Every night I read to my daughters at bedtime, then head back to the lab for a second shift. One night, my youngest daughter, then 4 and a half years old, asked, “Daddy, you leave for your research every night...but have you ever saved anyone’s life from the research you do in your lab, ever?” My answer was, unfortunately, “No. not from my research.” I could have said that nobody really ever has - path from basic science to clinical applicability seemed too complicated to explain. But she had valid question, and it got me thinking: wouldn’t children with cancer ask the same question, too?
Fast forward to Spring 2014, at the annual Children’s Oncology Group meeting. The Chair announced dramatic cuts in the National Institute of Health’s budget for the COG...suggesting that not every childhood cancer could have an open clinical trial: only the ones with preclinical justification. The standard approach (dropping in adult cancer drugs into trials for children) simply hadn’t worked. At the same meeting, the NCI announced that as a result of the sequester, the budget of the Pediatric Preclinical Testing Program was cut earliest, and deepest, of any NCI program (by 40 percent)!
Among colleagues who were leaders in pediatric oncology at academic centers, the feeling was that preclinical testing of basic science findings, to move exciting discoveries to clinical trials, was too tedious and narrow-scoped for university laboratories and government programs. As a result, the best and brightest scientific discoveries for childhood cancers never actually make it into the clinic. Rare cancers are the hardest hit, with survival rates remaining stagnant for decades. Knowledge that could save kids’ lives simply languishes in this black hole: the preclinical gap.
By chance, my reading material for the airplane ride home was A Life Decoded, the book by J. Craig Venter. In this story of the first group to sequence the human genome, Dr. Venter achieved remarkable speed and cost efficiency by “going outside the box” of academia. Curious, I drove straight from the airport to a biotech incubator. Renting a 250 sq ft lab space for per year: a mere $10,500.The “what if’s” began: what if we could change the existing paradigm of research grants leading to publications (leading to more grants and papers, but never tangible results)?
What if we could bridge the preclinical gap as a mission...with scientists partnering with families to achieve the cures they so desperately desired? What if science driving drugs into the clinic existed as a singular mission? My research team and I simply wanted to know how a non-profit biotech could answer my daughter’s question. The result is the Children’s Cancer Therapy Development Institute. We value our pharmaceutical partners, give parents a seat at the table, and really listen to the clinical trialists. All in the name of converting scientific discovery into clinical trials for children with rare and underserved cancers.
CureFast and the Legacy Gift program are at the heart of our efforts: by enabling parents of children with cancer to donate tumor tissue to the research community, we begin to fully understand why certain cancers are so difficult to treat. From this team effort, ways to treat the most challenging childhood cancers will emerge.
One in 5 children with cancer will not survive. We propose to address gaps in basic and translational research by improving model systems for pediatric diseases. To this end, we have developed a Legacy Gift (research autopsy) program called the Cancer Registry for Familial and Sporadic Tumors (CUREfast) to enable parents of children with cancer to donate tumor tissue to the research community. It may seem unusual to think that innovation can come from leftover surgical tissue or a research autopsy – but we believe it can be field-changing, especially for rare childhood cancers for which cell lines and mouse models do not exist, and for which functional studies have never before been performed. Examples of these pediatric cancer orphan diseases are intracranial germ cell tumor (no cell lines or mouse models until recently), metastatic hepatoblastoma (essentially no representative cell lines), anaplastic Wilms’ tumor (2 cell lines, 2 mouse models) and pediatric epithelioid sarcoma (1 cell line). By focusing on resource development for these childhood cancers, using treatment-refractory tumor samples, we open the door to true innovation. We have collected Legacy Gifts and advanced disease surgical material from over 500 patients across the country, resulting in 19 patient-derived xenograft (PDX) models created in collaboration with the Jackson Laboratory including four “first-in-world” disease models: epithelioid sarcoma, PAX7:FOXO1+ alveolar rhabdomyosarcoma, and parameningeal rhabdomyosarcoma. These autopsies still represent a small sample of the children lost to cancer every year, and thus a tragically lost opportunity for the research community that faces limited availability of pediatric models. To improve pediatric cancer model systems, we propose:
Aim 1: Create PDX mouse models with The Jackson Laboratory using tissue from relapsed or autopsy patients representing the “1 in 5” children. This aim will focus on sarcomas and other pediatric solid tumors.
Aim 2: Generate primary cell suspensions for direct “on the spot” drug sensitivity testing with a drug panel of 60 agents in the COG drug portfolio. This data will be paired for each case with DNA exome sequencing & RNA deep sequencing, enriching the utility and applicability of our data, which will be broadly shared before publication.
Pediatric preclinical models are few and often decades old; more representative models are needed to ensure that preclinical studies are done with predictive accuracy across different models of the same disease. New models developed in this work, both in vitro and PDX in vivo, will allow for the preclinical validation of novel treatments for critical diseases; when paired with primary culture drug screening and DNA and RNA sequencing data generated and shared readily with the research community, the materials generated in this work represent an innovative step and should prove pivotal to pediatric preclinical research efforts for ‘orphan’ childhood cancers.
Why is this important?
Overall cure rates for childhood cancer have remained nearly the same for more than a decade, necessitating an evolution of our approach. Two addressable gaps for better basic and translational research exist:
First, the basic materials for research are rare. For instance, rhabdomyosarcoma continues to be studied using the Rh30 and RD cell lines, which were established in 1987 and 1968, respectively; similarly, most brain tumor cell lines were established before the need for serum-free conditions was recognized. Furthermore, for certain brain tumors like intracranial germ cell tumor, nearly no cell lines have ever been reported. Finally, existing cell lines are generally taken from newly diagnosed patients – not relapsed ones.
Second, COG disease subcommittees often design trials of new agents with only indirect evidence for activity against childhood cancer – and with a limited number of biological replicates for each disease (that is, usually only a handful of cell line or animal models have been tested – and it would be difficult to say that these select model systems are representative of the disease). Whereas existing National Cancer Institute programs have insufficient resources to test all worthwhile ideas emerging from the COG disease committees, the requested funding here would help ensure that informative preclinical studies could be conducted by a wider range of laboratories with a more diverse set of tools.
Who will benefit?
We accept samples from anywhere in North America (pediatric tumors and sarcomas of any age). The research done on each child's tumor is meant to benefit children with that cancer as a whole. The altruistic gift of tissue often has intangible benefits, though, as described by the families below.
"My daughter Iris refused to be defined by her cancer. Instead she was a beacon of hope. Her dream was to find more humane treatments on the road to a cure. Continuing to support Dr. Keller's research keeps her memory alive for us. Please join us in providing ongoing support to the lab. His research touches the most devastating pediatric cancers. Be a beacon of hope for children with cancer."
“Through this life/death experience, our family has been made aware that we really have no control over our destiny. Anything can happen at any moment in time. Though we cannot be guaranteed a future, what we do in the present can make a world of difference for many others. If we have the resources to assist in the prevention of suffering, it is not a question of IF, but WHAT action would be most effective? … During his third, and last year of treatment, Io said, “This story doesn’t have a happy ending”. He expressed the desire to “give back” in gratitude for the efforts of his medical team, and to give hope for more successful outcomes with other young Rhabdomyosarcoma patients. Io's legacy gift was two-fold: His corneas were donated to needy recipients, and his autopsy provided urgently needed tissues for research at Dr. Charles Keller's research laboratory. … I was shocked to find that in this day and age, physicians are not trained to relate effectively with parents on the sensitive subjects which arise during treatment, and end of life issues for their dying children (including timely discussion of autopsy samples necessary for urgently needed research).
When I think of my son’s spiritual energy, I know in my heart, that by providing this legacy gift in his memory, his wish to accomplish something meaningful has been fulfilled. I encourage other parents who find themselves in a similarly unfortunate situation, to speak out through all phases of treatment as an advocate for their child, and to find some solace through the legacy gifts that their family may provide for the benefit of future patients. “
"The donation of Peyton's tumor to Dr. Keller and The Children's Cancer Therapy Development Institute has been so important to our family and our fight against childhood cancer. Peyton's legacy, through the donation of his tumor, will allow research for less toxic and more effective therapies. Our hope is that one day, Dr. Keller, cc-TDI and other researchers around the world will be able to find a cure for Rhabdomyosarcoma and other childhood cancers with research from Peyton's tumor. The time is now to make a difference in childhood cancer research and treatments. We are so grateful to Dr. Keller and cc-TDI for the time, effort and initiative to establish such an important research institute for childhood cancer."
“The decision to donate our son's tumors to research continues to give us hope. It allows us to fight for our son (Shane) and so many others until a cure is found. “
“As a postdoctoral fellow working at the Massachusetts General Hospital Cancer Center, I had the opportunity to attend a seminar by Dr. Keller on his work towards a cure for rhabdomyosarcoma. At the time, my niece (name) had been undergoing aggressive treatment to fend off alveolar rhabdomyosarcoma, one of the most lethal forms of this rare pediatric cancer. For five years, we watched (name) go through the unfortunately ineffective rounds of treatment, hoping that the next drug course would finally give positive results. Throughout these hard times, we kept contact with Dr. Keller who went beyond the call of duty to provide us with advice and updates on rhabdomyosarcoma research. When (name) passed away, a sample of her tumor which carried the Pax7:Foxo1+ translocation, was sent to The Children’s Cancer Therapy Development Institute (cc-TDI) and Dr. Keller’s team successfully implanted it into mice. The generation of the first xenograft model of Pax7:Foxo1+ alveolar rhabdomyosarcoma generated with (name)’s tumor came as soothing news to the whole family as we knew that it would greatly speed up the quest for an effective cure and help other children in their fight against this terrible disease. We are extremely grateful to Dr. Keller and cc-TDI for their advocacy and research efforts towards a cure for rhabdomyosarcoma and other childhood cancers. “
BudgetThe detailed budget breakdown below reflects the sample processing flow. Each sample requires $7,850 if all procedures are done. However, DNA and RNA sequencing can be deferred, and sometimes the transport fee isn't necessary (for instance, if the tissue sample came from a surgery). To be sure, a contribution of any amount helps the overall program. The $117,750 goal for the program reflects our effort to serve 15 patients and their families this year.
We are *so* grateful to the families and individuals who gave this grassroots, open science project its start! Can you help us spread the word?
Just $50 prepares a sample for future use;
Just $400 empowers creation of a cell culture;
Just $800 sequences all genes to find what is on & off in the cancer.
Above is an example of what can be achieved. With updated models, so much progress can be made!