Translational Archives - V Foundation

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.

Michelle Ozbun, PhD

HPV is a very common virus. Most of the time, the body clears it on its own. But sometimes HPV sticks around and causes abnormal cells to grow in the cervix, anus, genitals, or throat. If those abnormal cells aren’t caught and treated, they can turn into cancer.Right now, getting treated usually means clinic visits, special tests, and sometimes painful procedures to remove the abnormal cells. For people in rural areas, Native communities, or places without good healthcare access, that’s a real barrier. People living with HIV face even higher risk because their bodies have a harder time fighting off HPV.This means people who already have the least access to care are the most likely to develop cancers that could have been prevented.Researchers are working on a treatment that people could use at home — an antiviral that someone would apply themselves, without needing a clinic visit. Combined with at-home HPV testing and follow-up through telehealth or community health workers, this approach could make it much easier for people to get treated early.For patients, that could mean fewer procedures, less time away from work, less travel, and less of the stress that comes with waiting and worrying.The bigger goal is simple: if treatment is easier to get, more people will get it — and fewer people will develop cancer.

Christian Hinrichs, MD

Cancers caused by human papillomavirus (HPV), like cervical and throat cancers, are hard to treat once they spread. Our team developed a new approach called TCR-T therapy to fight HPV cancers. We take a patient’s own immune cells, called T cells, and modify the T cells in a lab so they can recognize cancer cells. After growing the cells for several weeks, we put them back into the patient. Think of it as programming T cells with a lock-and-key that fits only HPV cancer cells, allowing them to find and destroy tumors. In a clinical trial, two patients with advanced cancer saw their tumors disappear after a single treatment, and they have remained cancer-free for over a year. While successful, TCR-T therapy is slow and expensive because it must be custom-made for each patient. Some patients with fast-growing tumors simply cannot wait, and some hospitals cannot afford to offer the treatment. To solve this, we are developing a simpler treatment called a T cell engager. This protein works like double-sided tape: one side attaches to the cancer cell and the other to a T cell. By pulling the cells together, the immune system can attack the cancer. Because these proteins can be mass-produced and stored, treatment could become faster, cheaper, and more widely available. Our goal is to advance T cell engagers through lab testing and into clinical trials so more people with HPV cancers achieve lasting remission.

Natalie Silver, MD, MS, FACS

Anaplastic thyroid cancer (ATC) is a very dangerous type of cancer. Most people with this cancer only live a few months after doctors find it. The medicines we have now don’t work well. Sometimes the tumors get smaller at first, but the cancer almost always comes back. We need better ways to treat this disease.ATC is hard to treat because it tricks the body’s defense system. Our body has special cells that are supposed to fight cancer. But this cancer confuses some of these cells and stops them from attacking. When this happens, your body can’t fight back against the cancer. This study tests a brand-new way to treat cancer. Doctors take a small piece of each patient’s tumor and use it to make a special medicine just for that person. The medicine is packaged into tiny particles (called RNA-LPAs). These particles are designed to wake up the body’s defense system and teach it to find and attack the cancer. This treatment has never been tested on people with ATC before.In this early clinical test, patients will get the new treatment while doctors carefully check to make sure it’s safe. Doctors will collect blood and tumor samples to see if the body’s defense system is responding. This helps scientists learn if the treatment is working the way they hoped. If this works, it could help patients with ATC live longer. It might also help doctors treat other types of cancer that don’t respond to today’s medicines.

Craig Byersdorfer, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Treatment of childhood cancers is tough. However, our recent success rate has improved. This is because of our ability to redirect the immune system to attack cancer cells. These advances have resulted in many cures. However, success has not been perfect. Relapses continue. Further, we know the risk of cancer increases when immune cells go away. Or when the cells do not function properly. It has also become clear that knowing the energy pathways used by immune cells is vital. This knowledge can help predict how well our treatment will work. However, it has been challenging to reprogram immune cells. Many treatments restrict cell growth. Or limit cell number. In our studies, we discovered a new way to reprogram cancer-targeting immune cells. Our method improves their anti-cancer properties. Without limiting cell growth. Or function. We believe that these beneficial changes will increase the chance of a successful treatment. Especially when immune cells are given back to children with high-risk leukemia. In the current application, we will test our new treatment in many ways. We will test immune cells recovered from leukemia patients. We will compare our approach to similar treatment strategies. We will define whether immune cells need to stick around. And, we will extend our studies into ‘real world scenarios’. Together, we hope to bring our treatment to patients with high-risk leukemia. Within the next five years.

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

Funded with support from the Dangerfield Family Foundation and Hooters in honor of the Stuart Scott Memorial Cancer Research Fund

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.