Grant Archive - Page 4 of 139

Jessica Thaxton, PhD, MsCR

T cells are part of the body’s immune system. T cells ward off disease but are also capable of fighting cancers. In fact, immune therapies in cancers have produced major gains in allowing patients with cancer to survive long-term. T cells can invade cancers, but cancers create a hostile environment that limits T cell killing capacity. This makes immune therapies function poorly. We have discovered a pathway in T cells that is engaged by the hostile environment of tumors that induces T cell distress and death. We have found a group of drugs that inhibit this pathway. These drugs also protect T cells from sensing the stressful environment of cancer. This group of drugs allows T cells to live longer and fight harder to eliminate cancer. We have found that these drugs improve the long-term outcomes of immune therapies and hold potential to increase the number of patients cured of cancer when treated with immune therapy. This project plans to study this stress pathway in T cells in samples from patients with cancer and to test these drugs in several models so that they can be used in the clinic to fight cancer in patients.

Andrew Brenner, MD PhD

Some cancers can spread to the fluid that surrounds the brain and spine. This is called leptomeningeal metastases, or LM. It is a serious and often deadly problem. Today, there are very few treatments that work well for this condition.Our team is studying a new treatment called Rhenium Obisbemeda (186RNL). This treatment sends tiny amounts of radiation straight into the spinal fluid, where it can kill cancer cells. Unlike standard radiation, which can hurt healthy parts of the brain, this method targets cancer cells more carefully and reduces damage to normal tissue.In our research, we are collecting samples from patients to see how their cancer and immune cells respond to this treatment over time. We are also using lab models to test whether this radiation works better when combined with other treatments—like drugs that help the body’s immune system fight cancer or block cancer cells from fixing themselves.Our goal is to find safer and more effective ways to treat LM and possibly other hard-to-treat cancers. This research could lead to better options for people with advanced cancer, giving them more time and better quality of life.

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.

Chrystal Paulos, PhD

Melanoma is a serious and often deadly type of skin cancer. Although immunotherapy has saved many lives, it still doesn’t work for every patient. Our lab is developing ways to give the immune system another chance to succeed.We are creating a new kind of cell therapy using “helper” T cells, known as Th17 cells. These cells do more than attack cancer directly—they help guide and activate other immune cells, turning the fight into a team effort.We discovered that a molecule called ICOS helps these helper T cells survive longer and build immune memory. This memory may help stop cancer from coming back in the future.Our goal is to turn this finding into a new treatment for people with melanoma who did not respond to standard therapies. By helping the immune system work better, we hope to offer patients more than extra time. We want to offer lasting hope.This research moves us closer to making melanoma a disease we can truly overcome.

Yuxuan Miao, PhD

More people are getting head and neck cancer caused by the human papillomavirus (HPV). Traditional treatments like surgery or radiation can cause strong side effects. Sometimes, the cancer comes back. Because of this, doctors are looking for safer and better ways to treat these cancers. Immunotherapy is a newer treatment. It helps the body’s immune system find and destroy cancer cells. Some people with head and neck cancer do well with a type of immunotherapy called “immune checkpoint inhibitors.” But, patients whose cancer is caused by HPV usually do not benefit as much. A new immunotherapy called HB-200 is being tested. It is designed to help the immune system better find and attack cancer linked to HPV. Early studies show that HB-200 may work for patients with HPV-positive cancer, even if other treatments have not helped. Our research looks at tumor samples from people with and without HPV. All of these patients received different types of immunotherapy. We are using simple lab tests and special tools to learn why HPV-related cancers do not respond well to older treatments, but do respond to HB-200. Our goal is to make HB-200 better and find new ways to treat these cancers. We hope this will lead to better care and longer, healthier lives for patients.

Todd Fehniger, MD, PhD

Cancer immunotherapy is a medicine that helps the body’s immune system fight cancer. One type, called “CAR T cells,” changes immune cells so they can see and attack cancer better. This has been a big help for people with serious lymphoma, but it can cause strong side effects like bad flu symptoms, brain problems, and low blood counts.This project is trying a new kind of immunotherapy that uses different immune cells called “natural killer cells.” We found a way to make these cells remember how to fight cancer better. These “memory natural killer cells” have helped leukemia patients without causing strong side effects. But there are still problems, like having a hard time seeing all types of cancer (including lymphoma) and being stopped by a “brake” on their surface. Natural killer cells also need a special growth signal called interleukin 15 to stay alive and fight cancer well.This project will fix these problems by adding tiny “mini” proteins to the memory natural killer cells. These changes will help them attack tough lymphoma, remove the “brake,” and make their own growth signal. We hope this will create a new treatment for difficult lymphoma and help us find more ways to make natural killer cells better in the future.

Agnel Sfeir, PhD

Cells use DNA repair systems to fix damage and keep their DNA stable. When these systems fail, it can lead to cancer and make treatment harder. One toxic type of damage is a double-strand break (DSB), where both strands of DNA are cut. In healthy cells, DSBs are usually fixed by a process called homologous recombination (HR). This method is very accurate. Some tumors, especially those with BRCA1 or BRCA2 mutations, lose the ability to use HR. These tumors rely on backup repair methods that are less accurate. One of these is called microhomology-mediated end joining (MMEJ). MMEJ fixes breaks by using short, matching DNA sequences, but it often adds or deletes small sections of DNA.MMEJ depends on an enzyme called polymerase theta (Polθ), which is found at high levels in many cancers. Research shows that BRCA-deficient tumors need Polθ to survive. Because of this, Polθ is now being tested as a drug target, alone and with PARP inhibitors. This project studies how MMEJ helps cancer cells resist treatment. We focus on two key ways. First, MMEJ can create changes that fix BRCA1 or BRCA2, which restores HR and reduces the effects of PARP inhibitors. Second, MMEJ may support the growth of extra circular DNA (ecDNA) that carries cancer genes. This makes tumors grow faster and resist therapy. By understanding how Polθ drives these changes, we hope to find new ways to treat cancer and make current therapies last longer.

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.

Kyle Payne, PhD

Ovarian cancer is one of the deadliest types of cancer and has very few treatment options. However, there is hope that new types of treatment that help the body’s own immune system fight cancer could help patients live longer. Scientists have found that ovarian cancer patients who have more T cells—special immune cells that can find and kill cancer—often survive longer than patients with fewer T cells. But we still don’t fully understand what T cells are targeting when they attack ovarian cancer cells. This lack of knowledge has slowed down the development of better immune-based treatments for this disease. Our study is trying to solve this problem. Using new technology, we plan to discover what T cells are looking for when they fight ovarian cancer. We also want to create a new treatment that helps T cells better find and kill cancer cells. To do this, we will use a method called mass spectrometry to find targets on the tumor cells. Then we will use computer tools and lab tests in animal models to see if T cells can recognize and respond to those targets. If this approach works, we will move forward with a clinical trial to test if the new treatment helps ovarian cancer patients live longer. We also believe this work could lead to new treatments for other types of cancer.

Lewis Chodosh, MD, PhD

Breast cancer comes back in up to 30% of patients, sometimes many years after treatment. These recurrences cause nearly all deaths from the disease. The returning cancer comes from tiny “sleeper” cells that survive treatment. These cells stay in the body without growing, in a resting or dormant state.

If we can keep these cells from “waking up,” we may be able to stop breast cancer from coming back and save lives. In our earlier research using mouse models and patient samples, we found something surprising: breast cancer sleeper cells can change their behavior and start acting like bone-forming cells. This change may help keep them dormant and stop the cancer from returning. We also showed that this bone forming activity can be seen in animals using PET scans—a common imaging method used in hospitals.

Our project aims to build on this discovery and develop a new way to keep sleeper cells dormant. To do this, we will:

Study this bone-forming process in patient tumor samples under the microscope.
Improve how we detect the bone forming process using PET scans in animal models.
Use what we learn to design a clinical trial that looks for whether this process occurs in patients during treatment.

If successful, our work could reveal a new way the body keeps cancer cells asleep, help us find which patients are affected, and lead to new treatments to prevent breast cancer from returning.