Despite implementation of screening and preventative strategies, colorectal cancer (CRC) remains the third most common and second most deadly cancer worldwide. Furthermore, there is an alarming trend in early onset CRC with rising incidence in patients under the age of 50. Standard treatment for CRC consists of aggressive chemotherapy regimens that carry significant toxicity with limited benefit. While there have been a handful of newer combinations, targeted therapy designed to reverse specific malignant behavior of CRC cells has yet to enter the clinic. We therefore have a rather urgent need to develop new strategies to treat CRC. I strongly believe these novel therapeutics will be rooted in an improved understanding of CRC biology, emphasizing critical dependencies of the cancer in order to achieve meaningful clinical translation.

The intestine is a special organ in that it is the most rapidly renewing tissue in our body; the gut lining is replenished every 2 to 5 days, which is simply remarkable. Maintaining the intestinal lining therefore requires stem cells to constantly give rise to mature cells to perform specialized functions such as nutrient absorption before dying. Disruption of this natural maturation is a hallmark of CRC. In particular, CRC cells hyperactivate stem cell programs that block their maturation and prevent cell death, enabling these malignant cells to persist. The proposed research is tailored to define the factors that lead to uncontrolled stem cell activity and block proper maturation of cancer cells (Aim 1). By identifying these factors, we will generate a deeper understanding of the deviations in intestinal biology that lead to CRC. To translate this knowledge into new therapy, we have designed a unique discovery platform, which will enable us to screen thousands of drugs to find the specific agents that overcome this block in maturation (Aim 2). We strongly believe the next generation of therapeutics will restore proper maturation in colon cancer cells, reprogramming them to live out their natural life cycle. Finally, we have also noticed that factors responsible for stem cell behavior are mutated in a subset of CRC. Using an innovative mouse model and cutting-edge technology, we hope to define the clinical and functional significance of these recurrent mutations in CRC.

As a physician-scientist, my ultimate career goal is to combine clinical observations and patient-derived data with rigorous basic science investigation to yield opportunities for impactful translational advances. My passion for investigative research is fundamentally dependent upon its power to generate a deeper understanding of human disease and ultimately improve patient care. I am particularly committed to defining the fundamental mechanisms underlying genomic alterations that promote gastrointestinal cancers with the hope that such insight will translate into new mechanisms to prevent and treat cancer. The Department of Defense Virtual Scholar Career Development Award will dramatically accelerate my ability to accomplish these goals by providing funding, resources, and broad mentorship. Furthermore, the Virtual Cancer Center will provide an invaluable scientific environment for multidisciplinary research discussions, potential collaborations, and career guidance.

The proposed research will deliver a deeper understanding of critical mechanisms in CRC. We propose to characterize specific factors the allow cancer cells to persist by blocking their natural maturation and preventing cell death (Aim 1). Of clinical importance, the experiments proposed will help identify new drug compounds that can potentially treat CRC by overcoming the block in maturation that is central to malignant behavior (Aim 2). These are perhaps the most exciting studies proposed, as they will nominate therapeutic agents to be tested in future clinical trials. Finally, the last portion of the grant is focused on using a mouse model to study a specific subtype of colorectal cancer (Aim 3). This understanding could prove valuable as this subtype is enriched among younger patients with CRC (early-onset: age < 50).

Beyond the civilian population, CRC is one of the most common cancers among active and affiliated military members. CRC is increasing in incidence among the younger community, which unfortunately will have the most impact on active duty Service members. In addition to senior NCOs, field grade officers will be affected by this growing epidemic of early-onset CRC. There is also evidence that screening for CRC is delayed among Veterans, which places greater emphasis on improving treatment strategies. The experiments proposed in this grant will directly benefit military personnel by improving mission readiness among active duty Service members. We are confident that the knowledge gained from these studies will inform new and exciting treatment strategies with potentially immediate transational impact in CRC patients with military backgrounds.