California Archives - V Foundation

Tikvah Hayes, PhD

Lung cancer is the leading cause of cancer-related deaths worldwide. The most common type is called non-small cell lung cancer (NSCLC), which consists mostly of adenocarcinomas and squamous cell carcinomas. In about 15–20% of adenocarcinoma cases, the cancer is caused by changes in a gene called EGFR. This gene normally makes a protein that helps cells grow and divide in a healthy way. But when EGFR is changed, or mutated, it can send the wrong signals, causing cells to grow out of control and form cancers. There are already drugs that target some EGFR mutations. These medicines, called EGFR tyrosine kinase inhibitors, can be very effective for certain patients. However, they only work for specific mutations in one part of the EGFR protein. Other mutations, found in a different part of the protein called the extracellular domain (the section that sits outside the cell), don’t respond to any of the current treatments. These mutations are less common, but they still affect many people with lung cancer. Unfortunately, scientists know far less about them. Our project aims to change that. Using human lung cells and advanced 3D models called organoids, we are studying how these rare EGFR mutations cause cancer, how they interact with other cancer genes, and why today’s drugs don’t work. We are also using new genetic tools to search for weak spots in these cancer cells that could become targets for future medicines. By uncovering how these overlooked mutations drive cancer, we hope to open the door to better treatments for patients with lung cancer.

Hanna Mikkola, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Children with Down syndrome have a higher chance of getting blood cancer called leukemia. Many babies are born with a condition called transient abnormal myelopoiesis (TAM). TAM starts before birth and causes too many immature blood cells to grow. In most babies, TAM goes away on its own. But in some, it can be very serious or later turn into leukemia. Right now, doctors do not know why this happens or how to tell which babies are at risk.In this study, we will use new tools to look at single blood cells to learn more about how TAM starts, how it changes into leukemia, and why treatments sometimes stop working. We will study blood and bone marrow samples from children at different stages of the disease, as well as from pregnancies with Down syndrome, to find out when and where the first changes begin.Our goal is to find better ways to predict which babies with Down syndrome will get leukemia and to develop safer, more effective treatments. This work could improve survival and quality of life for children with Down syndrome and their families.

S. John Liu, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Diffuse midline glioma is a deadly brain tumor that affects children. Radiation is the main treatment, since surgery and chemotherapy do not work well. New drugs are being tested, but they are not proven yet. To find better options, we built a new method that combines gene disruption with detailed study of brain tumors. This lets us test the role of many genes in new ways. We found genes that may help tumors respond better to treatment. Now, we will study how these genes work. Our goal is to discover new treatment combinations that can help children with glioma live longer and healthier lives.

Christina Curtis, PhD

Why do some people get certain types of cancer, while others don’t? For some cancers, we know that inherited genes play a role. But for many, it’s still a mystery. One reason is that cancer is very complex and we don’t fully understand how a person’s genetic makeup and immune system affects their risk.In our recent research, we found something surprising. We discovered that both a person’s genes and their immune system work together to influence which type of cancer they might develop. This includes hard-to-treat types like HER2+ and ER+ breast cancer, which can come back many years after treatment.Some early changes in a tumor’s DNA can act like a warning signal, helping the immune system find and destroy these abnormal cells before they grow. But if the tumor hides from the immune system, it can become more dangerous. That’s why it’s so important to find and treat these cancers early.Our work helps to explain the role of genetic variation in cancer, even when no single gene seems to be responsible. It also points to new ways to determine who is at risk and to create treatments that are personalized—based on each person’s genes and immune system. We’re working to turn these discoveries into better tools to predict, prevent, and treat cancer more effectively.

Diana Hargreaves, PhD

Pancreatic cancer (PC) is a leading cause of cancer death in America. PC has few treatment options. Immunotherapy is a treatment that has promise. Immunotherapy can cure cancer, but it has never worked for PC. We found that some PCs respond well to immunotherapy. These patients have a mutation in a SWI/SNF gene. We began a trial to test how SWI/SNF mutant PCs respond to immunotherapy. We will collect blood to see what changes with treatment. We will make mice with SWI/SNF mutant cancer and test if these mice respond to immunotherapy. We will also test if blocking SWI/SNF with a drug can make tumors respond to immunotherapy. We hope to identify PC patients that can benefit from immunotherapy. We will also identify new treatments for PC that may help other patients.

Roger Lo, MD, PhD

Nick Valvano Translational Research Grant*

After successful treatments, cancer patients often dread their disease returning months or years down the road. Even a few cancer cells hidden in the body can find ways to grow again. We will find ways to block these cancer cells from mutating so that they cannot find ways to grow again. These studies seek to provide new ways to extend survival and improve quality of life.

Jennifer Rosenbluth, MD, PhD

Funded with support from Hockey Fights Cancer powered by the V Foundation presented by AstraZeneca

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.

Aram Modrek, MD, PhD

Funded with support from StacheStrong

Radio- and chemotherapy work by damaging the DNA of cancer cells, but malignant cancers, like glioblastoma, often regrow more resistant to therapy. Surprisingly, treated tumors don’t always have new mutations in their DNA, prompting the question: How did treatment change the tumor?

We believe that non-genetic chemical “scars” on DNA from therapy make cancer cells more aggressive. This theory is hard to study because radio- and chemotherapy cause random DNA damage. To overcome this, we developed an experimental system that creates DNA damage at precise locations, providing a clear map of the damage.

Our research shows that DNA damage leaves non-genetic changes in cancer cells’ blueprints, such as DNA methylation and changes in gene expression. We believe these non-genetic changes help cancer cells behave more aggressively and resist treatment. By understanding how these alterations occur, we aim to develop therapies that prevent cancer cells from adapting to treatment.

Heather Christofk, PhD

Funded by Constellation Brands Gold Network Distributors

One of the most common kidney cancer syndromes is called HLRCC. Individuals with HLRCC are at risk for developing highly lethal kidney cancer, painful skin tumors, and fibroids. Better cancer prevention and treatment strategies are needed for HLRCC patients. HLRCC is caused by a mutation in a gene involved in metabolism. We found that the tumors that form in HLRCC patients have a unique metabolism that is reliant on the purine salvage pathway. Medicines have already been developed to block the purine salvage pathway, and one such medication, called 6MP, is currently used to treat patients with other types of cancer or autoimmune diseases. We found that HLRCC tumors are highly sensitive to 6MP treatment, and now propose to conduct a Phase 1 clinical trial to test safety and dosing of 6MP in HLRCC patients. We also propose to examine ways to prevent kidney cancer formation in HLRCC patients. This proposed research could have a huge impact on the lives of HLRCC patients through enabling clinical translation of a promising approach to treat their cancer and reveal effective cancer prevention strategies in this vulnerable patient population.

Corina Antal, PhD

Pancreatic cancer is one of the deadliest cancers because it is very difficult to treat. There are only a few treatment options available, and they do not work very well for most patients. We propose to find new therapies by studying how certain molecules, called RNA-binding proteins (RBPs), contribute to pancreatic cancer growth. RBPs are important because they control how genes are translated into proteins and ensure that the right genes are expressed at the right time and in the right amounts. When they are not working properly, RBPs can contribute to cancer development. For example, how much of an RBP is made can be affected by certain changes in the cancer cells, like how genes are turned on and off. Additionally, how an RBP works can be affected by cancer-specific modifications to its protein structure. Our research will focus on understanding what goes wrong with RBPs in cancer and how we can fix it. We will determine which RBPs and which cancer-specific modifications of RBPs are important for tumor growth and drug resistance. This will help us find answers that could lead to new therapies for pancreatic cancer patients.