All-Star Archives - V Foundation

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.

Frank B. Furnari, PhD

A brain cancer called glioblastoma is one of the deadliest cancers. Even with surgery, radiation, and chemotherapy, most patients only live about 15 months. The biggest problem is that the cancer almost always comes back. Scientists are still learning why this happens. Some cancer cells, called “persister cells,” can survive radiation therapy by going into a kind of hibernation. When treatment stops, these cells wake up and start growing again, causing the tumor to return. Think of it like weeds in a garden. If you don’t remove all the roots, the weeds grow back.Our research discovered that a protein called BRD2 helps these persister cells survive radiation. When we remove BRD2 from cancer cells in the lab, they die from radiation. But when we use drugs to block BRD2, some cells still survive. They find other ways to stay alive.We’re now testing drug combinations. These drugs block both BRD2 and the backup routes cells use to survive, stopping cancer cells from returning after radiation. Another problem is getting drugs into the brain. The brain has a natural wall that blocks most medicines. We’re creating tiny particles that can carry drugs past this wall. Think of them as special delivery trucks that know a secret path into the brain. If this works, we could have new treatments that stop brain tumors from returning after radiation. This would give patients more time with their families, changing this deadly cancer into a disease we can control.

Justin Milner, PhD

Pancreatic cancer remains one of the most difficult cancers to treat. There is a clear need for more effective therapies. CAR-T cell therapy has shown promise in some cancers. However, pancreatic tumors create a harsh environment that weakens T cells and limits how they work. This project aims to reprogram T cells so they can persist and continue fighting in these conditions.T cells can be genetically engineered. This allows us to adjust the instructions that control how they behave. Most current approaches focus on removing barriers, like taking the brakes off. In this project, we take a different approach. We aim to strengthen T cells so they can better adapt and function within tumors.Our goal is to identify changes that make T cells more potent and longer-lasting. These insights will enable more effective CAR-T therapies for pancreatic cancer and other solid tumors.

Amit Verma, MD

Myelodysplastic syndromes (MDS) are a group of blood cancers that cause low blood cell counts. The most common problem is anemia, which means the body does not have enough red blood cells. This can make people feel very tired and often leads to the need for blood transfusions.In MDS, the bone marrow (where blood cells are made) shows higher levels of inflammation. The cells in the bone marrow produce proteins that increase this inflammation in the body. In this project, we aim to reduce inflammation by targeting a key system called the inflammasome. The inflammasome is a group of proteins that helps to produce a substance called IL-1beta, which can make the disease worse.We are studying a new drug called HT-6184 in our lab. This drug helps block the inflammasome and reduce inflammation. In early lab tests, it has lowered inflammation and increased red blood cell levels.In this study, we will first identify the proteins and cells that cause increased inflammation in MDS. Then, we will test ways to block these targets using antibodies and specific drugs in lab-grown cells and patient blood samples. Most importantly, we will test how well the inflammasome-blocking drug works in MDS blood samples and in mouse models of the disease. This drug has already been approved by the FDA for clinical trials.If our results are successful, this research could help move this drug quickly into clinical trials designed for patients with MDS.

Elsa Flores, PhD

Funded by the Stuart Scott Memorial Cancer Research Fund

Cancer happens when certain genes change and cells grow out of control. New efforts look closely at each patient’s tumor so researchers and doctors can pick treatments that shrink that tumor. This is important for finding ways to treat pathways that are hard to target with drugs. One of the hardest to fix is TP53 (also called p53), the gene most often changed in cancer. Because p53 helps normal cells work, trying to target it directly can cause harmful side effects. To get around that, our research studies two related genes, TP63 and TP73, which can do some of the same jobs as p53 to stop tumors from growing. Our earlier V Foundation funding in 2005 helped us discover new roles for TP63 and TP73, and now we plan to use the pathways they control to make up for lost p53 function. This idea may work better than trying to fix p53 directly, since those methods are often only partly effective or only work for certain mutations. We also found special non-coding RNAs that affect how tumors grow and respond to treatment. The new therapies we propose aim to target tumors precisely and cause less harm to patients. Although we focus on lung, breast, and ovarian cancers, these approaches could help any cancer with TP53 mutations.

Jeffrey Smith, MD, PhD

Funded by the Stuart Scott Memorial Cancer Research Fund

Prostate cancer risk runs in families. A man’s risk of prostate cancer roughly doubles for every close family member who has been affected. Men in the family also tend to share how aggressive the cancer is. For example, how long a father survives with the cancer is strongly predictive of a how long a son will survive with the cancer. Studies have uncovered genetic risk factors for prostate cancer that distinguish which men are at high risk. But these factors poorly predict disease course. Two separate features of a cancer predict how aggressive it will be. These are 1) how abnormal the cancer cells are and 2) extent of cancer spread. Using such clinical features, two-thirds of cases are thought to be less aggressive and follow a watch-and-wait strategy. But over half advance and require active treatment. Ability to better recognize the path that the cancer is likely to take is needed. This is a study to discover the factors passed down in families that guide this path. The study also tests whether these factors predict which men followed by watch-and-wait will advance and require treatment.

Andrew Lane, MD, PhD

Acute myeloid leukemia (AML) is a fast-growing blood cancer that is hard to cure. Even with today’s treatments, fewer than 1 in 5 people are alive five years after they are diagnosed. Many patients do well at first and are told they are in “complete remission,” which means doctors cannot find cancer with standard tests. But the cancer often comes back.This happens because a small number of leukemia cells survive treatment. These are called minimal, or measurable, residual disease (MRD). MRD cells are hard to find and hard to destroy. They can hide in the body, resist drugs, or change over time. Doctors are getting better at finding MRD, but we still do not fully understand why these cells survive or how they are different from the original cancer.This project aims to learn what makes MRD cells different and how to target them. Our early work shows that MRD is not just a smaller amount of leukemia—these cells act differently and depend on certain survival pathways. We have collected samples from more than 120 AML patients at different stages: diagnosis, remission, and relapse. Using advanced tools, we will study these cells closely to find new treatment targets. Our goal is to develop better treatments that remove MRD, stop the cancer from coming back, and help more patients stay in remission and be cured.

Trudy Oliver, PhD

Some cancers are very hard to treat because they grow fast and stop responding to therapy. One example is a group of tumors called tuft-like cancers. These cancers can form in several organs, including the lung. Patients with these tumors often have few treatment options, and the disease can progress quickly.Our research focuses on finding a new way to treat tuft-like cancers. Our lab discovered a drug target that appears to be very important for the survival of these cancer cells. Early studies show that blocking this target can slow tumor growth in laboratory models.This treatment may also help the body’s immune system fight cancer. In other words, hitting this target may deliver a “one-two punch.” The drug could weaken the tumor while also helping immune cells attack it.In this project, we will study how this target helps tuft-like cancers grow and survive. We will test drugs that block it in models that closely resemble human cancer. We will also study patient tumor samples to learn how these cancers interact with the immune system.Our goal is to move this discovery closer to clinical trials. If successful, this work could lead to the first targeted treatment for tuft-like cancers and give new hope to patients facing this aggressive cancer type.