Missouri Archives - V Foundation

Jeffrey Magee, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

My lab is working on new treatments for children with hard-to-cure cancers. We focus on a type of cancer called acute myeloid leukemia, or “AML” for short. AML accounts for about one-third of childhood leukemias. We have been less successful at treating AML than other childhood cancers. AML is challenging to treat because each patient may have different genetic mutations (alterations) causing their disease. A new drug that works for one patient might not work for another. Also, drugs that work in adult AML patients might not work well for childhood AML. To get around these problems, we create models that accurately reflect human childhood AML. We have created many different models to include the different types of mutations that patients can have. While studying these models, we discovered a protein called SPNS2 that might be a new drug target for tough AML cases. Early tests with an SPNS2 drug show promise in killing AML cells. This project aims to find out which patients will benefit most from SPNS2 drugs and see if combining these drugs with other AML drugs could improve treatment even further. We also aim to understand why SPNS2 is important in these cancers. My goals are to improve treatments and to broaden our understanding of AML in children.

Todd Fehniger, MD, PhD

Cancer immunotherapy is a medicine that helps the body’s immune system fight cancer. One type, called “CAR T cells,” changes immune cells so they can see and attack cancer better. This has been a big help for people with serious lymphoma, but it can cause strong side effects like bad flu symptoms, brain problems, and low blood counts.This project is trying a new kind of immunotherapy that uses different immune cells called “natural killer cells.” We found a way to make these cells remember how to fight cancer better. These “memory natural killer cells” have helped leukemia patients without causing strong side effects. But there are still problems, like having a hard time seeing all types of cancer (including lymphoma) and being stopped by a “brake” on their surface. Natural killer cells also need a special growth signal called interleukin 15 to stay alive and fight cancer well.This project will fix these problems by adding tiny “mini” proteins to the memory natural killer cells. These changes will help them attack tough lymphoma, remove the “brake,” and make their own growth signal. We hope this will create a new treatment for difficult lymphoma and help us find more ways to make natural killer cells better in the future.

Ramzi Abboud, MD

Funded by Kelly Chase and the St. Louis Blues Alumni Puck Cancer charity hockey game in support of Hockey Fights Cancer powered by the V Foundation

This proposal presents a plan to collect and manage blood samples from patients getting stem cell transplants. In this treatment, unhealthy blood-forming cells (stem cells) are replaced with healthy ones. With help from the V Foundation, this research will set up and manage a new system for storing these transplant samples at Washington University in St. Louis. The study will look at detailed biological data from 40 patients who receive these transplants. These patients will have different types of donors: siblings who match, unrelated donors who are matched and unmatched, and partially matched family members. The goal of the transplant sample storage program is to help researchers at Washington University find ways to make stem cell transplants safer and more effective for treating blood cancers.

This research will also help understand how new drugs that suppress the immune system work. With the support of the V Foundation, this project supports their mission to defeat cancer.

Nathan Singh, MD

Funded by the St. Louis Blues in support of Hockey Fights Cancer powered by the V Foundation

Therapies that modulate the immune response avoid the harmful side effects of standard cancer therapies and also have the potential to be more effective and longer-lasting. The most successful immune therapies to date rely on engineering a specific type of immune cells, T cells, to target and kill cancer cells. These therapies can be curative for some, but unfortunately still do not achieve their potential of cure for most. Our lab has identified a specific molecular pathway responsible for controlling the function of these immune cells. The goals of this project are to first understand how the driver of this pathway, a protein called BACH2, regulates engineered T cell function. Second, we aim to use advanced protein engineering tools to control the activity of BACH2, allowing us to thereby control engineered T cell function at will. If successful, these studies will shed light on a previously under-appreciated pathway that lies at the center of T cell function. Further, they will layout a pathway for “remote control” of BACH2 and nearly any T cell molecular program, allowing precision control of this potent anti-cancer therapy.

Sana Karam, MD, PhD

Bob Bast Translational Research Grant*

Pancreatic cancer is deadly. The only treatment that can cure it is surgery to fully remove the tumor, but that is only an option when the cancer is caught early, which is rare. Radiation to shrink the tumor before surgery has been tried, but with little benefit. By studying both patient and mouse models, we discovered that while radiation can kill cancer cells and stimulate some good immune cells, it also can make the environment harsh, help cancer cells escape, and bring in some bad immune cells. It can also scar the tumor, making surgery harder. In lab studies, we found a molecule called STAT3 that enables radiation’s negative effects. When we blocked STAT3 in mice, we harvested the radiation’s good effects while blocking its bad ones. In this proposal, we are testing a pill for patients to take with radiation that blocks STAT3. This is the first time it is combined with radiation to treat pancreatic cancer in humans. In liver cancer, this drug was so effective that the FDA has prioritized it for trials. In our proposed trial, we will collect blood and tissue from pancreatic cancer patients before and after the pill and radiation and study how this combination affects the tumor and the patients’ immune system. We hope to develop a test that predicts patient response to the STAT3 blocker with radiation combo and to identify other ways the cancer cells escape.

Kelly Bolton, MD, PhD

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.

Priyanka Verma, Ph.D.

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.

Haeseong Park, MD

Funded by the Stuart Scott Memorial Cancer Research Fund

Using immunotherapy to treat advanced cancer has improved the outlook of cancer treatment in many cancer types. However, most of the gastrointestinal cancers, including pancreatic adenocarcinoma, do not benefit from such advances in immunotherapy. Upon further research, we have learned that dense non-cancer cells that surround these cancers not only prevent the chemotherapy drugs from reaching the cancer cells, but also prevent the tumor-targeting immune cells that allow immunotherapy to be effective. Research from Washington University show that a molecule called IRAK4 can control such a process and make pancreatic cancer respond better to chemotherapy while allowing immunotherapy to be effective. Based on the promising data from the laboratory, we propose a clinic trial of CA-4948, a drug that inhibits IRAK4 and has shown to be safe by itself, to be added to standard chemotherapy drugs to ensure safety. Then an immunotherapy drug will be added to the combination. We plan to collect blood and tumor samples from the patients receiving the combination of CA-4948, chemotherapy, and immunotherapy, to understand how these drugs change the tumor and components of the immune system in patients. In addition, we plan to further test this combination in animal models to test additional mechanisms that can improve immunotherapy in pancreatic cancer.

Aadel Chaudhuri, MD, PhD

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.

Sidharth Puram, M.D., Ph.D.

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.