Multiple myeloma (MM) is a type of bone marrow (BM) cancer that remains a significant challenge to treat, despite therapy advancements. In this study, we aim to explore a new approach to enhance the effectiveness of standard MM treatments. Our focus is on a specific type of immune cells called myeloid cells, that play a role in tumor growth and immune evasion in MM patients. We observed that MM patients have an increase of a particular type of myeloid cell that express on their surface, a molecule called CXCR2, in the BM and places where the cancer has spread to bone: (osteolytic lesions). The myeloid cells may contribute to MM resistance to treatment and to evasion of the body’s immune system. Based on these findings, we propose a clinical trial to test a drug called SX-682, which targets CXCR2-positive myeloid cells. We will investigate whether adding SX-682 to standard MM treatment will improve patient outcomes. Our trial will focus on MM patients whose cancer has come back after initial treatment. The primary goal of our study is to assess the safety and tolerability of SX-682 with standard MM treatment. Additionally, we aim to understand how SX-682 affects the immune environment within the tumor and in the blood. By targeting CXCR2-positive myeloid cells, we hope to enhance the body’s ability to fight MM, improving patient survival. Our study represents a promising step towards developing more effective therapies for MM by harnessing the body’s immune system to better combat this challenging cancer.
Immune cells are always patrolling our intestines, even when we are healthy. This includes B cells, which produce antibodies. Antibodies are floating molecular fire extinguishers which bind to and neutralize infections. In our intestines, huge amounts of antibodies are made every day. These bind to the ‘friendly’ bacteria that we live with to make sure they are well balanced, which keeps us healthy. In inflammatory bowel disease (IBD), the intestine becomes damaged by the immune system and antibodies change which bacteria they bind to. This turns the population of gut-bacteria from friendly to harmful, and can cause IBD to become colorectal cancer.
We do not know which B cells make cancer antibodies, or how antibodies make bacteria harmful. To understand this, we need to know how dangerous B cells become selected to produce the antibodies that turn IBD into cancer. This requires special tools to tell the helpful cells apart from the harmful ones. We built mice with multicolored B cells so we can follow the B cells that become hijacked during IBD and cancer. We may then understand where cancer-causing antibodies are made, and what they bind to. By doing this, we hope to compile a list of common antibodies that are always made before IBD becomes cancer, and look for them as warning signs in IBD patients. This could give doctors more time to treat high-risk patients before tumors form. In the future, we hope our findings help design new cancer drugs to delete harmful B cells.
The rates of rectal cancer are increasing in young adults. Treatment for rectal cancer includes chemotherapy, radiation, and surgery. These therapies can have a negative effect on the quality of life of survivors. Radiation can cause infertility and problems with bowel and bladder function, as well as sexual health. Up to one third of the patients need a permanent colostomy so they do not have normal bowel function. Due to these issues, there has been an interest in finding ways to improve treatment for rectal cancer so that radiation and/or surgery may not be necessary. One way we are trying to improve treatment of cancer, including rectal cancer, is with immunotherapy. Immunotherapy empowers the patient’s own immune system to fight cancer. When this happens, it is very effective. Funding from the V Foundation will support a clinical trial that will treat rectal cancer that is mismatch repair proficient with immunotherapy first. The project team believes that improved immunotherapies like Botensilimab (anti CTLA4) and Basltilimab (PD-1), and earlier treatment before the tumor has spread, will lead to responses. This research has the potential to change the treatment paradigm of all early-stage rectal cancers and omit radiation and surgery in those patients whose cancers disappear with immunotherapy and chemotherapy alone. This will be an important finding for patients’ quality of life. It will also teach us how to make the immune system work against cancers where it has not worked in the past.
Funded by the Dick Vitale Pediatric Cancer Research Fund
We study a set of bone cancers that affect children and young adults. The treatment for these cancers has remained the same for the last 40 years – combinations of toxic medicines known as chemotherapy, followed by surgery or radiation to remove what is left of the cancer. While this strategy cures some patients, far too many children continue to die from these cancers. We believe we have found two specific weaknesses in these tumors: problems in their ability to repair damage to their DNA and a survival signal in a special pool of cancer cells known as “residual disease”. Through this research, we hope to bring new therapies to patients and cure more children with these bone tumors.
Funded with support from Carrie Collins in memory of Marty Collins
Immunotherapy helps the immune system recognize and kill cancer and it can cure patients where other treatments fail. Unfortunately, it still does not work for most patients. It is the goal of our research to understand why. Without a clear understanding of how cancer talks with the immune system, and how this conversation changes as cancer progresses, it is difficult to identify the root causes of why immunotherapy fails. Studying cancer evolution in patients is also challenging, as we rarely have the full history of tumor development and there is huge variability between tumors from one patient to the next. Through innovative genetic engineering, we are developing new mouse models of cancer that allow us to carefully study cancer development at all stages of the disease, especially at the moment when tumors acquire the ability to invade into other tissues—the reason cancer is so deadly. Why and how the immune system fails to stop cancer invasion and metastasis is not well understood and is a question of great importance. We will use the models we developed to study this question in creative and powerful new ways. We will also test exciting new immunotherapies, like cancer vaccines, in our models and determine why some tumors respond to treatment and others do not. Through this work, we hope to help match patients with the right immunotherapies and develop better immunotherapies that will be effective for many more patients.
Lung cancer is the deadliest cancer in the United States and lung adenocarcinoma is the most common type of lung cancer. While genetic mutations contribute to the development of cancer, cancer cells also activate gene programs over time that allow the cancer cells to become more aggressive and harder to treat. Advanced lung cancer cells evade current treatments such as chemotherapy or therapies that target the immune system. In our work, we have found that late-stage lung cancer cells expressed a unique transcription factor that activates gene programs which permit cancer cells to spread throughout the body. Of note is that these cancer cells also release molecules which we believe signal myeloid cells to enter the tumor. In doing so, the myeloid cells cause the immune system’s T-cells to be less effective and reduce how well current treatment strategies work. We seek to understand how late-stage cancer cells facilitate disease progression and how they limit response to current therapies. We have generated new mouse models which will allow us to investigate the gene programs that are active in these advanced cancer cells and to determine how these cells become resistant to therapy. Overall, our goal is to identify new options for targeting late-stage cancer cells which could be combined with, or used in place of, current treatment strategies so that we can increase how long patients with lung cancer live and improve their quality of life.
NRAS mutations are found in about 30% of melanoma, a dangerous type of skin cancer. Although recent advancements in melanoma treatments have helped many patients, those with NRAS-mutant melanoma still face challenges. Available treatments for these patients are often not effective, and their cancer can quickly become resistant to treatment. Recently, scientists have developed new drugs called pan-RAS inhibitors that can directly target the NRAS mutations responsible for tumor growth. These drugs have the potential to greatly improve treatment for people with NRAS-mutant melanoma, but we need to learn more about potential resistance to these new drugs. This knowledge will help us develop better treatments for this type of cancer. Studying drug resistance is difficult because tumor can be very different from one another. To overcome these challenges, our study uses advanced technology to observe how individual melanoma cells grow and change. Our approach allows us to monitor the rare cells that adapt to the new pan-RAS inhibitors, helping us understand why some cells become resistant. We will also compare the genes in these adapting cells to those in cells that do not adapt to determine what makes them different. By learning how NRAS-mutant melanoma cells adapt to new treatments, we can design better therapies for patients with this type of cancer. This will help us meet the needs of people with limited treatment options and improve their chances of recovery. Our research aims to move the body of knowledge forward, positively impacting cancer patients and cancer research.
Funded by the Constellation Brands Gold Network Distributors
Cancer often occurs because some pathways in our body’s cells become too active, and these pathways are the same ones normal cells use to function properly. Researchers made drugs to target these pathways and slow down cancer growth. However a major problem is that these drugs can also affect normal cells and cause harmful side effects. Our research focuses on a specific type of cancer called RAS-mutant, which represents more than a third of human tumors, including lung, colorectal, pancreatic, and skin cancers. RAS mutations cause the RAS pathway in cells to go into overdrive, and that leads to uncontrolled cell growth, causing cancer. Scientists have developed drugs to target the RAS pathway, like RAF and MEK inhibitors. However, these drugs have limitations because they can cause toxic effects in normal cells. The goal of our research is to find better ways to treat RAS-mutant cancers. We aim to understand why the drugs cause toxicities in normal cells by studying samples from patients and run experiments in the lab. We also found certain combinations of drugs that work better in cancer cells compared to normal cells. We will test these combinations in the lab and on animals to determine if they can effectively treat cancer without causing too many side effects. The ultimate goal of this research is to gather strong evidence to support quick clinical testing of these treatments in patients with RAS-mutant tumors, so we can develop better and safer treatments for people with these cancers.
Multiple myeloma is a type of cancer that affects the blood and bone marrow. Although there are many treatments, it almost always comes back. Scientists are looking for new treatments. Studies have shown, perhaps surprisingly, that the body’s ability to control a cancer is affected by the microbiome. The microbiome is the collection of bacteria that live in the gut. We hypothesize that myeloma, and how the immune system fights it, might respond to signals from the gut microbiome.
We are planning a new clinical trial to see if a fermented food product that may protect the microbiome will help nurture the microbiomes of patients getting bone marrow transplants. We will use samples collected from the trial participants to determine the effect of the fermented food on the microbiome and the metabolites that get into the patients’ bodies. Then we will study what happens to the immune system of patients in the trial. Finally, we will give myeloma to mice in the laboratory, while treating them humanely, and ask if antibiotics affect how the cancer behaves.
This study is important because it could help us understand how the microbiome affects MM and how to prevent cancer from coming back after treatment. The findings may also be helpful for developing new treatments for other types of cancer. Ultimately, we hope this will make people feel better and live longer.
Acute Myeloid Leukemia (AML) is a blood cancer that arises from cells that normally fight infections in the body. However, these cells can become fast-growing and hard to kill, which causes their over-production. Eventually, healthy cells in the blood stop working because the diseased cells take over. Patients with AML are often treated with a novel drug called Venetoclax, which kills the majority of AML cells. However, residual cancer cells that did not die eventually re-populate the body leading to the patient’s death. In this research proposal, we identified the protein BAX as a key effector of cancer cell killing by Venetoclax. We also made several scientific observations about Venetoclax and BAX that are critical to understanding why this drug works for some cancer cells and not others. A scientific goal of this V Foundation Award is to provide the scientific reasoning for why Venetoclax does not always work in AML patients. At the same time, a therapeutic goal is to examine the new drugs that directly activate BAX, which restores its ability to kill AML cells. Our scientific goal is to work together and to provide a deeper knowledge of cancer therapies with the aim of cancer cures.
Mailing List
