Funded with support from Hockey Fights Cancer in honor of Ben Stelter
Glioblastoma (GBM) is the deadliest adult brain cancer. Even with standard of care treatment, survival rates are low. A major challenge is that the brain’s protective barrier blocks most drugs. The tumor also weakens the immune system, making it harder for treatments to work. CAR-T cell therapy is a promising treatment that trains T cells, a special immune cell, to recognize and attack cancer cells. It works well in other cancers, but not GBM. Normally, T cells follow signals from proteins called chemokines and cytokines to locate and fight disease. However, GBM blocks these signals, stopping T cells from working properly. Our study will develop a new immune gene therapy using a harmless virus called AAV to help the immune system fight GBM. This therapy reprograms nearby brain cells (called astrocytes) to send signals that attract and activate immune cells, including CAR-T cells. Our gene therapy will deliver two key proteins: CXCL9 (which attracts T cells) and IL-2 (which helps them grow and stay active). This targeted approach ensures a steady immune response right at the tumor. We will combine this immune gene therapy with CAR-T cells to improve their ability to find, survive, and attack the tumor. Our research will study how AAV works in the brain, activates CAR-T cells, and which AAVs can be used in human clinical trials.
Cancer immunotherapy with checkpoint receptor inhibitors (ICIs) causes autoimmune side effects. These side effects occur in most patients treated with ICIs. These side effects are debilitating and difficult to treat. My goal is to find treatments for ICI side effects. I developed new mouse models where ICIs induce the same autoimmune side effects as in humans. I will use these models to understand why ICIs are toxic. I will also understand how to treat the side effects of ICIs.
Pancreatic cancer is one of the most difficult cancers to treat, with only about 1 in 10 patients living five years after diagnosis. New and more effective treatments are urgently needed. One promising option is CAR-T cell therapy, which uses a patient’s own immune cells to fight cancer. While this treatment works well in blood cancers, it has not been successful in solid tumors like pancreatic cancer. One major challenge is the environment around the tumor, which lacks nutrients and weakens the immune system. This makes it hard for immune cells to survive and do their job. Our research aims to solve this problem by using a single target to improve both the immune cells and the tumor environment. We have found that changing how immune cells use energy can help them stay stronger and last longer in the body. At the same time, targeting how cancer cells grow makes the tumor more vulnerable to attack. By combining these two strategies, we hope to improve how well CAR-T cells work against pancreatic cancer. With support from the V Foundation, we will test this approach in models of pancreatic cancer. If successful, this work could lead to better treatment options for people with pancreatic cancer and potentially other hard-to-treat cancers as well.
Lung cancer is the leading cause of cancer death worldwide and deeply affects many families. Twenty years ago, the discovery of mutations in the Epidermal Growth Factor Receptor (EGFR) gene and therapies that were effective for these tumors (targeted therapies) transformed the field and the lives of patients with this disease. This remarkable progress resulting from targeted therapies is countered by the fact that metastatic EGFR-driven lung cancer remains incurable due to the emergence of drug resistance. Therefore, there is an urgent need to improve treatment of EGFR-driven lung cancer so people live longer and ultimately cure the disease. Through our studies we have found new possible drug targets in this disease. In this proposal, we plan to understand whether these are new targets and how they work. We will also test drugs that have been developed against these targets in mouse and human models of EGFR-driven lung cancer. These studies will allow us to develop the foundation for designing a clinical trial for patients with EGFR-driven lung cancer with the goal of finding better ways of preventing and/or overcoming drug resistance and improving and extending the lives of people living with this disease.
We aim to stop suffering and deaths from ovarian cancer. Therefore, we will explore how to improve the immune system’s ability to fight cancer. Cancer forms when normal cells change and grow wildly. The immune system can destroy abnormal cells. But cancer cells often evade immune system attacks. Ovarian cancer is a challenge. Only 10% of patients improve or survive with current treatments that help the immune system fight cancer. We study immune cells (B cells) and “neighborhoods” (tertiary lymphoid structures, or TLS) where these cells live. TLS can organize immune cells to fight cancer, and we investigate factors in ovarian cancer that impact TLS. We will test how immune cells (B cells) and non-immune cells (stromal cells) affect TLS creation and function. Our studies will show new ways to fight ovarian cancer. We will develop and lead new clinical trials. We will be poised to test a treatment for patients within five years that could change lives.
The number of melanoma cases in the United States continues to rise. When melanoma spreads to other organs, it is very deadly. Patients with this disease are usually first treated with medicines that help the immune system fight the cancer. This treatment works well for some people, but many can’t take the drugs because they have too many side-effects or simply do not work. For others, the medicines shrink the melanomas at first, but then they grow back. When immune medicines stop working, people with some kinds of melanomas can take other medicines(targeted drugs). However, targeted drugs do not work for a type of melanoma called NRAS mutant, which is very deadly and hard to treat. We found that a medicine used to treat leukemia may help targeted drugs work better for patients with this type of melanoma. In this proposal, we will learn how and why the leukemia medicine helps the targeted drugs work. We also will test our FDA-approved leukemia drug together with two different targeted drugs in mice. If the drugs work together to shrink the melanomas, then, in the future, we will test the treatment in patients by starting a clinical trial. Through this work, our goal is to give these patients more time to spend with their families, and eventually find a cure for this terrible disease.
A recent study showed that short-term, low-dose therapy can provide lasting protection from cancer. Yet only two drugs are approved for breast cancer prevention in the US. One reason is the lack of clear signs that show a risk-reduction therapy is working. One possible sign is background enhancement on breast MRI. A higher level means a higher risk of getting breast cancer. When a patient lowers their risk by taking tamoxifen, the background also goes down. For others, it does not. This shows that the therapy is not working. We studied breast tissue to understand the reason for this background. We found that those with high levels had either high estrogen or signs of inflammation. In our new study, we will use tissue pieces from patients starting tamoxifen. Our goal is to find a molecular signal that shows the drug is working. For those who do not respond, we will test drugs that target inflammation. Finally, we will see if different background signals point to estrogen or inflammation. These signals could be assessed in a clinical trial at UCSF to support a personalized cancer prevention strategy.
This project is about making a type of cancer treatments called antibody-drug conjugates, or ADCs. ADCs are protein-based therapies designed like guided missles. They carry strong cancer-fighting drugs and deliver them directly to cancer cells using antibodies. But in many cases, the drug doesn’t get inside the cancer cell well enough, so the treatment doesn’t work as well as it could. We are trying to solve this problem by using a special feature on the surface of cancer cells called an internalizing receptor. This is a protein that acts like a fast-moving doorway—it pulls things inside the cell quickly. By connecting the drug to an antibody that targets this fast moving receptor, we hope to get more of the medicine inside the cancer cell, where it can do its job. We are focusing on two hard-to-treat cancers: triple-negative breast cancer and some types of lung cancer. We will test our new treatment in the lab and in models of these cancers. We will also study large research databases to learn which types of tumors might respond best. This research matters because many people with cancer still don’t have good treatment options. If this new approach works, it could lead to more effective and more targeted cancer treatments. It may help more patients benefit from ADCs, especially those with cancers that don’t respond well to current therapies.
Colorectal cancer (CRC) is frequently diagnosed when it has already spread to other parts of the body. When caught early, 65% of patients survive for five years, but if the cancer has spread, only 12% survive that long. This makes it critical to understand what causes CRC to spread and find better ways to treat it. Cancer spreads when certain genes become more or less active. Scientists have mostly studied how genes are turned on and off, but recent research shows that another process, called post-transcriptional regulation, is also important. This refers to all the steps that happen between when a gene is copied into RNA to when it is turned into a protein. These steps, such as modifying, transporting, or breaking down RNA, add another layer of control over how much of a protein a cell makes. RNA-binding proteins (RBPs) help manage this process. But when RBPs don’t work properly, cancer cells may grow and spread more easily. We will use a genetic screening method to find all RBPs that play a role in cancer spread. By studying these proteins, we hope to better understand how CRC spreads and discover new ways to stop it.
Myeloid cancers are a group of blood diseases that happen when blood-forming cells in the bone marrow become abnormal. These changes often come from genetic mutations. One important mutation occurs in a gene called ASXL1, which is linked to the development of blood cancers and associated with poor prognosis. However, it remains unclear how ASXL1 mutations could drive blood cancers in humans. We recently found that, in younger mice, ASXL1-mutant blood stem cells do not grow out of control. But in older mice, these mutated cells do grow and expand. These suggest that aged bone marrow environment (BMM) may help these abnormal cells grow and cause leukemia. We also found that in older mice, the bone marrow has more inflammation and a higher number of stromal cells (cells that support blood cell growth), which can be mitigated by anti-aging therapy. In this project, we will study how aged BMM helps these mutant cells grow and test if targeting the aged environment alters the development of blood cancers. By understanding this process, we hope to find new ways to treat or even prevent blood cancers in humans.
