Massachusetts Archives - V Foundation

William Hwang, MD, PhD

Abeloff V Scholar * (Tie for Top Rank)

Pancreatic cancer is one of the deadliest cancers. A condition called pancreatitis, which is prolonged inflammation of the pancreas, increases the risk of getting this cancer. For over 100 years, scientists have known that both pancreatitis and pancreatic cancer involve many nerves. But only recently have we started to learn that these nerves may actively cause pain, increase inflammation, and help cancer grow through direct interactions with cancer cells but also indirect effects on the immune system. However, we still do not fully understand how this works, and there are no treatments yet that target these harmful nerve-cancer interactions.Our research focuses on a type of nerve cell called a nociceptor. These nerves sense pain and use a protein called Nav1.8 to send signals. A new drug that blocks Nav1.8 was recently shown to be safe and helpful in reducing pain after surgery. In our project, we will test whether blocking Nav1.8 can also reduce pancreatic inflammation and slow cancer growth. We will also study how damaged nerves affect the immune system. Our early data suggests that injured nerves can change certain immune cells called macrophages, causing them to block T cells from attacking the tumor. Our overarching goal is to find new ways to prevent and treat pancreatic cancer by targeting the nerves that drive pain and disease. We hope these treatments will ease pain, stop cancer from forming or growing, and help patients live longer.

Emily Heikamp, MD, PhD

Acute myeloid leukemia (AML) is a deadly blood cancer that’s difficult to treat. Sometimes AML starts with a mistake in our cells. Think of DNA like a library of instruction books for your body. Imagine if pages from two different books accidentally got glued together—that’s what happens in AML when two different genes get stuck together to create a cancer-causing fusion protein. These fusion proteins take over the cell’s control system and make cancer cells grow without stopping.Our research team found that we can fight these cancer-causing fusion proteins by blocking other proteins that help them work. When we block these helper proteins, the cancer cells stop growing and start turning into normal white blood cells. We’ve shown that drugs blocking a helper protein called Menin can make cancer cells change back toward normal. Doctors are now testing these drugs in patients with AML. However, we’ll probably need to use several drugs together to completely cure this cancer.Our team also found two more important proteins called KAT6A and KAT7. These proteins help write the instructions that keep cancer cells growing. We’re studying how KAT6A and KAT7 work together with fusion proteins to cause leukemia. Understanding how these proteins cooperate to cause AML will help doctors create better treatments that cure more patients while causing fewer side effects.

Jared Rowe, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Neuroblastoma is the most common cancer in babies. It can act in surprising ways. Some forms grow quickly and are very hard to treat. Others, especially in babies under 18 months old, can shrink or even disappear without treatment. Doctors do not fully understand why this happens, but the immune system may play a key role. One type of immune cell, called the CD8⁺ T cell, is especially good at finding and killing cancer cells.This project will study whether the immune system in babies works differently from that of older children or adults, and whether these differences can explain why some tumors go away on their own. Baby T cells are often thought of as immature, but new research shows they can grow faster, work more efficiently, and resist “burning out” better than adult T cells.In our early work, we trained baby T cells to recognize neuroblastoma cells. They were better at killing these cancer cells than adult T cells. We also found that baby T cells rely on a nutrient called pyruvate for energy and function. They process pyruvate in a special way using an enzyme called GPT.We will test whether this unique metabolism is the reason for their strong performance. We will also see how the tumor environment changes T cell metabolism, and whether changing the way T cells use pyruvate can make them even better at fighting cancer.We will use umbilical cord blood as a safe, widely available source of baby T cells. If this approach works, it could lead to new cancer treatments designed for children. The goal is to make these treatments safer, more effective, and take advantage of the natural strengths of the infant immune system.

Alison Ringel, PhD

Immune therapy is a cancer treatment that turns on killer T cells to attack the tumor. It is a major advance in cancer care. As it is less damaging to healthy tissue than chemotherapy, it has fewer side effects. Most importantly, it can help patients with advanced disease who had few options before. However, many patients do not benefit from immune therapy. The reasons why are not fully understood. Cancer affects people of all ages, but it is much more common in the elderly. T cells are key to the success of immune therapy, but aged T cells do not work as well as young ones. We have discovered that a signal important for T cell function is lost as people age. The loss happens even before a tumor appears. As tumors grow, aging makes even more T cells lose this signal. Our research will test whether the loss of this signal explains why older patients do not respond to immune checkpoint therapies. We will explore ways to restore this signal to improve treatment outcomes. Through this research, we hope to make immune therapy effective for more patients, especially older adults who face the highest rates of cancer.

William Freed-Pastor, MD, PhD

Pancreatic cancer is a terrible disease, and we urgently need better treatments. The immune system can search the entire body to find and destroy cancer cells, just like it protects us from viruses or bacteria. The immune system does this by recognizing small “flags” on the surface of cancer cells. Unfortunately, cancer cells can often “hide” from the immune system so they don’t get destroyed. We urgently need to find new ways to use the immune system to fight pancreatic cancer to develop better treatments for patients. We’ve been using something called “organoids” to study pancreatic cancer. These are tiny, 3D versions of tumors grown in a dish from a patient’s own cancer cells. Using these organoids, we’ve been able to identify the “flags” on the surface of pancreatic cancer cells that the immune system might be able to recognize. We’ve also created a special system to help us figure out which of these “flags” are the best ones for the immune system to fight and ultimately destroy the tumor. Our plan is to use what we’ve learned to carefully test many new targets on the surface of pancreatic cancers to see if the immune system can recognize them. This will help us develop improved therapies for pancreatic cancer patients.

Mario Suva, MD, PhD

Glioblastoma is the most common and aggressive type of brain cancer, and sadly, most people only survive 12 to 18 months after being diagnosed. This hasn’t changed in the last 20 years. One of the reasons it’s so hard to treat is that glioblastoma is very complex and different from one patient to another.To improve treatment, we need to better understand this complexity and figure out how to target each part of the cancer. The Suva lab has spent the last decade studying glioblastoma in depth using advanced genetic tools to understand how it varies. We’ve discovered that glioblastoma can be broken down into four important parts, and each part is essential for the cancer to grow.In this research, we will develop strategies to target each of these four parts. We’ll use new technologies developed by the Bar-Peled lab that can target elements of the cancer that were once thought too hard to treat. Our first step will be to analyze tumor samples from patients to find new drug targets. From there, we will work on drug development to eventually test them in clinical trials.

Jacalyn Rosenblatt, MD

Dr. Joseph Moore Excellence in Oncology Grant*

Multiple myeloma is a type of cancer that affects plasma cells. This disease can lead to infections, kidney problems, and bone pain or fractures. There have been great improvements in the treatment of multiple myeloma in recent years. However, most people are still not cured by current therapy. Treatments that use the immune system have shown great promise. One important example is CAR T-cell therapy. CAR T cells are made by taking a patient’s T cells (a type of immune cell), and changing them so they can recognize and kill cancer cells. These cells are then given back into the patient by an intravenous infusion. CART cell therapy has resulted in dramatic improvements in outcomes for patients with multiple myeloma. Our group has studied a new combination approach to improve upon responses to CART cell therapy. We have developed a personalized cancer vaccines using a patient’s own cancer cells. To make the vaccine, a patients plasma cells are collected from the bone marrow and are combined with immune cells called dendritic cells, which help activate the immune system. In a national study, this vaccine was shown to be safe, could be made at centers across the country, and was shown to stimulate immune responses. In this new study will test the vaccine in combination with CAR T-cell therapy. This DC/MM fusion vaccine has the potential to stimulate a broad immune response, preventing the development of resistance and can expand the CART cells to enhance their durability and effect.

Xin Zhou, PhD

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.

Giada Bianchi, MD

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.

Gabriel Griffin, MD

Our lab works on finding new and better immunotherapies for cancer. To do this, we try to understand how cancer cells hide from the immune system. We also try to understand which proteins could be targeted with a drug to help the immune system find and kill cancer cells more effectively.

To accomplish this, we are studying ancient viruses that live in the DNA of all human cells. Usually, these viruses are kept quiet by “epigenetic repressors”. Our lab is studying how to turn on these viruses in cancer cells, with the goal of activating the immune system to kill the tumor.

We envision this approach leading to a new type of cancer therapy, which could be used in patients that don’t respond to standard immunotherapies.