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
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.
Breast cancer is the most common cancer diagnosed among US women. The discovery and treatment of breast cancers has improved, but survival differences continue. African-American women have greater deaths across all types of breast cancer. While many social, economic, lifestyle, and biologic factors contribute to survival differences, we believe that fat and its impact on the cancer environment is an important factor. More African-American women are obese than Whites, and obesity has been linked to increased odds of breast cancer occurring again, spreading to other locations, and death. In older women (>50 years), most of the hormones that drive breast cancer are from total body fat. But, certain changes specific to breast fat may influence breast cancer. Early data show that one of these changes may be the development of crown-like structures (CLS). CLS of the breast (CLS-B) has been linked to greater inflammation, hormones, and poor survival among White women. We believe that CLS-B are more common in African-American than White women across body size, and that they are related to worse survival leading to the observed differences by race. This award would support the first study of obesity, CLS-B presence, and related outcomes in group of African-American and similar White women being treated for breast cancer (400 women total). Our study will advance the understanding of obesity and the breast cancer environment, as well as explain the value of CLS-B as a predictor of treatment response, breast cancer outcomes, and possible driver of differences among African-American women.
Each year, around 10,000 patients with Acute Myeloid Leukemia (AML) in the US will die from the disease. About a quarter of AML patients have a particular change in the FLT3 gene. This change leads to a lower chance of surviving the disease. This genetic change causes a FLT3 protein to be defective. Drugs such as tyrosine kinase inhibitors (TKIs) are used to treat the effects of abnormal FLT3 protein (FLT3-ITD). However, they are not very effective.
A particular type of cancer cells called leukemia stem cells (LSCs) is not removed by drugs like TKIs. Researchers think LSCs are responsible for the disease coming back in people with AML. Thus, LSCs with FLT3-ITD are considered responsible for resistance to TKI treatment. Understanding why LSCs are resistant to TKIs will allow us to target these stem cells, and possibly cure people.
FLT3-ITD signals can be changed by modifying the protein in different ways such as methylation. Our studies found a link between methylation of FLT3-ITD and LSC resistance to TKI treatment. Thus, we think that FLT3-ITD methylation helps these stem cells resist drug treatment. We want to understand better how methylation helps LSCs survive. Also, we will test whether a lower amount of methylated FLT3-ITD protein leads to fewer cancer stem cells in test animals. Targeting protein methylation could lead to new ways to treat people with FLT3-ITD leukemia.
The overall purpose of our research project is to identify if there are patterns of genetic changes (i.e. mutations) that explain why some children with acute myeloid leukemia (AML) fail to effectively respond to chemotherapy and ultimately relapse. Relapsed disease is strongly associated with poor outcome and early death in children with AML. Frequently, when AMLs relapse they do so through the outgrowth of a cell population (subclone) that was present at a low level at the time of diagnosis. These subclones frequently have mutations that allow them grow better after therapy. Unfortunately, we have a poor understanding of these subclones in pediatric AML and methods to detect them and study them are lacking. The proposed studies in this grant will identify these mutations in a large group of relapsed pediatric AML and then address if sensitive approaches to detect mutations in patients after therapy will increase our ability to predict relapse. Currently our methods to predict relapse are not applicable to all cases and likely do not effectively capture all leukemic subclones for analysis. In the second part of this grant we propose a model system to introduce mutations that will allow us to more effectively study the subclonal complexity of AML to understand why some subclones are more resistant to chemotherapy. Collectively these studies will dramatically increase our understanding of pediatric AML with the long-term goal of pushing the outcomes of pediatric AML closer to pediatric ALL.
Pancreatic cancer is one of the most lethal cancers and has a five-year survival rate of ~9%. This outcome is largely due to limitations in current diagnostic strategies as well a lack of effective therapies. Thus, there is a dire need to better understand this disease. Recent studies in cancer research have indicated a causal relationship between the capacity of cancer cells to cope with stress and cancer progression and therapy resistance. Pancreatic tumors are driven by a gene called KRAS that is mutated in 95% of all human pancreatic cancers. We have recently found that one critical process driven by mutant KRAS is the formation of stress granules. Stress granules serve as a protective mechanism from chemotherapeutic agents, which kill cancer cells by inducing stress. In this proposal, my laboratory will determine the role of stress granules in the drug resistance of KRAS-driven pancreatic cancer, and develop strategies to block stress granules as a therapeutic tool. This approach has not been explored and could provide impactful insight for the treatment of this disease.
Funded by the Stuart Scott Memorial Cancer Research Fund
Acute Myeloid Leukemia (AML) is a blood cancer that affects individuals of all ages. AML is the most common form of acute leukemia in adults. The incidence of the disease increases with age, with the majority of patients being diagnosed over the age of sixty. With aging, the disease does not respond as readily to treatments. Despite advances in the field, clinical outcomes for AML patients over the age of sixty remain poor. To improve upon current treatment options for AML patients over the age of sixty, it is essential to better understand the mechanisms that drive the disease in these patients and determine which patients benefit from current treatments. The project proposed will identify molecular features that characterize patients over the age of sixty and determine how to predict which patients benefit from current treatments and what potential mechanisms drive the disease in individuals over the age of sixty.
Tumor cells carrying driver oncogenes such as mutated BRAF, EGFR and EML4-ALK appear to sustain an oncogene addiction state, in which growth and survival are highly dependent on the continued activity of the oncogenic pathway. The discovery of such dependencies has informed drug development strategies for a variety of cancers. However, patient responses to therapeutic inhibitors of oncogene action are often incomplete and limited by drug resistance. Although genetic factors in resistance are part of the story, emerging evidence suggests that tissue-specific epigenetic mechanisms and reprograming following oncogene inhibition can induce adapted states where there is reduced dependence on the oncogenic activity. These epigenetic states generate heterogeneous sub-populations of drug-tolerant cells that not only limit drug effectiveness, but also constitute a reservoir from which genetically resistant clones are ultimately selected and contribute to disease progression. This represents a major challenge facing development and use of targeted therapies for a variety of cancers. Our research aims at addressing this problem for BRAF-mutant tumors. We are proposing an integrated strategy to dissect the poorly understood epigenetic states at the single-cell level, identify their key regulators, and predict and test efficient ways to block the heterogeneous populations of drug-resistant cells and maximize tumor cell killing. Our findings will help us utilize targeted therapeutics more generally, more precisely, and more effectively to cure cancer.
