Gastric cancer is the fifth most frequently diagnosed malignancy in men and women, with nearly 800,000 deaths per year, making it the third leading cause of cancer related death worldwide.Therefore, it is critical to find more effective therapeutic approaches for this disease. Our group has investigated the molecular make up of gastric cancer using large patient cohorts to better understand the differences of molecular markers in gastric cancer and to identify new targets for drug development. Our research was able to find one of the main regulator of tumor growth and spread. This genetic alteration is called lysine methyltransferase 2 (KMT2) which is frequently altered in gastric cancer and a key driver of tumor growth.When normal tissues loses this gene, this tissue can became cancerous by promoting the development of tumor cells. Our group (Wang J, et al., JCO, 2020) was one of the first working on this particular gene and has recently conducted a comprehensive analysis of 1,245 patients with advanced gastric cancer, whose tumors were analyzed using with comprehensive and cutting edge molecular testing technologies. We found that patients with the KMT2 mutation have very unique tumor characteristics such as changes in the DNA repair pathways which makes them very vulnerable to specific chemotherapeutic drugs but also novel targeted therapies. Our project focuses onstudyingwhat the best treatment therapies for this uniquely subgroup of gastric cancer patient will be and explore existing and novel agents to improve outcome in patients with gastric cancer. The goal is that our project will lead to more effective and less toxic treatment options for patients with gastric cancer.
Leukemia is a cancer that starts in blood-forming cells found in the bone marrow. It is the most common cancer in children and teenagers, accounting for almost 1 out of 3 cases. Despite recent advances in the treatment of childhood leukemia, a substantial proportion of patients are resistant to conventional treatments. For these children, the probability of cure is very low (<30-50%). The best treatment for leukemia patients, especially those who have not responded to other therapies, is stem cell transplant, but the application of this life-saving treatment has been traditionally limited by a lack of suitable donors. The lack of suitable donors is a particular problem in African American or mixed heritage populations because finding a matched donor is less likely in these populations. We have developed a stem cell transplant strategy that greatly increases the number of patients who can receive transplants. However, this strategy cannot provide the critical anti-leukemic and infection fighting functions required to kill all the leukemic cells and is therefore unable to give patients who receive transplants long term cancer-free outcomes. In this project we willperform three clinical trials designed to testthe safety of three innovativecell therapies, which, when givenin conjunction with our stem cell transplant strategy, have the potential to fight leukemia. Our ultimate goal is to identify the optimal anti-leukemic cell product that improve cancer-free outcomes for children with leukemia.
Co-funded by the Dick Vitale Gala, and WWE in honor of Connor’s Cure
DIPG is a universally fatal brain tumor that occurs in children. Thanks to extensive research, we now understand the biologic causes of DIPG, but no one has found an effective way to treat the disease. Patients receive radiation to slow the disease and relieve symptoms, but they almost all die within two years of diagnosis. We have found that a target known as GD2 is highly expressed on DIPG. GD2 can be targeted with an antibody that is FDA approved to treat another type of cancer. When the antibody finds its target, it recruits immune cells to “eat” the cancer cells. Here, we propose combining anti-GD2 with another antibody that stimulates the immune system to “eat” cancer cells (anti-CD47). Because antibodies cannot reach the brain when given in the blood, we will deliver these two antibodies by direct injection into the tumor. Our main goal is to test this approach in mouse models of DIPG to see if it is safe and effective. This will hopefully serve as the basis for a clinical trial for children with DIPG. We will also explore alternative and complementary ways to attack the tumors.
My research interest is cancer genetics with an emphasis on clinically relevant questions that will improve our understanding of the cancer genetics of clinical phenotype and simultaneously improve patient care in oncology. I have extensive bench research experience in the fields of genome sequencing technology development, human genetic analysis through human genome sequencing and molecular assay development. My research benefits from the various innovations in genomic and genetic technologies that my group has developed.
V Scholar Plus Award – extended funding for exceptional V Scholars
Tamoxifen is an extremely effective drug for patients with estrogen sensitive breast cancer but it comes with a variety of side effects, including hot flashes. We use mice to test if symptoms similar to hot flashes are mediated by the effects of tamoxifen on the brain. We study a region of the brain that is very sensitive to estrogen and controls body temperature. We have identified differences in this region that are associated with changes in body temperature during tamoxifen treatment. Our immediate goal is to test if we can use this knowledge to block temperature changes in mice receiving tamoxifen. Our hope is that these studies could one day help us reduce hot flashes and improve the lives of breast cancer patients and survivors.
Volunteer Grant funded by the V Foundation Wine Celebration in honor of Roger and Sally Krodel’s granddaughter, Angie Cerreta-Palauqui
Therapies to kill cancers typically get rid of the dividing cells. However, the few that remain are a mixture of resistant cells that can return later to form more tumors. This is a difficult problem to solve. My research looks into finding out which genes cancer cells choose to use when they are not dividing to repair their damaged DNA and survive. Our goal is to develop treatments that will interrupt those genes that cancer cells use so they can die. We also want to develop treatments that can not only work to stop many different types of cancers, but that can also work in combination with other therapies to block the return of cancers later in life. The potential long-term success of our research will help to ease the anxiety of cancer survivors by extending the cancer-free period indefinitely.
The overarching goal of research in my laboratory is to understand how cancer cells metastasize and spread to vital organs in the body, such as the lung, liver, bone and brain. In breast cancer patients, metastasis leads to death in over 40,000 women in the U.S. each year. The possibility of progression to stage IV, metastatic disease is a constant source of fear and anxiety, since 30% of patients eventually progress to metastasis and survival for these patients is very poor (<3 years). Despite its prevalence, metastasis is an incredibly complex biological process that is very challenging to study due to the limited availability of authentic model systems. My laboratory has developed an innovative new approach to study metastasis in high resolution, using cutting-edge new single-cell technologies to study how individual cancer cells spread in human patient tumor models of breast cancer. Using our approach, we have found that cancer cells use a specialized form of cellular metabolism in order to spread. In our proposed study, we will investigate why and how this form of metabolism promotes cancer cell spread, and we will explore the effectiveness of using metabolic inhibitors to prevent metastasis and fatality in cancer patients.
Funded by the Constellation Gold Network Distributors
Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Many NSCLCs are caused by exposure to carcinogens, such as cigarette smoke, which cause changes to a cell’s DNA. These genetic changes can be detected by DNA sequencing methods. Next generation sequencing of tumors can provide clinicians, patients, and researchers with essential knowledge about the genes and proteins that cause and contribute to disease. Unfortunately, most human proteins (>95%) remain undrugged or inaccessible to labeling by FDA approved small molecules. Consequently, most cancer-associated proteins identified by DNA sequencing cannot be drugged. Therefore, we need new methods to identify druggable pockets in cancer-causing proteins. Our research develops such technology. In this study, we will develop a new approach to translate genetic changes into therapies. Our first step is to identify drug vulnerabilities that are specific to tumors. We will achieve this goal by combining next generation sequencing with new proteomics methods developed by our group. Next, we will synthesize drug-like molecules that can specifically label these tumor-associated proteins. Finally, we will determine how the protein targets of our compounds cause or contribute to cancer. Long-term, our studies will help guide the development of new precision therapies that will have fewer side effects and improved patient outcomes.
The term “metastasis” describes the spread of cancer cells from their original location in the body to nearby or distant organs. Almost 90% of all cancer deaths are because of metastasis. Unfortunately, this estimate has not changed in the last 50 years and our understanding of metastasis is limited. In order to effectively treat metastasis, we need to first understand them. Both cancers and their metastasis contain mutations in their DNA. Using our advanced algorithms, we can utilize these mutations to generate a tree that shows the evolution of a cancer in an individual cancer patient. On this tree, we can map the most important changes that can be used by doctors for making treatment decisions. In addition to using individual mutations, we can also use the patterns of all mutations in a cancer patient to pinpoint the processes that were active during evolution of the cancer. Some of these processes can be used as clocks to time the important changes found on the tree. Overall, we will create a high-definition timeline of the molecular events in the metastatic cancer of each individual cancer patient. The project will examine almost 2,000 cancer patients and increase our understanding of the events needed to transform a cancer to a metastasis. This knowledge is an essential step in providing patients with metastatic cancer with an informed and optimal cancer treatment.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Only half of children with neuroblastoma that is found to be “high-risk” (HR-NB) live after getting the best known treatments. To change this, we need to know what makes HR-NB grow, and find new targets to attack. The New Approaches to Neuroblastoma Therapy (NANT) (www.nant.org) is a team of doctors working with patients and/or in labs to find new treatment ideas and test them in children whose tumor didn’t go away after getting the best known treatments. If NANT’s new treatments are safe and make some tumors get smaller, they are then tested in more children to see if the new treatment is better than the best-known treatments. A little blood, bone marrow, and tumor are also taken from patients on NANT treatments to study in labs to see why our new idea did or didn’t work, and how we can make them better. There are 18 NANT hospitals in the United States, Canada, Australia, and Europe. NANT is the only group working only on new/better HR-NB treatments. This grant will support NANT doctors, labs, and the people who work in the NANT office to quickly take new ideas from labs and turn them into treatments being given to children with HR-NB. It also helps us to store patient samples so they can be used to keep finding new and better ideas. Our goal is to find safe treatments that will help more children with HR-NB to live.
