T cell therapy, like CAR-T, utilizes our body’s own immune defense to fight against cancer. While CAR-T therapy has worked well for some types of blood cancers, it faces challenges in solid tumors like breast cancer. One problem is that CAR-T cells don’t kill cancer cells effectively in the suppressive environment of solid tumors although they can target them. They can also cause harmful side effects by over-releasing cytokines in the body. Another challenge is that making CAR-T cells from a patient’s blood takes a lot of time and money. To overcome these challenges, my lab is developing programmable viral particles that can target tumor like CAR-T cells while bypassing the limitations of CAR-T therapy. In this project, we will engineer CAR-T mimic viruses that can target breast cancer cells and deliver gene circuits to them. These gene circuits can make cancer cells suicide or reprogram them to turn “cold” tumor “hot”. The unique feature of these viral particles lies in their ability to target and rewire tumor environment, their ease of manufacturing, and compatibility with evolving gene circuit technologies. We hope that these innovative anti-tumor viruses will become a versatile and accessible treatment that can synergize with other therapies to enhance cancer treatment.
Colorectal cancer is the third leading cause of cancer-related deaths in both men and women. Most people that get colorectal cancer are not genetically predisposed and while the causes are not clear there are three key players in the intestine: 1) immune cells, 2) microbes, and 3) environmental factors such as diet. How these players interact to determine cancer risk needs to be understood. We recently found that mothers can shape intestinal microbes and immune cells for multiple generations by influencing diet in early life (breastmilk). Our big question is, Can mothers protect their offspring from developing colorectal cancer by shaping their immune system? We will use mouse models to address maternal influence on multigenerational colorectal cancer susceptibility. Using a multi-omics approach, we will study the mechanisms of how breastmilk factors shape intestinal microbes and immune cells and protect from colorectal cancer. Our studies will provide the much-needed insight into immune cell-microbe-diet interactions and their role in cancer initiation and progression, and in the future we could harness protective factors in breastmilk to prevent or treat colorectal cancer.
In just over the past 10 years, new drugs that improve our own immune system’s ability to clear tumor cells have become an incredibly powerful class of cancer treatments. These therapies known as immune checkpoint inhibitors or ICIs work broadly against many different tumors, providing hope for many patients to better fight off their cancer. However, each patient is unique, and ICIs can work better for some patients than others. There are many reasons for these differences, including a person’s genetics, their type of cancer, and their environment. Recently, studies including our own have shown that microbes in our bodies also affect how well ICIs stop the growth of tumors. In our lab, we aim to understand how these microbes function during cancer treatment. We focus on how microbes make molecules that stimulate our immune system, which work with ICIs to fully activate tumor-fighting cells. In our work sponsored by The V Foundation, we will find new enzymes to make these active molecules. Using these enzymes, we will build better probiotics and test whether they can help to clear ICI-resistant tumors. Together, these studies will advance our long-term goals to understand how gut microbes affect cancer treatment and to generate new bio-based therapies that improve outcomes for cancer patients.
This research is focused on better understanding and improving treatments for a specific kind of blood cancer, known as B-cell acute lymphoblastic leukemia, or B-ALL. Although the treatment for childhood B-ALL has been greatly improved, long-term survival for adult patients is still under 50%. Our research showed that about 13% of adult B-ALL patients have mutations in PAX5 gene, which is critical for B-cell development. Two B-ALL subtypes are defined by PAX5 mutations: PAX5alt and PAX5 P80R. Surprisingly, survival rates vary greatly between these two subtypes (30% vs. 65%), which suggests that different genetic characteristics are involved. The goal of our research is to better understand the biological changes and genetic markers linked to B-ALL from different PAX5 mutations. Based on our preliminary study, we believe that certain PAX5 mutations block normal B-cell development, thus creating cells that are more likely to develop into leukemia. Our objectives are to 1) Explore how PAX5 mutations influence the normal DNA patterns and gene activities in B cells, and 2) Investigate how these mutations drive leukemia development step by step. We anticipate that our work will shed light on how PAX5 mutations disrupt B-cell development, thereby initiating leukemia. Our results will provide a comprehensive insight into understanding PAX5 mutations in B-ALL. This will enhance our knowledge about the role of PAX5 mutations and the mechanisms in disease initiation and clinical outcomes. Understanding these mechanisms could pave the way for more effective, targeted therapies for this high-risk leukemia subtype in adult patients.
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.
Funded by the Constellation Brands Gold Network Distributors
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.
Funded with support from Sarah Ferguson, The Duchess of York
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.
Pancreatic cancer kills just about every patient that has it. Patients are first seen with advanced disease and rarely respond to current treatments. More advanced therapies are needed to save lives. Recent studies suggest that pancreatic cancer cells are especially reliant on cellular recycling processes for growth. Mouse models of pancreatic cancer show that blocking these recycling processes can decrease the growth of tumors. These results have led to the launch of several clinical trials. However, initial results from these clinical trials show that pancreatic cancer cells stop responding. The tumors become resistant to blocking recycling pathways. We have made pancreatic cancer cells resistant to these therapies in the lab. We will use these cells to uncover better therapies to prevent resistance and increase patient survival.
Previously, research showed that these recycling processes promote tumor growth. But, in some contexts these same recycling processes can block pancreatic tumor growth. Researchers still don’t know how or when this switch happens. This dual role could contribute to the therapeutic resistance seen in patients. To study this phenomenon, I will use mini-pancreatic organs, called organoids, that can be grown in the lab. For the first time, we will be able to study the mechanisms that regulate the dual roles of cellular recycling in pancreatic cancer. Together these studies will allow us to target the tumor promoting functions of the recycling pathways while preserving the tumor blocking functions. This will prevent resistance and increase patient survival.
Funded by the V Foundation Sonoma Epicurean in honor of Leslie Sbrocco
CAR-T cell therapy is a type of therapy where a cancer patient’s immune cells, called T cells, are removed from the patient, altered in the laboratory to make them recognize cancer cells, and then given back to the patient. These CAR-T cell therapies have been unbelievably successful for liquid cancers like leukemias and lymphomas, however they have not yet been very successful for patients with solid tumors. Recently, a clinical trial of a certain kind of CAR-T cells for patients with stomach and pancreas cancers showed that CAR-T cells can fight these cancer cells in the body, but the patients only had short responses and their tumors came back. CAR-T cells need to be good serial killers of cancer cells, however they can often get tired in battle and stop working well. We want to apply our knowledge of gene engineering to make new and better versions of these CAR-T cells that do not tire quickly and can therefore fight cancer for longer. We do this by making different kinds of alterations in the genes of the CAR-T cells that give them more endurance, changing them from sprinters to long-distance runners. We can also make entirely new CARs (the part of the CAR-T cell that recognizes the tumor cells) that can bind the tumor cells with slightly different strengths, which we know can also make the cells less exhausted in battle. If successful, we will push these CAR-T cells to new heights, achieving longer remissions for patients battling gastrointestinal cancers.
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