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.
Cancer cells are always growing, and they need nutrients to keep up this fast growth. An exciting idea is that we might be able to starve cancer cells without harming healthy cells by getting rid of nutrients that cancer cells need. A drug being developed right now called ADI-PEG20 destroys a nutrient called arginine, which is an amino acid that is used to make protein and is particularly important for cancer cells. My lab studies what happens when cancer cells don’t have enough arginine. We want to understand how ADI-PEG20 works, how to improve it, and which cancers to treat with it. We have found that restricting arginine disrupts ribosomes, the machines that build new protein, causing them to get stuck and abandon their jobs early. We want to study three things to figure out how this impacts ADI-PEG20 treatment. First, why is protein production in cancer cells so sensitive to arginine levels? Next, what machinery in the cell is responsible for causing “starved” ribosomes to press the eject button in the middle of doing their jobs? Finally, what effect does this have on a cancer cell? This work will help us understand how a nutrient like arginine can directly control very important processes in the cell like protein production. It will also reveal how we can take advantage of cancer’s dependence on arginine to shrink tumors.
Multiple myeloma and AL amyloidosis are incurable cancers of blood cells. These blood cells are called plasma cells. There is only one therapy that is available for AL amyloidosis patients. In severe stages, AL amyloidosis patients survive less than one year. Amyloidosis plasma cells cause damage to the body by spilling in the blood a sticky protein. These sticky proteins attach to each other and build up in the heart. Buildup of proteins in the heart causes progressive poor function. AL amyloidosis is a major cause of malfunctioning of the heart and death. To cure AL amyloidosis, we need drugs that 1- stop plasma cells from spilling sticky proteins; 2- kill the cancer plasma cells; and 3-remove the buildup of sticky proteins from the heart. These drugs do not exist, because we do not know how sticky proteins get spilled and why the build-up is not removed.Recently, our lab found out how sticky proteins get out of amyloidosis plasma cells. We also showed that if we stop this process, cancer cells die. Finally, we discovered that cleaner cells that should remove sticky proteins from the heart are reduced and do not function in amyloidosis patients. Based on these data, we will make two novel drugs. One will stop spillage of sticky proteins and kill cancer cells. The other will remove sticky protein from the heart without the need of cleaner cells. Our work is doable and will create therapeutic options for AL amyloidosis patients that could cure their disease.
Every year, over 25,000 people need to have a stem cell transplant to treat their blood cancer. While this can cure their cancer, it also weakens the immune system. A weak immune system is a problem because it means people get more infections and can experience other complications like their cancer coming back. When we are healthy, our gut is filled with helpful bacteria. During cancer treatment, many patients lose these helpful bugs. Patients who lose the good bacteria after they have a transplant, don’t recover as well as patients who keep their helpful bugs. These good bacteria are needed for strong immune system recovery. We are working in the lab to find new ways to support healthy bugs during cancer treatment. We think this will help the patients’ immune system. Having a healthy immune system means fewer infections and a longer life. If successful, this research could lead to new treatments that help patients feel better during their transplant, avoid infections, and live longer. In the future, we will run clinical trials in transplant patients, which will lead to new standard treatments.
