Charles Keller, M.D.
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, but the path from basic science to clinical applicability seemed too complicated to explain. 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 (inserting 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)!
Amongst 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 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 (www.cc-tdi.org). We continue to pursue many of the same publication and grant funding goals as we had in academics (we have been a continually NIH-funded laboratory for 15 years, with our most recent NIH/NCI R01 (4th percentile) having begun in August 2015)... but we also 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.
What if drugs could be chosen and prioritized for their ability to stop and shrink cancers that spread (metastasis)?
The Go4TheGoal Foundation has created a challenge for a 1:1 match on this crowdfunding project to fund purchase of a Zeiss Stereo Microscope. This microscope will empower us to observe sarcoma progression using tumors taken from our genetically-engineered mouse models. These mouse models are for rhabdomyosarcoma and related soft tissue sarcomas. Specifically, alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma and undifferentiated pleomorphic sarcoma (see Genes Dev. 2014 Jul 15;28(14):1578 and Cancer Cell. 2011 Feb 15;19(2):177).
This instrument is vital to our mission: our genetically-engineered mouse models (featured in this Nobel laureate lecture) have tumor cells that harbor firefly luciferase and jellyfish fluorescent proteins undergoing the ‘metastatic decathlon’ … that is, moving from a primary tumor site, across connective tissue, into a blood vessel or lymphatic channel, then out of that vessel/channel to establish a tumor at a metastatic site. The system we developed has all of these required tumor microenvironment components: the quail chorioallantoic membrane (CAM) assay. An example of observing rhabdomyosarcoma cells (fluorescent red) and blood-borne metastatic cells is at this link:
Why is this important?
With the Zeiss microscope in hand, we will be able to:
- Screen for drugs whose primary purpose is to prevent metastasis, understanding which step in the decathlon that the drug acts at,
- Reconstitute the tumor microenvironment by adding not only tumor cells but also non-tumor cells (e.g., immune cells like macrophages … the function of which in rhabdomyosarcoma is highlighted in our publication Stem Cells. 2013 Nov;31(11):2304), and
- Move towards reconstitution of tumor cells and non-tumor cells from biopsy material.
The first step to these studies is acquisition of this specialized microscope enabling this experimental approach. This instrument is different and substantially more sensitive and specialized than any other one in our laboratory, is central to our basic science and preclinical drug development programs, and would be one of the most empowering tool for our research and innovation.
Who will benefit?
This study will benefit children, adolescents, young adults and older adults with rhabdomyosarcoma and related soft tissue sarcomas.
BudgetThe Go4TheGoal Foundation has created a challenge for a 1:1 match on this crowdfunding project to fund purchase of a Zeiss Stereo Microscope. They will match $25,000 in crowdfunding with an additional $25,000.
Dear Supporters, the microscope arrived and was installed yesterday. It is A-m-a-z-i-n-g! Stay tuned as we generate and share data with you. The whole lab is buzzing with excitement. Thank you for making this possible! Sincerely, Charles & Team