the Washington University School of Medicine and involves whole genome sequencing of 600 childhood cancer cases. PCGP-derived data for low-grade gliomas (LGGs), a difficult-to-treat subtype of the most common childhood tumor of the spine and brain, have revealed that 2 genes are responsible for >50% of LGGs. Based on these genetic alterations, there is some evidence that these tumors may be susceptible to drugs in development.
Further efforts to move the genome into the clinic include the NIH’s Clinical Sequencing Exploratory Research (CSER), which is supporting a consortium of researchers around the US to develop methods to bring genomics to patients, in an ethical manner. The CSER includes childhood cancer. Another example is BASIC (Baylor College of Medicine Advancing Sequencing into Childhood Cancer Care), for which the focus is to move from a “one size fits all” to a more precise treatment approach in high-risk solid tumors and brain tumors in children. BASIC is attempting to identify “actionable mutations”, assessing the impact of DNA data on diagnosis, clinical decision making, and patient-physician communication. Early results are promising. Thus far, 165 newly diagnosed patients (plus their parents) have been enrolled, identifying potentially actionable mutations in 30% to 40% of patients.
The next topic was cancer immunotherapy, which was heralded by Science magazine as the 2013 breakthrough of the year. Advances in cancer immunotherapy were made possible by research addressing the question of: what stops the body from waging its own “war on cancer”? New approaches have since been identified that unleash the power of the immune system to search for and destroy cancer cells. These approaches include blocking protein receptors that hinder immune responses, namely CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD1 (programmed death 1), as well as genetically engineering immune cells to target tumor cells.
Dr. Collins presented the pioneering work of pediatric neuroblastoma therapy. Neuroblastoma is a rare cancer of nerve cells but the most common cancer affecting infants, and <40% children are alive 5 years after diagnosis. New hope for patients with neuroblastoma lies in an immunotherapy approach using an anti-GD2 antibody, which has been in development for 20+ years and has been found effective in phase III clinical trials. Currently, the NIH is collaborating with United Therapeutics on late-stage development and the regulatory approval process. Anti-GD2 antibody has received orphan drug designation from the FDA; it is pending FDA approval.
Chimeric Antigen Receptor (CAR) therapy is another type of immunotherapy, whereby T-cells are derived from the patient and are taught to recognize and attack tumor cells. Dr. Collins showed an example of a young boy, a nonresponder to conventional therapy for acute lymphoblastic leukemia (ALL), who achieved remission from CAR therapy and is alive and well today.
Per Dr. Collins, there are reasons to be optimistic for the future, yet there are also reasons to be frustrated. The last topic of discussion pertained to issues with NIH funding. The NIH budget doubled in 1998 but has since been subject to a stead downward slide. When the inflation-adjusted budget is plotted against the budget that would reflect real annual growth (of 3.7%), there is a gap of $9.5 billion in 2012 dollars, putting the actual budget 23% below projected levels. The budget increase that was the result of stimulus funding was only transient. For our best and brightest researchers who seek NIH funding, the chances of being awarded funding is its lowest in history, at 16%. Moreover, an estimated 18% of researchers are considering leaving the US.
Dr. Collins closed with a message of one voice for conquering the challenges of the current era, in which the promise of medicine and medical research is the highest ever yet funding support is lacking and impeding advances.
As part of the Q&A, members of the audience asks questions pertaining to the NIH support of basic research, tools to prioritize childhood cancer research, and access to unapproved drugs for testing in children. Here is a synopsis:
It is well appreciated that a lot of what we know about cancer stems from basic research. In discussing basic research, one point that was brought up is the closing of small laboratories, which have historically relied on NIH support. One of 6 grant applications by basic scientists is being approved in the current era. Thus, turning around of the funding curve in a way that sets forth a sustainable path is imperative. Dr. Collins believes that this would re-energize the community, and he reaffirmed his own dedication to studying orphan diseases.
Regarding tools for prioritizing childhood cancer research, Dr. Collins alluded to a new program, which would be announced by Dr. Harold Varmus. (see – NCI Announces a Pediatric MATCH Trial for Childhood Cancer) He also explained that sharp dividing lines, such as pediatric vs adult cancer and leukemia vs sarcoma, are beginning to melt away as each cancer is a unique entity in itself. Accordingly, per Dr. Collins, it is important to keep in mind that therapeutic advances that occur outside of the 4% of funding allotted to pediatric cancer research may still be relevant to patients with childhood cancer.
In terms of access to new drugs, before they are approved in adults or immediately after approval, Dr. Collins believes there may be opportunities to set a path forward within the NCI as well as the National Institute of Childhood Health. He welcomes further collaborative conversations on this front. Additionally, the NCATS may provide some new opportunities. This center is testing drugs that have been determined to be safe but ineffective in the disease(s) for which they were originally developed, totally 100s of drugs. For example, drugs that have been developed initially for diabetes are being studied in cancer, and vice versa. No single company has the ability to do this type of repurposing, and there are challenges stemming from intellectual property. At the same time, however, it may be feasible to make these safe but failed compounds available to the entire intellectual community via crowdsourcing. As of a year ago, 58 drugs were identified as suitable for further study. Some projects are already moving forward, including some for childhood cancer. In the end, it may be possible to obtain answers to important clinical questions in about 3 years (rather than 14 or so).

Presentation – Dr. Ronald DePinho

Dr. DePinho began his presentation by providing a clinical research snapshot of MD Anderson Cancer Center (MDACC). MDACC serves 122,000 patients on tits Houston campus and 114,000 patients across a national network, with 30 sister institutions across 23 countries. Research expenditures total approximately $700 million, and the number of clinical trial protocols exceeds 1,000. Of 71 drugs approved by the FDA in the last 5 years, MDACC led trials for 22 of these compounds.
MDACC’s Children’s Hospital includes the George E. Foreman Pediatric and Adolescent Inpatient Unit, the Robin Bush Child and Adolescent Clinic (outpatient), and Kim’s Place (a unique recreational area for visitors age 15-30 years).
DSC_1081Dr. DePinho gave an overview of therapy development issues for childhood cancer, noting that most are extremely rare and indications for drugs are rarely obtained. There are limited numbers of children with a specific tumor type and molecular subtype, and recruitment for clinical trials is difficult and lengthy. The exorbitant cost and time needed to produce a single drug for adult tumors can be mitigated by the size of the market; however, this is not the case for pediatric oncology drugs. Children also have unique, developmentally specific differences in terms of toxicity, metabolism of drugs, and the need for different formulations. Not only do children present with different diseases, but the biology of diseases differ from what is seen in adults. Children and adults with the same actionable targets may respond differently in terms of efficacy. Additionally, a lack of pharmacokinetic data in children can lead to increased toxicity (overdosing) and less efficacy (under-dosing) with a new drug. Toxicities may reflect differences in pediatric metabolism, which varies with developmental stage.
Overall, there is a belief in the greater community that children should not be subjected to risk, resulting in delayed access to new therapies. In the setting of poor-risk cancers, this approach is detrimental to child health now and to advancing cancer treatment for children in the future.
On this basis, “smart clinical trials” are needed to illuminate novel therapeutic opportunities. It is recognized that one-third of childhood cancers respond poorly to current standard of care. One of MDACC’s sister institutions, Germany Cancer Center (DKFZ) has set forth on a new path, the foundation of which is complex deep genomics. At Germany Cancer Center, all children are treated in protocols by pediatric oncologists, allowing for recruitment of all recurrent cases. At the time of relapse, a second biopsy is obtained for an in depth genomic analysis at the cancer genome sequencing facility. Extensive molecular profiling is performed for 2 reasons: (1) to learn about the genomic basis of tumor recurrence and treatment resistance of pediatric tumors and (2) to identify targets for novel drugs, which are added to the usually unsuccessful standard treatment in an experimental trial setting.
Currently, a second chance for children with cancer campaign is ongoing, involving studies being conducted by the Germany Cancer Center Consortium and at MDACC.

  • The Germany Cancer Center Consortium has launched the INFORM trial on a national basis; if the approximately 2,000 childhood cancers diagnosed annually, about 500-600 develop recurrent disease. In the first 50 cases, deep sequencing analysis identified actionable mutations that led to the initiation of an experimental therapy for those children.
  • At MDACC, the PREDICT trial provided the first proof-of-concept that genome-informed enlistment into clinical trials increases response rates in phase I trials. In PREDICT, 11 genes are genomically profiled. Among molecularly informed patients, the response rate to date has been 27%.
  • The Triumph Over Kids Cancer and MD Anderson Genome Sequencing project will be launched for recurrent cancer, initially focused on osteosarcoma. Steps will need to be taken to ensure access to drugs for actionable mutations, which will involve bringing scientists and regulators together to save lives.

Dr. DePinho shifted to an overview of regulatory collaborations and advances from 1997 to 2012, ranging from the FDAMA Pediatric Exclusivity Act (1997) to the Creating Hope Act (2012) that he believes will save lives. The Pediatric Research Equality Act (PREA) was passed in 2003 and reauthorized in 2007, proving the FDA with the authority to require studies in children if an adult indication also occurs in children. However, PREA does not provide much support for tumors only occurring in children. Per Dr. DePinho, revisions to PREA—mandating the consideration of molecular targets as a criterion for pediatric testing—could help to bring new agents to children and would be beneficial for the agency to consider.
The next topic of discussion was compassionate use. For context, Dr. DePinho noted that approximately two-thirds of patients do well with standard of care treatment. The remaining patients, about one-third, fail standard therapies. In these instances, providers and caregivers for these patients are typically committed to searching for life-saving options—generally experimental or novel therapies that can offer hope for a cure, an extension of life, or a better quality of life. Sometimes the only hope is access to a drug requiring special consideration by the therapeutic sponsor, equating to single use of a new or novel treatment. Reforms and solutions are needed for this process, including a constructive dialogue with the many stakeholders involved in these decisions. Industry, providers, patients, survivors, and policy makers need to come together to identify the related issues and regulatory and legal barriers, as well as to develop solutions. Per Dr. DePinho, MDACC is strongly interested in developing a pathway, or framework, for expedited review and approval of drugs or therapeutics for patients with extremely rare circumstances. Potential solutions must ensure that biopharmaceutical companies can move forward with clinical trials to test novel agents and that companies can enter into single use agreements in a way that clinical testing results are not hampered by a compassionate use arrangement.

Presentation – Dr. Amrit RayDSC_1098

Dr. Ray began his presentation by illustrating the principles that will lead to better cancer treatments, including a deeper scientific understanding, stronger collaborations, and a continued emphasis that “patients come first”. He also went on to review some challenges in pediatric drug development, which include the relative rarity of the diseases, observations that medicines act differently in children and cancers act differently in children, and hurdles from a technology standpoint.
There have been numerous developments in oncology, as reviewed by Dr. Ray. These include advances in various disciplines, such as diagnostics, immune-oncology, cancer interception, and use of biomarkers and their correlation with clinical outcomes, and modeling and simulation techniques.
As part of the ongoing need for collaboration and the connection of great minds in research, innovation can be catalyzed by applying Children’s Oncology Group (COG) cell lines, clinical data transparency, and clinical trial networks, as well as by tapping into expertise.
In keeping patients front and center, it may be necessary to reframe the discussion to achieve balance and transparency in clinical research, promote independent, evidence-based decision making, and act with a sense of urgency. This patient-centric approach has tremendous potential for advancing treatments for childhood cancer.
Dr. Ray closed with 2 poignant quotes, bringing hope the importance of collaboration and the need to change the way we approach the challenge of childhood cancer:

  • “Science is a field which grows continuously with ever expanding frontiers. Further, it is truly international in scope …. Science is a collaborative effort. The combined results of several people working together is often much more effective than could be that of an individual scientist working alone.” ‒ Nobel Laureate John Bardeen
  • At first, people refuse to believe that a strange new thing can be done, then they begin to hope it can be done ‒ then it is done and all the world wonders why it was not done centuries ago.” ‒ Frances Hodgson Burnett, The Secret Garden


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