Over the last 10 years, great progress has been made in identifying the genetic alterations present in the blood systems of patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). One of the most important and unexpected findings from these studies has been the identification of mutations in genes which perform RNA splicing. Mutations in these genes are the single most frequent category of mutations seen in MDS patients but are currently not well understood. Under normal conditions, RNA splicing is responsible for ‘processing’ RNA so that the genetic code can be effectively translated to produce normal proteins. It has been postulated that mutations in this pathway impair RNA splicing. However, how precisely these mutations dysregulate splicing and how this actually results in the development of leukemia is unknown. More importantly, how this genetic knowledge can be translated to yield novel drug targets in leukemia has yet to be investigated. The protein SRSF2 is particularly important, since it is associated with the most clinically dangerous forms of MDS and AML. We have recently generated a number of mouse and human cell leukemia models with and without mutations in SRSF2. We now propose to utilize these models to understand how mutations in SRSF2 cause leukemia and how we can treat the leukemia caused by these mutations.
V Scholar Plus Award- extended funding for exceptional V Scholars
Cancers are diseases caused by faulty genes. Finding these faulty genes will provide effective targets for treatment. To this end, researchers have discovered many gene mutations in all kinds of cancers. However, cancer cells can acquire random mutations, as they are highly unstable. Thus, it is critical to find out which mutations play a causal role in cancer.
To address this problem, we have developed a novel method for studying cancer mutations. We used stem cells to create breast cancer models carrying patient relevant mutations. Using these models, we will study which mutations are responsible for the resistance to cancer treatment. We focus on the treatment that block an important cancer gene, PI3 Kinase. Faulty activation of this gene has been found in many breast cancers. Thus, it is an important cancer target. We have found a specific gene mutation that causes the resistance to this treatment. In this project, we will understand how does this mutation cause the resistance. Based on our mechanistic finding, we will also develop new strategies to overcome the resistance. Thus, successful outcomes of our study will aid the development of effective cancer therapies.
Pancreatic cancer is one of the deadliest cancers, largely because most therapies are poorly active in patients or are too toxic when administered. Indeed, pancreatic cancer patients become ill very quickly, and cannot withstand the side effects of chemotherapy that patients with other types of cancer can tolerate. Therefore, we need to identify new therapies that kill pancreatic cancer cells effectively and are well tolerated by patients. To accomplish this goal, we have developed a new model system from pancreatic tumors, called organoids. Organoids are 3D cultures grown in an extracellular material rich matrix, called Matrigel, and can faithfully mimic the patient’s tumor, from which it was derived. Organoids can be used to sequence for mutations in the cancer cells and to test for therapies that could kill the cells. Using organoids, we have identified a number of compounds that can surprisingly kill the different cell types present in pancreatic tumors, including several drugs that are given to millions of people daily and are well tolerated but not previously considered to be cancer medicines. Importantly, we also find that certain combinations of these new drugs can shrink human pancreatic tumors engrafted in mice. Here, we propose to extend these exciting preliminary findings to a broader collection of drugs and a larger collection of organoids, and develop the most promising candidates as new strategies for an early phase clinical trial. Our goal is to test at least one novel combination of non-traditional drugs in pancreatic cancer patients within three years.
The initial treatment of men with prostate cancer is highly successful in stopping the primary cancer. However, years later men often develop cancer again and it is commonly deadly. One explanation for cancer returning is that the cancer was sleeping and in doing so, it was not affected by the first medicine. Our team discovered a new treatment to put cancer to sleep in the body. By using laboratory tests and information from patients, we discovered a “fingerprint” that can tell us if and how the cancer is sleeping or growing. However, for reasons that remain unclear, the sleeping cancer eventually awakens in a deadly form. We discovered that using known medicines we could keep the cancer asleep. We propose to use these medicines that are available for other diseases to induce an constant sleeping state in cancer, preventing its awakening. We will also find new indicators of the sleeping or growing state of cancer using a blood test. If successful, our new treatment to keep cancer sleeping may provide a new cure for men with prostate cancer.
Funded by Hooters of America, LLC., in memory of Kelly Jo Dowd
In humans, an early age of first pregnancy reduces the risk of breast cancer by an incredible 30%. The effects or pregnancy on reducing breast cancer risk is present in multiple mammalian species, and confers a long-lasting cancer protection. However, we know little about the modifications that confers breast cells with a cancer resistant state. The goal of our proposal is to understand pregnancy-induced breast cancer protection and to discovery how to manipulate its effects. Our ultimate goal is to devise preventive strategies to mimic the preventive effects of pregnancy and potentially reduces breast cancer occurrence.
