State: Missouri

Myeloid neoplasms (MN), including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are fatal diseases because they are highly resistant to therapy. Ultimately, efforts at preventing MN might be the most successful way to eradicate this disease. Clonal hematopoiesis (CH) is thought to be the origin of MN. CH is a process whereby a hematopoietic stem or progenitor cell (HSPC) acquires a mutation (alteration in the nucleic acid sequence) that leads to a growth advantage compared to normal HSPCs. CH can be detected many years prior to a person developing MN but as of yet, there are no established therapies to prevent progression of CH to MN. We hypothesize that CDK4/6 inhibition might be a potential treatment to prevent MN through halting the progression of CH. Here we seek to: 1) further characterize the potential of CDK4/6 inhibitors to prevent CH expansion through analysis of pre-existing clinical trial data; and 2) using mouse modeling evaluate the potential of CDK4/6 inhibitors to inhibit CH independent of chemotherapy. If successful, this work will justify the development of clinical trials using CDK4/6 inhibitors to prevent CH from progressing to MN in high-risk populations. In the long term, we hope to use targeted approaches to eradicate high risk CH mutations to prevent the development of MN.

There are certain genes called “oncogenes” that when over expressed in cells can result in several deadly forms of cancers. Cancer patients with high oncogene levels show poor survival and have no defined cure. Therefore, there is an urgent clinical need for new therapies to treat these cancers. We are developing ways to selectively target oncogene-high cancer cells, while leaving normal cells unaffected.

DNA replication is important for cell survival. Our results suggest that oncogene-high cancers face many problems during DNA replication. These observations suggest that these cancers can be more dependent on pathways that allow them to fix the problems during DNA replication. Therefore, inhibiting these pathways will selectively kill oncogene-high cancer cells. In this grant, we will: (i) identify how oncogene-high cancers deal with problems in DNA replication and manage to survive; and (ii) identify why cancer cells with high oncogene levels do not respond to traditional cancer therapies. Our results can help find new ways to treat this high-risk group of patients who have little to no cure.

Cancer is a major cause of death worldwide. Immunotherapy is one of the most promising new ways to treat advanced stages of cancer. It works by “taking the breaks” off the immune system to let immune cells kill cancer cells better. Immunotherapy has revolutionized the treatment of cancers like melanoma, lung cancer and bladder cancer. Still, many patients do not respond to treatment. It is hard to know early who will respond and who won’t. We are developing and testing a method to predict response to immunotherapy early. We are doing this through a simple blood test that measures signal from immune cells deep inside a patient’s tumor. We are testing our method in melanoma patients. If successful, our method will revolutionize the ability to predict cancer response to immunotherapy. This will give doctors vital information early and improve patient survival. 

Head and neck tumors are composed of cells that are not all the same, but instead have different functions, much like bees in a hive. While some cells act like drone bees that are primarily responsible for expanding and growing the colony (or in this case, tumor), others are responsible for directing and orchestrating the tumor like a queen bee. Still other cells mimic worker bees who travel outside the hive and are responsible for the spreading the tumor to new locations. We are interested in these worker bees of head and neck cancers and understanding what triggers them to exit the hive. In particular, we are trying to identify the specific genes that serve as markers of the worker bees, in order to determine if they are present in tumors and whether they can help to predict when a cancer may spread. We are also trying to understand the specific genes that allow these worker bees to perform their function. Much like a specific wing shape or other adaptations worker bees have in nature, we are curious about whether these cells have specific cellular machinery they use to spread beyond the tumor. Together, these studies could help us develop new ways of identifying patients at risk for their cancer spreading as well as new treatments to prevent the spread of cancer all together.

A new approach to treating cancer is to use each patient’s natural immune system to attack their tumor. This approach takes advantage of the fact that cancer is caused by mutations that occur only in tumor cells. We now know that these mutations allow the immune system to see a tumor as a “foreign” invader, almost like a viral infection. This knowledge has led to the idea that we could design cancer vaccines. Each vaccine would be unique to each patient and train their immune system to attack their unique tumor. The vaccine treatment involves injecting small amounts of harmless pieces of tumor protein into the arm of each patient. Cancer vaccines are promising because they have few side effects compared to other cancer treatments. If cancer vaccines are to be a success, we need to become good at finding the tumor mutations that are best for training each patient’s immune system. So far, early attempts to find good mutations have focused on the simplest and smallest forms of mutations. In some patients, we do not find the right mutations to create a vaccine. In our study we will explore a type of larger and more complex mutation that causes incorrect assembly of proteins in tumor cells. These provide more options for vaccine design. Finding such mutations should lead to better cancer vaccines. Our study should also allow us to design vaccines for more patients and help us to understand what makes a good cancer vaccine.