New York Archives - Page 4 of 12

Margaret Callahan, MD, PhD

Funded by the Stuart Scott Memorial Cancer Research Fund in memory of James Ebron *

Immune checkpoint blockade (ICB) is one type of immunotherapy that has been FDA-approved for the treatment of melanoma, bladder cancer, lung cancer, and other cancers. For some patients, ICB can lead to dramatic shrinkage of their tumors and extend their life. However, many patients do not see this benefit and some patients develop serious side effects. For most cancer patients, there is no way to predict if they will benefit from or be hurt by ICB. A test that could give doctors and patients a better understanding of the risks and benefits for ICB treatment for each individual is urgently needed. Examining the blood of patients, we discovered certain immune cells in patients who are less likely to benefit from ICB. We have found this is true for both melanoma and bladder cancer patients. We plan to examine whether these cells also matter for patients with other cancers and if there are differences in these immune cells depending upon a patient’s race. We also would like to better understand this special population of immune cells and how they may be linked to immune cells in the tumor. We hope that this will lead to the development of a safe and easy test that will provide patients better information about how ICB treatment will work for them. With this information, we hope to allow patients to feel and function better and live longer by finding a therapy that will be more likely to help and less likely to hurt them.

Adrian Krainer, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

We aim to develop a novel and effective therapy for a lethal pediatric brain cancer (diffuse midline glioma, DMG). No effective treatment for DMG currently exists. This cancer arises when a mutation appears in a gene called H3F3A, causing it to produce a toxic protein. The mutant protein makes cells grow unchecked, forming a tumor in an inaccessible brain region and eventually killing the patient. Each of our genes makes RNA—so-called messenger RNA (mRNA)—and the mRNA is then read in another part of the cell to make the protein encoded by that gene. The technology we use, called “antisense”, allows us to target the mRNA made from a gene, and either destroy it or change it. Either way, the toxic protein is no longer made, and because the tumor cells require it for growth, they stop growing and die or change into normal cells. Once our antisense drug is developed, it will be injected into the fluid surrounding the spinal cord, allowing it to reach the brain tumor. Another gene, called H3F3B, encodes the same protein as H3F3A, so our method will get rid of the defective protein but not the normal protein. Therefore, the drug should not harm normal tissues outside the tumor. We will design, test, and perfect our antisense approach using cells derived from DMG tumors, and mouse models of this brain cancer. If this project is successful, the resulting antisense drug will undergo further safety tests, in preparation for clinical trials involving DMG patients.

Jun Wang, PhD

Funded by the Wine Celebration in honor of Carol Bornstein

Tumors are constantly growing and mutating – they are different from healthy cells, and thus should be able to be recognized by your immune system. However, immune cells respond to molecules that act as brakes, which can be used by tumor cells to escape being killed. While some of these immune brakes have been discovered, drugs blocking these do not work in most cancer patients, and many remain unknown. To improve survival for everyone, we need to figure out what the other important brakes are so we can reprogram your own immune system to fight cancer. We have recently discovered Siglec-15 as a new immune cell brake in tumors. Blocking Siglec-15 shows improved immune activity in studies involving human cells and mice. Based on these results, clinical trials targeting Siglec-15 are currently ongoing. Initial trial results show that targeting Siglec-15 is safe and slows down tumor growth in patients who have already failed other therapies. Thus, we need to understand the biology of Siglec-15 so we can design the best cancer therapy possible. Here, we will study how Siglec-15 suppresses tumor immunity and identify strategies to maximize its clinical response. Our proposal will improve our knowledge of cancer immunology and help patients in the fight against late-stage cancers.

Timothy Cragin Wang, MD

Funded by Gastric Cancer Foundation

Gastric cancer develops in the setting of chronic inflammation that both promotes cancer progression and that also blocks the body’s immune response which otherwise might restrain tumor growth. Chronic inflammation comprises a number of different types of white blood cells, but one type, called “myeloid derived suppressor cells”, plays an important role in blocking T lymphocytes, the main immune cell that protects us against cancer. We have shown in several mouse models that “myeloid suppressors” expand in gastric cancer and mediate some of the resistance to the newest immune therapies (called immune checkpoint inhibitors such as anti-PD1 drugs). We are proposing to study the importance of these myeloid suppressor cells further using several different mouse models and also analysis of human gastric cancer tissues. We will be testing a novel peptide shown by our lab to inhibit the expansion of myeloid suppressors, and also a small molecule that we have shown can inhibit the production of these cells in the bone marrow. Overall, our goal is to advance new therapies to target inflammatory cells that resistance to immune therapies in cancer.

Steven Reiner, MD

Nick Valvano Translational Research Grant *

Previously, the main treatments for cancer patients were surgery, radiation, and medicines with many unpleasant side-effects. The discovery that there are ways to turn our own defense system against cancer became a medical revolution. In some patients, this new treatment led to miracle cures that had never been seen before. The discovery was so incredible, it won a Nobel prize. Unfortunately, this new treatment does not work in as many patients as we would like. It is still a mystery why two people with the same cancer will respond differently to treatment, one patient might be cured and the other patient does not get better. This project is trying to figure out ways that will help doctors know who will be cured and who will not get better with this new treatment. We are developing a blood test to predict who will be cured before treatment begins. For those patients that are not likely to be cured, we are doing experiments to develop a medicine that can be added to the treatment in order to make the treatment cure many more patients.

Adilia Hormigo, MD, PhD

Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need

Glioblastoma (GBM), the most common malignant brain tumor, is one of the most aggressive forms of cancer with limited therapeutic options and a dismal prognosis. The median survival of patients is 14.6 months. A significant barrier to treatment is the immunosuppressive tumor microenvironment (TME). A cancer vaccine is a form of immunotherapy that boosts the body’s defenses to fight cancer. We have developed personalized cancer vaccines based upon patient-specific neoantigens unique to a patient’s tumor to prime and boost immunity with the long-term goal to delay or prevent a recurrence. Twelve patients have been vaccinated with a peptide-based vaccine that incorporates up to ten personalized epitopes. Our preliminary results show induction of systemic immunity and an estimated favorable 6-month progression-free survival of 90.9% and 12-month survival from surgery date of 87.5%. We detected circulating antigen-specific cells in the blood that were apparent in ex vivo assays, suggesting priming of high-level responses. We now intend to apply new technologies (spatial sequencing, mass cytometry (CyTOF), imaging mass cytometry and O-link proteomics) to analyze the TME in GBM in depth, determine cross-talk of the tumor cells with the immune cells and other brain cells hijacked by the tumor to grow, and screen for circulating immune factors and their co-stimulatory and inhibitory molecules. The cellular and molecular profile and distribution of cells in the TME and the in-depth analysis of blood cells and soluble protein biomarkers will help predict response or resistance and identify new immunotherapy targets.

Jasmine McDonald, PhD

FUNDED BY THE STUART SCOTT MEMORIAL CANCER RESEARCH FUND

Understanding young women’s breast cancer is a public health priority. In the United States, the rate of metastatic breast cancer is rising faster in women aged 25-39 compared to older women. Pregnancy is associated with an increased risk of breast cancer for 10 years after birth. Being diagnosed with breast cancer during this period is called postpartum breast cancer (PPBC). PPBC tumors are often more life threatening. Also, while breastfeeding reduces breast cancer risk, we do not know how breastfeeding impacts PPBC. Identifying unique tissue features within the PPBC tumor could lead to better outcomes. We will use the New York Breast Cancer Family Registry to analyze tumor tissue from 150 women. 50 samples from women diagnosed with breast cancer less than 5 years from childbirth (PPBC cases). 50 samples from women diagnosed more than 10 years from childbirth. 50 samples from women diagnosed who have never given birth. We will stain the tumor tissue with four biological markers. These markers have been associated with the spread of breast cancer and death from breast cancer. Staining, or adding coloring, to the tumor tissue will help identify unique features across the breast cancer cases.

Aim 1: Identify unique features within the tumor samples using the four markers in 150 cases.

Aim 2: Examine if the unique features predict breast cancer clinical features in 150 cases.

We know little about the PPBC tumor tissue. Identifying unique tissue features that map to the PPBC tumor can improve survival outcomes for young adult patients.

Justin Perry, PhD, MA

Funded through the Stuart Scott Memorial Cancer Research Fund by the Marks Family in honor of Lisa Curtis

The human body is estimated to remove over a billion cells every day, a process achieved by a relatively rare population of cells called phagocytes. When a phagocyte ingests a dying cell, it essentially doubles its content (analogous to a neighbor moving into your house). Yet, phagocytes such as macrophages often ingest multiple targets in quick succession. How these phagocytes maintain their homeostasis and manage the excess influx of dead cell cargo, are interesting scientific problems that are largely unexplored. This is an important topic in understanding cancer development broadly, and the development of cancer therapies specifically, because the clearance of cancer cells directly establishes an environment for the tumor to grow. Exciting avenues of therapy involve trying to either break down this tumor-promoting environment or by increasing the immune response against the tumor. These approaches show much promise; however, they often only work in specific patient populations. We believe that to develop a more effective therapy, we must understand the underlying processes that link clearance of cancer cells to generating an anti-cancer immune response. To this end, my lab focuses on studying phagocytes that are prevalent in Triple-Negative Breast Cancer (TNBC), how tumor cell clearance contributes to TNBC progression, and discovering new ways to target these cells to treat TNBC.

Chao Lu, PhD

Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Fund

Leukemia is the most common cancer among children in the US. It is also the leading cause of death from cancer before 20 years of age. Despite advances in diagnosis and treatment, a subset of leukemias affecting infants predict poor outcomes. Leukemic cells in these patients carry a fusion gene known as MLL rearrangement (MLL-r). MLL-r is critical for the development of leukemia cells, and has been well studied over the years. However, current therapies targeting MLL-r showed modest clinical activity. Therefore, there is a need of finding additional drug targets. We have found a previously unknown protein complex required for the survival of MLL-r leukemic cells. In this project, we propose to test if blocking this complex delay the growth of MLL-r leukemia in cells and animals. We will also investigate the molecular mechanisms behind. Taken together, our work will provide preclinical evidence for a new protein complex as a potential target for MLL-r leukemias. More broadly, our technologies will help the study of other childhood cancers.

Benjamin Izar, MD, PhD

Abeloff V Scholar * (Three-way Tie for Top Rank)

Melanoma is an aggressive form of skin cancer that frequently spreads (metastasizes) to other organs. While some patients with metastatic melanoma benefit from novel drug therapies, such as immunotherapies, which reinvigorate the body’s own immune system to detect and eliminate cancer cells, most patients do not. Interestingly, patients who have metastasis to the liver are significantly less likely to respond to immunotherapies, and the underlying reasons are unclear. Here, we established a melanoma mouse model that, similar to patients, experiences liver metastasis, and therefore enabling us to study the impact of these lesions on responses to immunotherapies. We use cutting-edge methods, such as genome-editing tools and high-resolution molecular profiling and imaging methods to dissect both how liver metastases develop and how they impact the immune system in the entire body. The ultimate goal of this work is to develop improved therapies for melanoma patients with metastases to the liver.