Type: V Scholar

Cancer researchers have found that the immune system plays an important role in cancer. Our immune system I programmed to kill cancer cells. But, cancer cells eventually develop ways to escape the immune system and grow and spread. While it is unclear how this happens, many scientists are now developing therapies to reactivate the immune system to attack cancer cells. This field is called immunotherapy. While promising, we are still in early days, and there is much about the cancer immunology we don’t understand. Through our studies, we have identified a protein called APOBEC3A that might prevent the immune system from destroying cancer cells. APOBEC3A is an interesting protein since it is found in high amounts in many types of cancers, including lung, breast, colon and pancreatic cancer. Here, we will try to understand how APOBEC3A exactly affects the immune system in cancer. Secondly, we have found that human and mouse tumors that have high levels of APOBEC3A also tend to have high levels of molecules that specifically stop immune cells from attacking cancer cells called checkpoints. In a novel preclinical trial, we will see if a combination of drugs that target these molecules can effectively treat cancers that express high levels of APOBEC3A. If this trial works in mice, then this approach may be lead to a new treatment strategy in a subgroup of patients with many types of cancer, including pancreatic cancer.

Funded by the Dick Vitale Gala and Northwestern Mutual in memory of John Saunders

Over one-quarter of children with acute myeloid leukemia (AML) have a form called core binding factor (CBF) AML. Despite intense therapy, ~30% of these patients will relapse. Thus, identifying new therapeutic targets is necessary to develop more effective, less toxic treatment regimens.
The CBF complex coordinates the expression of genes required for normal development of blood cells. CBF AMLs harbor one of two genetic changes (t(8;21) or inv(16)) that interferes with the function of the CBF complex. While often grouped together, t(8;21) and inv(16) affect different members of the CBF complex and have unique disease features, suggesting important, yet unknown, biological differences exist. Interestingly, t(8;21) AML and inv(16) AML have different combinations of other cancer-causing mutations, providing potential clues to the genesis of t(8;21) and inv(16) AML. In particular, mutations affecting another complex that regulates gene expression, called the cohesin complex, are common in t(8;21) AML, yet never occur in inv(16) AML. The frequency of cohesin mutations with t(8;21) suggests that cohesin dysfunction cooperates with t(8;21) to cause leukemia by collaboratively activating cancer-causing genes, which could represent targets for therapy. Conversely, the absence of cohesin mutations with inv(16) indicate a dependence upon intact cohesin function, and perhaps the cohesin complex itself could be targeted in inv(16) AML.
We will explore the interactions between the cohesin and the CBF complexes in AML using murine and human systems. Our study will provide novel insight into the mechanisms driving CBF AML, likely uncovering herapeutic targets for the treatment of children with this disease.

Tumors that spread to the brain, called brain metastases, are the cause of death of half of patients with metastatic melanoma. The metabolic environment of the brain is uniquely low in two amino acids, serine and glycine, which carry messages between nerve cells. This ensures accurate nerve cell communication, but should prevent or slow the growth of tumors, as tumor cells need large amounts of serine and glycine to make DNA and proteins to divide and grow. Yet, tumors can spread to the brain, and are incurable once they have done so. 
 
We hypothesize that tumors metabolically adapt to the brain’s metabolic environment by increasing their ability to make serine and its product glycine, and that blocking the production of serine should either attenuate the development of brain metastases or help treat existing brain metastases. We will determine if serine synthesis is increased in brain metastases, and if tumor cells adapt to, or are selected for, the environment of the brain by increasing their production of serine and glycine. In addition, we have developed small molecules that inhibit serine synthesis, and will test these compounds in mouse models of melanoma brain metastases with the goal of reducing their initiation or growth. These studies will demonstrate that targeting the serine synthesis pathway might be useful in treating melanoma brain metastases and offer proof of concept that small molecule inhibitors of serine synthesis might be effective in treating patients with melanoma brain metastases and brain metastases from other tumors