Grant Archive - V Foundation

Jashodeep Datta, MD

Pancreatic cancer is very hard to treat. Even after surgery, it often comes back. One reason is the tissue around the tumor. This tissue can help the tumor grow and hide from treatment. Our work targets a key set of harmful signals in this tissue. Many of these signals use one helper protein, called IL1RAP. We will test a drug called nadunolimab that blocks IL1RAP. We hope this will quiet these signals and help standard treatment work better, especially when treatment is given before surgery. We will study the effect of IL1RAP in two main cell groups: 1. certain white blood cells that can block the body’s immune attack, and 2. support cells that can build a barrier around the tumor. We will also study tumor samples from patients. We will test whether the presence of IL1RAP-rich cell “neighborhoods” predict how well treatment works or does not work. In animal models of pancreatic cancer, we will test if adding nadunolimab before surgery can delay or prevent relapse after surgery. Finally, we will develop simple tissue and blood tests to show early if the drug is working. These tests can guide future trials and improve care for people with pancreatic cancer.

Yun Li, MD, PhD

This project aims to find better treatments for advanced prostate cancer. This type of cancer is very hard to treat once it spreads. Many treatments, including immunotherapy (which helps the body fight cancer), have not worked well for these patients. One reason is that prostate cancer can “hide” from the immune system.Our research focuses on combining two types of treatment: radiation and immunotherapy. Radiation can damage cancer cells, but it can also help “wake up” the immune system. When cancer cells are hit by radiation, they send out signals that make them easier for the immune system to see. In this project, we use a newer type of radiation that travels through the bloodstream and can reach cancer cells throughout the body. Unlike standard radiation that targets only one spot, this approach can find and treat cancer wherever it has spread and may help activate immune cells across the whole body. After this, we give a newer form of immunotherapy that helps immune cells find and attack the cancer more directly. You can think of radiation as turning on a signal, and immunotherapy as helping the immune system follow that signal to the tumor. We will study blood and tumor samples over time to learn how the immune system responds to this combination. Our goal is to find the best timing and way to give these treatments, so they work better together. This research could lead to more effective and longer-lasting treatments for patients with advanced prostate cancer and may help improve care for other cancers as well.

Douglas Mitchell, PhD

The immune system normally protects us from cancer by finding and removing abnormal cells before they grow. Many solid tumors develop when they learn how to hide from the immune system. Frequently, immune cells cannot enter the tumor because the tumor builds a strong barrier around itself. A major part of this barrier comes from a signal called TGF-beta. Tumors use proteins called integrins as “on-switches” that turn on TGF-beta. When TGF-beta is active, it creates conditions that keep immune cells out. If we can safely turn off this switch inside the tumor, the immune system may be able to enter and attack the cancer. Our research develops very small and stable proteins called lasso peptides that are designed to turn off this TGF-beta switch in tumors. By blocking the switch, these lasso peptides may open the door for immune cells to enter and may help existing drugs work better to kill the cancer cells. We will test these new agents in models of solid tumors to see how they change the tumor environment and support immune responses.We are also creating an imaging tool that lets doctors see whether the drug appropriately reaches a patient’s tumor. This information will guide future clinical studies and help match patients with the right treatment. If successful, this work will make immunotherapy effective for many more people with solid tumors and give patients a better chance at longer and healthier lives.

Marcela Maus, MD, PhD

Funded by the Stuart Scott Memorial Cancer Research Fund

As we continue this study of a new treatment called TriPRIL CAR-T cells for patients with multiple myeloma that has come back or not responded to treatment, we want to understand why the treatment works for some people but not for others.To do this, we will study samples of blood and bone marrow from patients over time. We will compare what we find to results from patients who received other approved CAR-T cell treatments.We will look at how the CAR-T cells behave and work, how the cancer and the bone marrow environment change, and whether the body develops a response against the treatment itself. We will compare patients who improved with the treatment to those who did not.In the end, what we learn will help us improve CAR-T cell treatments for multiple myeloma.

Anupriya Agarwal, PhD

Blood cancers are challenging to treat. The main reason is that cancer is found at late stages, where current treatments often fail. To save more lives, we must change our approach. We need to shift our focus from treating late-stage disease to stopping it early. We can achieve this by understanding how cancer starts. Many studies report that warning signs appear decades before cancer diagnosis. As people age, mutated blood cells can form in the body. This raises the risk of blood cancer by twelve times. Our research found that more chronic inflammation within bones creates a hostile environment. This inflammation acts like fuel for mutated cells. It helps them grow while harming healthy ones. A primary driver of inflammation is obesity, a condition that affects 40% of U.S. adults, and is a cancer risk factor. This long lead time offers a vital window of opportunity for early treatment. We propose a strategy to starve these bad cells. We aim to cut off the fuel supply linked to cancer cells to prevent cancer. We will test how obesity-driven inflammation helps mutated cells grow and weakens the immune system. Using human and mouse models, we will determine whether anti-obesity treatments can prevent cancer. We will test whether these treatments can reduce cancer growth and improve immune function. We will use computational tools to find high-risk patients. This project will help detect and halt leukemia in people most affected by obesity. The goal is to prevent devastating diseases before they begin.

Andrea Schietinger, PhD

Our immune system has special cells called T cells that can recognize and attack cancer. Even though these tumor-fighting cells are often present, many tumors still grow because T cells stop working properly during cancer development. Cancers can be grouped into two main types based on how the immune system responds. Some are called “hot” tumors. In these cancers, T cells are able to enter the tumor, but the tumor environment weakens them so they cannot kill cancer cells. Other cancers are called “cold” tumors which comprise approximately half of all human cancers. In cold tumors, T cells are mostly missing from the tumors. Cold cancers do not respond well to immune-based treatments. Scientists still do not fully understand why T cells fail to enter cold tumors or why these cancers resist treatment. To study this, we created preclinical mouse models in which tumors grow naturally and show cold immune phenotypes. Using these models, we found that tumor-fighting T cells are present in nearby lymph nodes but do not move into the tumor. Over time, these T cells become resistant to immune treatments, which is linked to the loss of important genes needed for T cell function. In this project, we will study in mice and patients with cancer why T cells get stuck, fail to enter tumors, and stop responding to treatment. This research may lead to new ways to make immunotherapy work for patients with immune-cold cancers.

Yali Dou, PhD

Acute myeloid leukemia (AML) is a fast-growing blood cancer. It is hard to treat, and it often comes back even stronger after treatment. One reason AML is so difficult to fight is that cancer cells take control of the normal systems that turn genes on and off. These systems are called epigenetic controls. When they do not work properly, leukemia cells can grow quickly, avoid treatment, and push out healthy blood cells.This research focuses on one of these gene regulators called MLL1. MLL1 helps turn on important genes in blood cells. In some leukemias, the MLL1 gene is broken or rearranged. However, we now know that a small group of adult AML patients have extra copies of the MLL1 gene. These patients often develop AML after having other blood disorders or after receiving chemotherapy. Sadly, they usually do not respond well to current treatments. Right now, there are no therapies made specifically for this group.Our study uses new knowledge about how MLL1 helps cancer cells grow. We will test whether leukemia with extra or altered MLL1 has weak points that new drugs can target. We will also explore ways to directly target MLL1. Our goal is to develop more personalized treatments that help patients live longer and healthier lives.

Theodore Braun, MD, PhD

Many people are diagnosed each year with blood cancers called myeloproliferative neoplasms, or MPNs. These cancers cause the body to make too many blood cells. Doctors treat MPNs with medicines that block the signals telling cancer cells to grow. These medicines work well for many patients at first. But over time, the cancer often stops responding. When this happens, patients have very few options left.We have found a clue that helps explain why some cancers stop responding to treatment. Certain gene changes, in genes called ASXL1 and SETBP1, cause cancer cells to form protein clusters inside the cell nucleus. These clusters act like command centers that keep cancer genes switched on, even when treatment is trying to shut them down. This makes the cancer much harder to kill.The good news is that we have found drugs that can break up these clusters. In our early studies, these drugs worked well in cancer cells grown in the lab and in animal models. Now we want to understand exactly how these clusters form and how best to destroy them. We will build cancer models in the lab that closely mimic what we see in patients. We will then test new drug combinations to find the best strategy for shutting down these command centers.Our goal is to use what we learn to launch a new clinical trial at OHSU within three years. We hope this work will give patients with treatment-resistant MPNs new options and ultimately help them live longer, healthier lives.

Kevin Cheung, MD

Funded with support from the Butler Family Gift Fund

Triple-negative breast cancer, or TNBC, makes up 10 to 20 percent of all breast cancers. It often returns within five years and becomes very hard to treat once it spreads through the body. Treatments that destroy spreading cancer cells before they form new tumors could greatly improve survival. Most TNBC tumors contain cells called basal-like tumor cells. These cells look similar to normal cells in breast tissue, and research shows they play a major role in helping cancer spread. Targeting these cells could help stop the cancer from coming back, but researchers have not yet found the right weak points to attack.Through this grant, we plan to explore an exciting idea. We believe TNBC cells can be changed into cells that resemble epidermis, the normal outer layer of skin. This matters because the body sheds skin cells every day and has strong systems to keep them from growing out of control. Early findings show that when breast cancer cells are shifted into this skin-like state, they lose their ability to grow and spread. By learning how and why this change happens, we can work toward finding drugs that trigger this shift. These shape-shifting drugs could one day become new treatments for breast cancer patients.

Kira Gritsman, MD, PhD

Waking up the immune system to kill tumor cells has become an effective way to treat some types of cancer. Unfortunately, this does not work well for acute myeloid leukemia (AML), a lethal type of blood cancer. This is because leukemic cells have found ways to put T cells to sleep. New strategies are needed to re-awaken T cells, an important component of the immune system, to help them kill leukemic cells. The protein PI3 kinase (PI3K) delta is found both in leukemic cells and in T cells. When PI3K delta is blocked, this can activate T cells in mice or in cancer patients. We found that loss of PI3K delta in leukemic mice improves survival by activating T cells. We are testing a new drug that blocks PI3K delta and activates T cells in cancer patients without causing many side effects. We found that treatment of leukemic mice with this drug can also activate T cells. The drug venetoclax is frequently used to treat leukemia patients, but some patients relapse. We will test whether adding the PI3K inhibitor to venetoclax could kill more leukemic cells than venetoclax alone by activating T cells to kill leukemic cells. If this treatment effective in leukemic mice and in a culture dish, then we will design a clinical trial to test this drug combination in leukemia patients.