Funded by the Stuart Scott Memorial Cancer Research Fund
Tamoxifen is an estrogen-like drug that is used to treat breast cancer patients, breast cancer survivors, and patients with a family history of breast cancer. As a treatment, tamoxifen is extremely effective at decreasing the changes of getting cancer and increasing patient survival. Unfortunately, tamoxifen also causes negative side effects such as hot flashes and bone loss. Because of these concerns, up to a quarter of all patients fail to complete the treatment. The goal of our research is to understand how tamoxifen can cause hot flashes and bone loss. We will use genetically engineered mice to identify the brain regions that mediate the effects of tamoxifen on temperature control and bone density. We will also use cutting-edge molecular tools to determine precisely how these brain regions are affected by tamoxifen. To model the treatment conditions in humans, our studies use females of reproductive age and a long-term treatment using the same dosage given to humans. In the end, our studies will identify the specific areas that are responsible for the negative effects of tamoxifen. This information will help us design and begin to test strategies for alleviating hot flashes and/or bone loss in patients. Any treatments that provide relief from the side effects of tamoxifen will increase patient quality of life, increase the chances that patients will complete their treatments, and ultimately save lives.
Metastatic breast cancer is a result of breast cancer cells that spread to and grow in other organs. It is one of the most feared consequences of breast cancer, and the main cause of death from this disease. Yet, we still do not know what causes breast cancer cells to spread and become resistant to cancer treatment. For years, researchers have attempted to learn what makes individual cancer cells within tumors most able to migrate and grow elsewhere. My lab recently found that the cells that are the most successful at metastasizing do so as clusters. Clusters are also more resistant to cancer treatment. In this project, we will evaluate the different ways that tumor cells within these clusters communicate with each other. By studying these signals, how they are transmitted and their consequences, we may uncover the key vulnerabilities needed to disrupt and destroy tumor cell clusters. We will take advantage of a technology we invented that allows us to study ‘mini-tumors’ in a dish. We will also analyze the genetic code of the various cell types in the mini-tumors. We will then cross-reference what we learn with very large studies of breast cancer patients. Through shifting our mindset from the individual to the collective, our ultimate goal is to identify new leads for the development of therapies to treat – or prevent- metastasis so that we can save lives.
Funded by the Dick Vitale Gala in memory of John Saunders
My research team is developing and applying novel tools for genetics, genomics and systems biology to tackle fundamental problems in cancer biology and therapeutics. In this project, we will focus on childhood cancer, the leading disease-related cause of death among children in the United States. Better treatments for these types of cancer will thus deeply benefit children. Developing such treatments will require addressing the highly complex and heterogeneous nature of cancer, for any given tumor can contain an enormous repertoire of genetic mutations within it that can also change over time. Understanding the roles of cancer genes has been hampered by the lack of large-scale methods to directly identify and interrogate the function of large numbers of genes in vivo. My goal is to invent such a platform, which will allow simultaneous mapping of the effects of many genes on cancer progression and therapeutic responses. The platform will combine genome editing, synthetic biology, in vivo animal models, high-throughput genetic screening and high-performance computing. I will develop this platform and apply it to study both solid tumors and liquid cancers diagnosed in children. I will first use it to perform large-scale in vivo genetic analysis in medulloblastoma to reveal the global genetic landscape of the progression of this disease. This analysis will also discover important driver genes, providing knowledge for more precise diagnostics and prognoses, and potentially better therapeutic strategies. Discovery of such targets will ultimately lead to improved therapeutics to save many children’s lives from childhood cancer.
2017 V Foundation Wine Celebration Volunteer Grant in honor of Susan Leick and Joe McCrary
Lung cancer is the leading cause of cancer-related deaths worldwide, and is a very complex disease with different cell types that make up each tumor. Immunotherapy is ground-breaking because it is able to cure some patients with late stage tumors. However, the number of patients that have this great response is still low. In this proposal, we will test the combination of a second drug with immunotherapy to increase the likelihood that squamous lung tumors will respond to treatment. To do this, we will use two mouse models of squamous cell carcinoma. These models are ideal for testing immunotherapy because they have intact immune systems and have many features of the human disease. We will test whether the second therapy changes the cell types that make up the tumor, and whether these changes lead to better therapy outcomes. If our results show that the second drug can boost the immunotherapy, we can rapidly transition this work to clinical trials in human lung cancer patients.
Funded by the Stuart Scott Memorial Cancer Research Fund
Pancreatic ductal adenocarcinoma (PDAC) is a uniformly lethal cancer with a five-year patient survival rate of fewer than eight percent. This dismal statistic is caused in part by the inability to detect PDAC early enough for surgical resection and PDAC tumors do not respond to standard chemotherapies. Ninety-five percent of PDAC tumors have an activating mutation in the gene KRAS. Despite 30 years of research invested in anti-RAS therapies, it is still not possible to directly inhibit RAS clinically. Hence, research has focused on identifying cellular processes that help KRAS mutant cancers grow, survive, and resist treatment with chemotherapies. One cellular process that mutant KRAS turns on in PDAC is autophagy, which is a process of ‘self-eating’ in which cells digest themselves in order to recycle building blocks needed as fuel sources for aggressive growth. Chloroquine, a drug that blocks autophagy, reduces PDAC tumor growth in preclinical models and clinical trials. In addition, the tumor-inhibiting effects of gemcitabine, a frontline chemotherapeutic for advanced PDAC, are enhanced when autophagy is decreased with chloroquine. However, chloroquine blocks autophagy non-selectively, requires high doses, and turns on autophagy when treatment is prolonged. Therefore, alternative autophagy inhibitors are needed. Recent studies in our lab discovered that limiting the availability of the transition metal copper to KRAS mutant cells reduces autophagy and in turn tumorigenic properties. Thus, the proposed studies will address whether copper-reducing drugs used to lower copper levels in humans can be repurposed for the treatment of KRAS mutation-positive PDAC by blocking autophagy.
People that get cancer usually take medicines, called “chemotherapy”, that often made them feel very tired and sick. These problems can last for many months, even after they are completely cured. In our laboratory we demonstrated that animals that take chemotherapy lose weight and are weaker. As of now, we do not know how to prevent this, in particular because we do not know the causes. For this reason, we want to learn why patients with cancer show the signs of fatigue, so that we can also find new medications to improve their health and help them feel better. Very recently, we discovered that the medications used to kill cancer also destroy the “mitochondria”, that are the little engines in the cells, in our muscles. Because of this, we think that if we can prevent the mitochondria from being lost then we can also help the patients feel better and less tired. We plan to give mice with cancer the regular medications, with or without a new drug, called MitoQ. We think MitoQ will protect the mitochondria in the muscle of mice, will prevent them from losing weight and will make them feel stronger. If we our idea is correct, in the future we will propose the use of MitoQ also in people with cancer. By doing so, the patients will feel better, will have fewer troubles due to the chemotherapy and will also have a better chance to get completely cured and go back to a normal life.
Funded in partership with WWE in honor of Connor’s Cure
Young girls who survive cancer may also face the devastating prospect of reduced fertility and hormonal problems when they reach adulthood. Treatment of pediatric cancer damages ovaries and lifetime egg supplies in up to 20% of young girls. Current strategies to correct loss of fertility involve removal of eggs from patients prior to treatment, but this is invasive and does not prevent the chronic health problems that result from ovarian damage.
To improve quality of life for young female cancer survivors, we must develop strategies to protect their egg supplies, which are critical for continuous endocrine function of ovaries and fertility. Our goal is to identify egg-saving treatments that can be used along with standard cancer therapies.
We will begin by analyzing how eggs and other cells in the ovary respond to different cancer treatments. By detecting changes in the levels of proteins in response to various cancer therapies, we can learn which proteins are responsible for egg death and identify drugs that target those proteins to prevent eggs from dying.
Our lab has previously found that a specific protein, CHK2, promotes elimination of eggs in response to the kind of damage caused by cancer treatments, making this a promising target. We will test the feasibility of targeting CHK2, and we expect that our work will demonstrate the benefits and potential risks of CHK2-targeting drugs for protecting eggs. We also expect to provide a list of novel drug targets for egg protection in cancer patients.
Scientists have recently made tremendous progress in treating cancers by activating the immune system to attack the tumor. However, these therapies are not effective against cancers with less DNA damage due to insufficient anti-tumor immune responses. The immune system is capable of attacking these tumors, but suppressive immune subtypes such as regulatory T cells (Tregs) are coopted by the tumor to protect itself. Tregs are associated with poor survival in many cancers, and show enrichment for particular T cell receptors (TCR). The TCR senses targets by binding to their peptide-MHC ligands, which display a cross-section of peptides expressed by a particular cell. Despite their important role in protecting tumors, the identity and specificity of tumor-resident Tregs is poorly studied. We are working to profile what T cells are enriched in low mutation rate cancers. We can then use approaches we have developed to find what these T cells as seeing in the tumor. This information will help us understand of one of the most important tumor-protective cell types, and may open the door to new cancer immunotherapies.
About 12% of U.S. women will develop invasive breast cancer over the course of her lifetime. Despite advances in early diagnosis and treatment of the disease, breast cancer remains the most commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer death in American women. Acquisition of resistance to current therapies is a major challenge in everyday clinical practice, which significantly reduces the disease-free survival and overall survival in breast cancer patients. Thus, it is important to develop new therapeutic approaches for circumvention of resistance and also to identify predictive biomarkers for more effective treatment decisions. Our previous work found a protein called EZH2 as a very promising therapeutic target in metastatic breast cancer that becomes refractory to hormone therapy. Several highly selective inhibitors of EZH2 are currently being tested in phase I/II clinical trials in patients with B-cell lymphoma. In this study, we will evaluate the efficacy of these EZH2-targeting drugs in metastatic, endocrine resistant breast cancer. We further demonstrated that DNA methylation of one of EZH2-regulated target genes, called GREB1, is highly associated with EZH2 activity in advanced breast cancer. So we will test whether methylation of GREB1 can be used to identify patients who will respond to EZH2 inhibitors. Results from this clinical study provide a novel targeted therapy for advanced breast cancer and a biomarker for choosing the right treatment. Our work will pave the way for the development of personalized medicine as an alternative approach to fighting metastatic, endocrine therapy resistant breast cancer.
Great strides have been made toward finding cures for cancer, which is expected to strike 1.6 million Americans this year. Although many cancer patients still die from their disease, the overall cancer death rate is declining due to improved detection methods and novel therapies. The exciting development of immune therapy has shown that activating a patient’s own immune system to attack and kill cancer cells can lead to cancer cures and improved life spans for patients with many forms of cancer. However, there are still many patients whose tumors are resistant to immune therapy. We recently found that tumor associated macrophages, immune cells that are found in great numbers in tumors, cause resistance to immune therapy. We identified new drugs that break this resistance to immune therapy; these drugs led to cures in animals with cancer. We will test these drugs in patients with head and neck squamous cell carcinoma, monitoring for changes in biomarkers of immune suppression and tumor progression. We will also identify new immune therapy drug combinations that can improve cancer care. These studies will contribute to the development of novel, effective immune therapies for cancer patients.
