By studying how the DNA instructions are broken inside childhood cancers (especially the solid tumors called sarcomas), we now know one class of genes is often disrupted: transcription factors. If the human genome is a library of books, these transcription factors are the librarians. These factors choose which “books” to open (which genes to turn on). In childhood cancer, I recently discovered DNA mutations that create abnormal and super-strong transcription factors work by forming large “super-clusters” at cancer-causing genes. In my new lab, I want to next discover why and how these super-clusters form in cancer, by studying the proteins that transcription factors recruit to build these super-clusters. I expect this will open new pathways of scientific discovery and opportunity. Additionally, I will develop and study new drugs that can dissolve/stop these super-clusters and selectively kill pediatric cancer cells (specifically, I will focus on rhabdomyosarcoma). Several of the molecular discoveries I have made in the last 3 years have resulted in the initiation of clinical trials, where we no longer give the same therapy to patients based on disease tissue type, but we match the therapy to the genetic error causing each child’s cancer. My new work will provide a new class of therapy, and scientific evidence, to the heroic medical doctors who decide what new therapies to test in their patients. Also, because childhood cancers are very rare, it is difficult to get large enough patient populations for a clinical trial. My work will enable grouping patients according to whether they have a “super-cluster” driven disease, and whether or not their tumor will respond to an anti-super-cluster drug. I will also test the idea that drugs targeting super-clusters will have minimal side effects because healthy cells lack super-clusters. Safer therapies are urgently needed in pediatric and adolescent cancers, where current harsh treatments increase the frequency of secondary cancers later in life.

My primary goals are (1) to become a visionary leader in the field of scientist who study how the human genome functions, (2) to create new small molecules to drug cancer-promoting processes inside the genome, and to (3) make a lasting impact on the treatment outcomes for children with cancer. My career path is a mix of training in chemistry, drug development, genomics, 3-dimensional epigenetics, and cancer biology. This award will enable me to launch a robust research program, where I will lead a team that weaves together these diverse disciplines in the fight against cancer. I am excited that the Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Areas include pediatric, adolescent and young adult cancers, as this is an area where I have made significant scientific contribution, an area where I have a depth of experience and knowledge, and an area where breakthroughs are very needed.

The proposed research plan will not only advance my career as a leading cancer investigator, it will also impact mission readiness by filling a gap in treatment and survivorship for the children of active Service military and Veterans. The new treatment strategies are designed to minimize toxicity and relapse, thus minimizing hospital time for their children, and maximizing the time Service members can be on duty.

I am very enthusiastic about the Department of Defense Virtual Cancer Center, as it is a unique opportunity to accelerate and bolster my independent career, enhance my development by creating new interactions and collaborations, and provide me an opportunity to lead by promoting the integration of my discoveries and approaches into the thinking and research of other scientists.