Although significant progress has been made treating melanoma and the recent approval of several drugs for the treatment of advanced disease, several challenges remain. For example, clinical responses are generally short-lived as tumors quickly become drug resistant and patients relapse. Moreover, tumors can develop drug resistance through a diverse number of molecular mechanisms, making the development of second-line therapies extremely daunting. Therefore, it is critical to identify therapeutic targets that are common to the majority of resistant tumors. We have recently found that a protein kinase called S6K is activated in melanomas resistant to BRAF and MEK inhibitors. Moreover, we showed that inhibition of this protein using a triple drug combination blocked the growth of resistant tumors. This provides strong rationale for establishing S6K as a novel target for melanoma therapy. Notably, S6K is a common node for most resistance pathways. We propose to investigate the role of S6K in melanoma and determine the therapeutic value of targeting this protein. Towards these goals we will determine the consequences of blocking S6K in melanoma, identify the proteins that are regulated by S6K and use this knowledge to delineate combinatorial approaches that can lead to long-term tumor remission in a large number of melanomas, including those resistant to BRAF and MEK inhibitors. We expect that the data generated by these studies can be quickly translated into new strategies aimed at maximizing the therapeutic efficacy of MAPK inhibitors in melanoma and provide actionable information that will guide the design of future clinical trials.
Co-funded with Carousel of Possible Dreams/Friends of Cathryn and the Dick Vitale Gala
Only 45% of children with high-risk neuroblastoma are cured. The New Approaches to Neuroblastoma Therapy (NANT) consortium links laboratory and clinical investigators to develop therapies with high potential for improving survival and performs the first testing of them at 13 neuroblastoma centers. We propose new clinical trials for patients with resistant or recurrent disease that aim to 1) improve immunotherapy; 2) improve chemotherapy by targeting key drivers of the disease; and 3) improve measurement of response and prediction of outcome with a “biomarker” test for blood and bone marrow. We anticipate that these innovative studies will improve survival for children with high risk neuroblastoma.
A growing body of scientific evidence suggests that up to half of all young women’s breast cancers are related to a recent pregnancy. Approximately 12,000-15,000 young mothers each year in the U.S. and 180,000 women worldwide will be diagnosed with breast cancer within 5 years of childbirth, demonstrating that young mother’s with breast cancer is a global problem. Our lab found that this population has a three-fold increase in metastasis and death, and we traced the increased death to the inflammatory effects of breast tissue “remodeling” following pregnancy –the time when breast tissue is removed to phase out of the job of lactation. Using rodent models of postpartum breast cancer, we found that ibuprofen treatment given for only 10 days after weaning blocks the development of postpartum breast cancers. Studies supported by the Kay Yow Cancer Fund permitted us to use our mouse models to determine whether ibuprofen can be used to prevent postpartum breast cancer, as well as let us investigate whether ibuprofen can be used to help treat young women already diagnosed with postpartum breast cancer. Our goal is to determine if a relatively low-cost intervention, such as ibuprofen or aspirin, can be readily incorporated into current treatment regimens to prevent the occurrence and/or progression of young women’s breast cancer. Results from this Kay Yow Cancer Fund grant confirm that the window of time following weaning is unique, characterized by tissue remodeling that is driven by the same protein that drugs like aspirin and ibuprofen inhibit. We anticipate that aspirin and ibuprofen, when combined with standard of care treatments for breast cancer, will reduce mortality in young women diagnosed with postpartum breast cancer. Further, our mouse studies identify why ibuprofen prevents progression of postpartum breast. We find that postpartum breast cancers are infiltrated with high levels of “bad” immune cells that block the ability of “good” immune cells to attach the cancer. We find that ibuprofen specifically blocks these “bad” immune cells and activates the “good” immune cells, permitting tumor destruction. In future studies, we will confirm that ibuprofen and drugs similar to ibuprofen activate the “good” arm of the immune system in postpartum women, as we see in mice, and we will conduct the first clinical trial designed to fight postpartum breast cancer.
There are over 170 FDA approved chemotherapeutic medications. These medications have shown benefit to a particular segment of cancer populations, often multiple groups of patients. Because of the rarity of pediatric cancers, very few of the medications that are used to improve the lives of children with cancer are FDA approved for that specific use, so called off-label use. Incorporating new medications into childhood cancer treatment often involves testing one agent at a time across a variety of diagnoses followed by focusing on a subset or a few types of cancer. This process has been slow to identify new agents in a group of tumors known as sarcomas. Recently, there have been a significant number of medications approved and it would be impossible to test them all on patients in the manner described above. Furthermore, studies in models of sarcomas have not always been reliable predictors of the medications because they have been tested in amounts that are not achievable in humans or for durations that cannot be achieved without unacceptable side effects. We propose looking at many FDA approved agents at levels that can be safely achieved in people across a panel of sarcoma models to identify agents and then combinations of agents that can be rapidly incorporated into a disease specific trial. We aim to test these agents, and, in the coming two years, identify promising combinations in the four most common sarcomas: osteosarcoma, Ewing Sarcoma, alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma.
Breast cancer is the most common cancer among women in general and among older women in particular. Adjuvant chemotherapy has played a major role in improving survival in both younger and older patients, but in older women, especially, its associated toxicities can lead to declines in function, quality of life, and even survival. For clinicians treating older women with a breast cancer diagnosis, how their patients survive and thrive during and after adjuvant chemotherapy is as important as preventing cancer recurrence and prolonging life. Toxicities that result in decreased physical activity and increased fatigue can lead to chronic detrimental changes in body composition, including loss of lean body mass, loss of muscle mass, and an increase in adipose tissue. Interventions to decrease these risks are needed. The overall goal of this research is to identify whether a home-based physical activity program initiated during adjuvant chemotherapy can attenuate the molecular and clinical consequences of adjuvant chemotherapy on the aging process in a sample of breast cancer patients age 65 or older. Specifically, this study will investigate the impact of an exercise program-a simple walking program that can meet the exercise needs of older cancer patients-on changes pre-and post-chemotherapy: (1) in a gene that is a dynamic biomarker of aging (p16INK4a) and (2) lean body mass, physical function, fatigue, and quality of life. The study will also evaluate how data from a wireless activity tracker correlates with measures of physical function and quality of life during chemotherapy. if it is shown that this easy-to-implement physical activity intervention can maintain function and lessen toxicity among older breast cancer patients receiving chemotherapy, it would be ideal for incorporation into adjuvant treatment in both academic and community-based cancer care settings.
Children with diffuse intrinsic pontine glioma– a specific brain tumor type- continue to have a dismal prognosis and most children die from this disease within months from diagnosis. Despite multiple national clinical trials, no change in outcome has been achieved over the last several decades. Two potential reasons why we have not made any progress in this disease are a) treatment is not matched to each child’s individual tumor characteristics and b) due to the presence of a tight blood-brain barrier medications given either by mouth or vein are not getting in sufficient enough concentrations to the tumor. To address these issues we are currently conducting a clinical trial through the Pacific Neuro-Oncology Consortium (www.pnoc.us, PNOC003). In this trial we will profile each child’s tumor with state of the art next generation sequencing and determine a treatment plan based on the specific characteristics of the tumor. A specialized tumor board that consists of several neuro-oncologist, pharmacologists and researches with an expertise in next generation sequencing meet and discuss the results and determine a specialized treatment plan, which consists of up to four FDA approved drugs. Specific attention is being paid to the drug brain penetration of recommended drugs. Correlative aims of this feasibility study is to develop patient derived mouse models as well as to test if tumor specific DNA can be detected in blood and be used as a marker for clinical response.
Almost all cells of an individual share the same genetic information. Yet each individual has many different cell types with distinct characteristics and functions (e.g. skin cells and brain cells of the same individual are indistinguishable genetically). One the most vexing questions in biology is: how is this dizzying array of cell types made within an individual, all of which come from the same blueprint of genetic information? We now know what differs among the different cell types of an individual is not the genetic information; instead, it is the ‘on’ and ‘off’ state of genes in that cell type. In other words, a cell’s unique gene expression signature determines its characteristics. A molecular memory system, called epigenetics, establishes and remembers the cell type’s unique gene expression pattern during development. One way by which cells become cancerous is by losing their ability to remember who they are. This also impairs their ability to protect their DNA against damage and instability. Recent work has revealed the identity of some proteins whose job is to regulate these important processes. We have found that two of these proteins work together to create a special DNA structure, which protects our DNA against instability and remembers if a gene is ‘on’ or ‘off’. We plan to understand the mechanism by which these and other proteins regulate gene expression and genome stability. This work impacts our basic understanding of many different cancers, and will likely allow the development of new drugs and new strategies for killing or reprogramming cancer cells.
Bladder cancer patients experience widely variable clinical outcomes. Some are cured of their disease with surgery alone, whereas others require chemotherapy, and only about half of individuals who receive chemotherapy benefit from it. These differences in clinical behavior are almost certainly based in differences in cancer biology, and the overall goal of our bladder cancer research program is to deeply define them so that optimal therapeutic approaches can be offered to each patient. We recently discovered that bladder cancers can be grouped into “intrinsic subtypes” that are remarkably similar to the ones that exist in breast cancers. One of the bladder cancer subtypes (“p53-like”) is similar to “luminal A” breast cancers, and like them, tend to be resistant to chemotherapy and metastasize to the bone. Their most distinguishing feature is that they contain large numbers of normal cells (termed “fibroblasts”) that are being implicated in drug resistance and bone metastasis in laboratory models of other types of cancer (including breast cancer). In this project we will examine further whether the p53-like tumors are chemo-resistant and metastatic to bone by analyzing several additional cohorts of patients treated with chemotherapy in clinical trials. Then we will directly examine the contributions of the fibroblasts to chemoresistance and bone metastasis in laboratory models. Our goal is to use the information to distinguish patients who will benefit from chemotherapy from those who will not. And by studying the biological mechanisms influenced by the fibroblasts, we should be able to identify new, more effective therapies for patients with chemoresistant bladder cancers.
Leukemia stem cells (LSCs) are able to regenerate leukemia after chemotherapy and cause leukemia relapses. LSCs are transformed from the normal blood stem cells by mutations. We found that one of the commonly found mutations NRAS is able to re-program the signaling pathways in normal blood stem cells and chamge them into LSCs. Our studies showed that Nras does this through an unexpected pathway and targeting this pathway may lead to elimination of LSCs to potentially cure leukemia.
Alveolar rhabdomyosarcoma is one of the most common children tumors. No effective therapy is available for advanced disease. Poor understanding of the etiology of the tumor is partly responsible for the lack of advancement in treatment. We are using tumor-signature events to study the cell of origin for the disease. Our results may shed light on the development of the tumor, and potentially lead to better diagnostic and therapeutic tools.
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