Grant Archive - V Foundation

Britta Will, PhD

Acute myeloid leukemia (AML) is a deadly blood cancer that starts in the bone marrow, where our blood cells are made. This cancer is especially dangerous for people over 65 – more than 9 out of 10 patients die from it. The treatments we have now work for a while, but then they stop working. This happens because some cancer cells are tough and can survive the treatment, causing the cancer to come back. Scientists have discovered something important about how these cancer cells survive. They found that the way cancer cells use iron helps them fight off treatment. Iron is a mineral our bodies need, but cancer cells change how they handle iron to stay alive when doctors try to kill them. We believe that iron helps cancer cells resist drugs that are supposed to make them grow into normal, healthy blood cells. We made an exciting discovery: when they used drugs that grab onto iron, the cancer cells became much easier to kill with regular treatments. This seems to work on many different types of this blood cancer, even the hardest ones to treat. We plan to test this new approach by mixing iron-grabbing drugs with current treatments. We will use real cancer cells from patients to see if this combination works better. We want to find out if it can really get rid of the cancer stem cells (the “parent” cells that keep making more cancer). If this research works, doctors could have a new way to treat older patients with this blood cancer. Many older patients can’t get bone marrow transplants because they’re too risky. By targeting how cancer cells use iron, doctors might be able to beat treatment resistance and help patients live longer without using harsh chemotherapy drugs.

Chonghui Cheng, MD, PhD

Cancer vaccines are a promising new treatment that help the immune system find and destroy cancer cells. These vaccine work by teaching the body to recognize special signals, called neoantigens, that appear only on cancer cells. Most cancer vaccines today use neoantigens caused by changes in DNA. But because these changes are different for each person, it is hard to make a vaccine that works for everyone. Our research aims to develop a more widely useful cancer vaccine for triple-negative breast cancer (TNBC), a fast-growing and hard-to-treat cancer. We are studying a new type of neoantigens, that comes from a mistake in how cells process RNA. Normally, cells remove parts of RNA called introns before making proteins. But in some cancer cells, this process fails when a protein called hnRNPM is missing. As a result, the introns stay in, leading to unusual protein pieces that the immune system can recognize and attack. Our team includes experts in RNA, data science, and vaccine development. We are working together to find common neoantigens in TNBC that come from faulty introns and to make a strong mRNA cancer vaccine. We will look for the most common neoantigens made this way in TNBC and build better tools to find neoantigens that current methods miss. We will create mRNA vaccines that teach the immune system to attack these cancer signals. If this works, the vaccine could help treat TNBC and possibly other cancers that make the same neoantigens.

Djordje Atanackovic, MD

T cell acute lymphoblastic leukemia (T-ALL) is a serious cancer that affects part of the immune system called T cells. It’s especially hard to treat in adults, and current treatments often don’t work well. A special treatment called CAR T cell therapy—where doctors change a patient’s own immune cells to fight cancer—has worked well for some other types of cancer. But using it for T-ALL has been very difficult. One problem is that the CAR T cells can accidentally attack healthy T cells, and sometimes even attack each other.We recently identified a new target called CD229, a marker found on both cancerous and some healthy T cells. We made CAR T cells that attack cells with CD229. The exciting part is that these new CAR T cells can still kill cancer cells but don’t harm as many healthy T cells. This is because healthy T cells lower the amount of CD229 when they are activated, so they are not attacked.We improved our CAR T cells even more by making them less “sticky,” so they are more careful about which cells they attack. Tests in the lab and in animals showed that these new CAR T cells still fight cancer well and are safer. Now, our team is testing this treatment on real samples from many T-ALL patients. If it works, we will start a small clinical trial. This new treatment could be a big step forward, giving hope to people with T cell cancers by offering a better and safer option.

Jessica Thaxton, PhD, MsCR

T cells are part of the body’s immune system. T cells ward off disease but are also capable of fighting cancers. In fact, immune therapies in cancers have produced major gains in allowing patients with cancer to survive long-term. T cells can invade cancers, but cancers create a hostile environment that limits T cell killing capacity. This makes immune therapies function poorly. We have discovered a pathway in T cells that is engaged by the hostile environment of tumors that induces T cell distress and death. We have found a group of drugs that inhibit this pathway. These drugs also protect T cells from sensing the stressful environment of cancer. This group of drugs allows T cells to live longer and fight harder to eliminate cancer. We have found that these drugs improve the long-term outcomes of immune therapies and hold potential to increase the number of patients cured of cancer when treated with immune therapy. This project plans to study this stress pathway in T cells in samples from patients with cancer and to test these drugs in several models so that they can be used in the clinic to fight cancer in patients.

Andrew Brenner, MD PhD

Some cancers can spread to the fluid that surrounds the brain and spine. This is called leptomeningeal metastases, or LM. It is a serious and often deadly problem. Today, there are very few treatments that work well for this condition.Our team is studying a new treatment called Rhenium Obisbemeda (186RNL). This treatment sends tiny amounts of radiation straight into the spinal fluid, where it can kill cancer cells. Unlike standard radiation, which can hurt healthy parts of the brain, this method targets cancer cells more carefully and reduces damage to normal tissue.In our research, we are collecting samples from patients to see how their cancer and immune cells respond to this treatment over time. We are also using lab models to test whether this radiation works better when combined with other treatments—like drugs that help the body’s immune system fight cancer or block cancer cells from fixing themselves.Our goal is to find safer and more effective ways to treat LM and possibly other hard-to-treat cancers. This research could lead to better options for people with advanced cancer, giving them more time and better quality of life.

William Freed-Pastor, MD, PhD

Pancreatic cancer is a terrible disease, and we urgently need better treatments. The immune system can search the entire body to find and destroy cancer cells, just like it protects us from viruses or bacteria. The immune system does this by recognizing small “flags” on the surface of cancer cells. Unfortunately, cancer cells can often “hide” from the immune system so they don’t get destroyed. We urgently need to find new ways to use the immune system to fight pancreatic cancer to develop better treatments for patients. We’ve been using something called “organoids” to study pancreatic cancer. These are tiny, 3D versions of tumors grown in a dish from a patient’s own cancer cells. Using these organoids, we’ve been able to identify the “flags” on the surface of pancreatic cancer cells that the immune system might be able to recognize. We’ve also created a special system to help us figure out which of these “flags” are the best ones for the immune system to fight and ultimately destroy the tumor. Our plan is to use what we’ve learned to carefully test many new targets on the surface of pancreatic cancers to see if the immune system can recognize them. This will help us develop improved therapies for pancreatic cancer patients.

Chrystal Paulos, PhD

Melanoma is a serious and often deadly type of skin cancer. Although immunotherapy has saved many lives, it still doesn’t work for every patient. Our lab is developing ways to give the immune system another chance to succeed.We are creating a new kind of cell therapy using “helper” T cells, known as Th17 cells. These cells do more than attack cancer directly—they help guide and activate other immune cells, turning the fight into a team effort.We discovered that a molecule called ICOS helps these helper T cells survive longer and build immune memory. This memory may help stop cancer from coming back in the future.Our goal is to turn this finding into a new treatment for people with melanoma who did not respond to standard therapies. By helping the immune system work better, we hope to offer patients more than extra time. We want to offer lasting hope.This research moves us closer to making melanoma a disease we can truly overcome.

Yuxuan Miao, PhD

More people are getting head and neck cancer caused by the human papillomavirus (HPV). Traditional treatments like surgery or radiation can cause strong side effects. Sometimes, the cancer comes back. Because of this, doctors are looking for safer and better ways to treat these cancers. Immunotherapy is a newer treatment. It helps the body’s immune system find and destroy cancer cells. Some people with head and neck cancer do well with a type of immunotherapy called “immune checkpoint inhibitors.” But, patients whose cancer is caused by HPV usually do not benefit as much. A new immunotherapy called HB-200 is being tested. It is designed to help the immune system better find and attack cancer linked to HPV. Early studies show that HB-200 may work for patients with HPV-positive cancer, even if other treatments have not helped. Our research looks at tumor samples from people with and without HPV. All of these patients received different types of immunotherapy. We are using simple lab tests and special tools to learn why HPV-related cancers do not respond well to older treatments, but do respond to HB-200. Our goal is to make HB-200 better and find new ways to treat these cancers. We hope this will lead to better care and longer, healthier lives for patients.

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.

Agnel Sfeir, PhD

Cells use DNA repair systems to fix damage and keep their DNA stable. When these systems fail, it can lead to cancer and make treatment harder. One toxic type of damage is a double-strand break (DSB), where both strands of DNA are cut. In healthy cells, DSBs are usually fixed by a process called homologous recombination (HR). This method is very accurate. Some tumors, especially those with BRCA1 or BRCA2 mutations, lose the ability to use HR. These tumors rely on backup repair methods that are less accurate. One of these is called microhomology-mediated end joining (MMEJ). MMEJ fixes breaks by using short, matching DNA sequences, but it often adds or deletes small sections of DNA.MMEJ depends on an enzyme called polymerase theta (Polθ), which is found at high levels in many cancers. Research shows that BRCA-deficient tumors need Polθ to survive. Because of this, Polθ is now being tested as a drug target, alone and with PARP inhibitors. This project studies how MMEJ helps cancer cells resist treatment. We focus on two key ways. First, MMEJ can create changes that fix BRCA1 or BRCA2, which restores HR and reduces the effects of PARP inhibitors. Second, MMEJ may support the growth of extra circular DNA (ecDNA) that carries cancer genes. This makes tumors grow faster and resist therapy. By understanding how Polθ drives these changes, we hope to find new ways to treat cancer and make current therapies last longer.