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.
Anti-cancer monoclonal antibodies (mAbs) are a type of treatment for cancer that has helped many patients but they do not work for everyone. The overall goal of our research is to make mAbs better cancer treatments. MAbs stick to cancer cells and attract cells of the immune system known as Natural Killer cells (NK cells) that then kill the mAb-coated cancer cells. We have found that NK cells start to kill mAb-coated cancer cells, but stop killing cancer cells unless they get help from a different type of immune system cell known as T cells. This suggests one reason mAb might not work for some patients is a lack of help from T cells. We also found that a different type of antibody known as a bispecific antibody (bsAb) can increase the help T cells provide to NK cells. This suggests the combination of bsAb to mAb could be a better treatment for some cancers. In this project, we will conduct studies in both mouse models and in samples obtained from patients to evaluate the role of T cell help in anti-cancer mAb therapy and determine whether giving mAb and bsAb together is a better approach to cancer therapy. Our studies are focused on lymphoma, but the results could result in improved mAb therapy for a variety of cancers.
One of the biggest challenges to extending patient survival from recurrent ovarian cancer is to understand how these tumors can “hide” from detection by cells of the immune system. Immunotherapy involves treatments that use the body’s own immune system to help fight cancer. Despite successes in other cancer types, immunotherapy treatments for ovarian tumors have had limited success in promoting patient survival. Our work builds upon the idea that ovarian tumors upregulate immune “protective” molecules and that these provide a “shield” against immune cell attack. We have found that the activity of a protein (FAK) within ovarian tumor cells drives protection signals and that the combination of chemotherapy blocking FAK (weakening the shield) with immunotherapy resulted in tumor shrinkage. Mouse survival was associated with the gathering of immune cells within and nearby tumor sites in the process of tumor killing. In mice, we have also identified measurable markers that circulate in blood, the presence of which increased as tumors were being attacked by immune cells. In this proposal, we will treat mice with a novel combination of tumor- and immune-targeting therapies and will validate the timing and extent of marker changes in tissues and blood as the tumor shrinks. A clinical trial to test this novel treatment combination and marker evaluation is proposed. The benefit of measuring markers in blood is that this does not involve surgery and that this may provide the clinician with early insights of patient response.
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.
Bladder cancer is a lethal disease with limited treatments. While we know that we can turn on patients’ own immune system to fight this cancer, using treatments called immunotherapies, most patients do not respond. We have been working on developing better immunotherapies that turn on a new kind of “killer” immune cell that can attack bladder tumors but has not been targeted before. With the support of the V Foundation, we will study samples from bladder cancer patients who received immunotherapy in a clinical trial. We will perform a deep dive into their tumors to see what other kind of cells and genetic changes make up the “neighborhood” that talks to these killer immune cells. We hope that this will provide key direction for a near-term clinical trial for bladder cancer patients who may benefit from a novel treatment targeting these killer cells. This will benefit bladder cancer patients in need by helping them live longer while also relieving the suffering from this disease.
Today oncologists have in their arsenal highly active and precise systemic therapies but often times cannot predict which patients would benefit the most. A major contributor to this knowledge gap is the cancer’s ability to resist therapies. Here, we will focus on malignant melanoma, an aggressive type of skin cancer, where two major precision-oncology therapies were first developed. One targets the so-called ‘MAPK cancer pathway’ that sustains the growth of many cancer types, not just melanoma. The other consists of immune checkpoint blockade (ICB) therapy, which unleashes the body’s cancer-killing immune cells and has been approved in >30 cancer types. In patients with melanoma, >70% and >40% of patients respond initially to MAPK targeted and ICB therapies, respectively. However, after initial responses, ~20-40% of patients experience relapse due to their melanomas developing resistance to therapies. In this study, we dissect how melanomas evolve resistance so that we can prevent resistance. In response to therapies, melanoma and other cancers diversify their genetic makeup, creating new species, and this diversity increases their chance of survival or ‘fitness’ through Darwinian natural selection. We will identify ways in which melanomas diversify in response to these two pillars of modern-day cancer treatment in order to construct new therapies to prevent cancers from coming back. Preventing resistance will spare patients from the emotional and physical tolls of clinical relapses and surgical and radiation therapies to control resistant tumors. Ultimately, preventing resistance will improve the patients’ quality and quantity of life and reduce financial tolls.
Colorectal cancer (CRC) is a common and deadly cancer that often arises from abnormal pre-cancerous growth of polyps in the colon. Colonic polyps can be detected and removed during colonoscopy, therefore reducing the risk of cancer development. While most CRC cases occur randomly, about 25% of CRC cases have a familial component, including hereditary syndromes like Lynch Syndrome and Familial Adenomatous Polyposis (FAP).
Individuals with FAP have a very high susceptibility to developing CRC, requiring frequent diagnostic testing. However, for FAP patients, the number of colon polyps is often too high to be removed through colonoscopy. In these situations, patients may require surgery to remove their colon, which is costly, has risks, and changes bowel movement habits. Therefore, finding new ways to slow down the development of polyps and CRC would greatly benefit FAP patients.
Using mouse models of FAP and an intervention study in FAP patients, our study aims to develop a new approach to prevent CRC in FAP, called chemoprevention, by exploring the potential of a new substance to reduce the development and/or progression of colon adenomas. We have observed that beta-hydroxybutyrate (BHB), which is a natural substance that our bodies produce while in a starving state or when on a ketogenic diet, can slow down colon tumor growth. As there is currently no standard chemoprevention treatment for FAP, our study aims to address this critical need for effective approaches to reduce CRC risk and improve the lives of those with genetic conditions that lead to colon cancer.
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.
Pancreatic cancer is deadly. The only treatment that can cure it is surgery to fully remove the tumor, but that is only an option when the cancer is caught early, which is rare. Radiation to shrink the tumor before surgery has been tried, but with little benefit. By studying both patient and mouse models, we discovered that while radiation can kill cancer cells and stimulate some good immune cells, it also can make the environment harsh, help cancer cells escape, and bring in some bad immune cells. It can also scar the tumor, making surgery harder. In lab studies, we found a molecule called STAT3 that enables radiation’s negative effects. When we blocked STAT3 in mice, we harvested the radiation’s good effects while blocking its bad ones. In this proposal, we are testing a pill for patients to take with radiation that blocks STAT3. This is the first time it is combined with radiation to treat pancreatic cancer in humans. In liver cancer, this drug was so effective that the FDA has prioritized it for trials. In our proposed trial, we will collect blood and tissue from pancreatic cancer patients before and after the pill and radiation and study how this combination affects the tumor and the patients’ immune system. We hope to develop a test that predicts patient response to the STAT3 blocker with radiation combo and to identify other ways the cancer cells escape.
While there are an increasing number of treatments for breast cancer, a sizeable number of patients develop resistance to these agents and experience disease recurrence. These numerous therapies have been enabled by our deepening understanding of the biology of breast cancer at the molecular and cellular levels, which continues to advance as a result of powerful technologies. To date most treatments have focused on targeting the molecular drivers present within tumor cells, it is increasingly apparent that the effective treatment of aggressive tumors, will necessitate strategies that harness the patient’s immune system to detect and eradicate tumor cells. Such immunotherapies have been highly effective in other tumor types, but their use has lagged breast cancer as this tumor type is thought to be immune cold. Here we perform detailed studies of breast tumor samples from patients enrolled clinical trials evaluating the efficacy of novel targeted and immunotherapeutic strategies in both early-stage and advanced breast cancers with the goal of uncovering the molecular hallmarks of tumors that respond to these agents, as well as those that do not. These studies harness powerful new technologies to study tumor tissue in its native context, while preserving spatial relationship between tumor cells and surrounding immune and stromal cells. This approach will uncover molecular interactions that can be exploited to overcome resistance and to optimize therapies across different subgroups of disease.