In college, I followed my intellectual curiosity and became a mathematics/computer science/electrical engineering hybrid. But curiosity alone was missing something fundamental. I craved a way to use my knowledge and skills to help people in a unique and meaningful way. A class with the professor who later became my graduate advisor provided that answer. A small-scale collaboration with Dr. Charles Keller became the foundation of my doctoral work, and a moonshot chance to help cancer patients around the country. A few tumultuous years later, and I’m a proud member of cc-TDI.
At first, working on a disease like cancer that afflicts so many people in this country and around the world was a source of deep gratification. But, as I connected with siblings and parents of pediatric cancer patients, as I felt their anguish and frustration and listened firsthand to stories of their family’s fight against cancer, that distant pride faded. I recognized it is a privilege to fight for all the children to come, to carry on the legacy of those we have lost, and to serve families impacted by childhood cancer. That privilege drives me to work until 2 AM through bleary eyes, to write grants, code essential algorithms, and analyze data for pediatric cancer research.
My time working in pediatric cancer biology has shown me the great need for approaches that move beyond the world of standard biological research, incorporating new approaches and new technologies that embrace mathematics and engineering alongside biological research. The Cancer Math methodology we have developed represents this expansive way of approaching the next stage of cancer research: treatments designed by mathematics and biology, personalized to the patient.
My daughter, Ava, was a fearless 4-1/2-year-old with an adventurous spirit. As soon as she could, she wanted to ride horses – she was never afraid of them and would walk right up to them in the pasture. She loved all the animals at the farm and even hugged Larry the llama. She loved swimming with the dolphins and kissing them – spreading her love to all of God’s creatures. She would jump right off the boat into the lake or into the deep end of the pool without fear, possessing a confidence that is rare in children of her age. She loved dancing and dressing up but also playing soccer and riding her bike, any activity she did, she did with gusto, once again providing an example of how to enjoy life.
Ava was only two weeks away from starting pre-kindergarten when she was diagnosed with stage four cancer. She had developed a large bump on her head that persisted for nearly two weeks, and a precautionary CT scan showed that she had several bleeds on her brain. From there on out, each day brought on more devastating news as we learned that she had tumors in her heart, liver, kidneys, spleen and adrenal gland. Within three days of her first scan, she began her first round of chemo, and we were suddenly tossed into the world of childhood cancer. All of the pathology tests were completed and were inconclusive, so they labeled her cancer as Undifferentiated Sarcoma.
Ava always told us how much she loves everybody, “even people I don’t know,” in her words! She had amazing strength during her battle. Her smiles and laugh were contagious, even when she was spending her days in the hospital. Her strength and courageous spirit have allowed us to continue this fight against childhood cancer.
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.
No matter their age or disease, patients undergo first- and second-line therapy. When these approaches fail, clinically or pre-clinically validated options are often limited or nonexistent. These patients without treatment options deserve something new. We believe the most promising treatments for these patients are well beyond the one drug, one target approaches commonplace among precision medicine or clinical trial approaches. Rather, the answer will be found in combination drug therapies personalized to the patient. We believe personalized approaches represent the future of cancer treatment for high-risk patients. Oncologists treating patients with rare and high-risk diseases agree.
From our research, we believe that life-extending, personalized drug combinations can be developed by integrating experimental, genomics and computational approaches to understand the biological mechanisms underlying tumor cell survival. We have developed an integrated computational approach termed Probabilistic Target Inhibitor Maps (PTIMs), or “Cancer Math”, and we have validated our approach of creating personalized drug combinations in silico, in vitro and in vivo to create these personalized drug combinations. However, to take this computational approach from the lab to the clinic, we need more preclinical evidence.
Our goal with this project is to take the first key step towards building the evidence we need to help children battling sarcoma and their families get personalized drug combinations. The most exciting aspect of this research is that while the initial proving ground of “Cancer Math” is sarcoma, once validated we could use apply “Cancer Math” to treat patients with any cancer type.
Why is this important?
Identifying a drug combination to treat sarcoma, a disease that when resistant to chemotherapy is often fatal, is critical for the patients and families managing this disease. Additionally, the Cancer Math method used to identify the two-drug combination could be used to identify personalized therapies for any person with any type of cancer.
Who will benefit?
Initially this project will benefit sarcoma patients and their families as well as treating physicians. Ultimately, this innovative engineering forward, cancer math approach could be used to identify personalized therapies for any type of cancer.