The reasons why cancer patients do or do not participate in cancer (clinical trials) research are complex. Often this is due to the lack of awareness of which studies are occurring by both the patient and their primary care clinicians. Another very important reason is that patients, especially patients that do not speak English, are not invited to participate because the research team does not have non-English speakers or study materials in the patient’s language. We at the UC San Diego Moores Cancer Center (MCC) have the opportunity to better understand and address low clinical trials participation among our largest under-represented racial/ethnic group, Hispanics. Working with a multidisciplinary team of physicians and non-physician scientists, we propose to 1.) Educate community providers about breast cancer trials at MCC, and 2.) Assess specific interests and needs among the MCC breast cancer team, and combine this with existing evidence, including interview findings (knowledge and Hispanic from a recent (2016) V Foundation grant), to develop and implement minority clinical trial accrual training for the MCC breast cancer team. By focusing on minority breast cancer patients, V Foundation funds complement and expand our emerging efforts to increase minority clinical trials enrollment (accrual) and related outreach and inform how to intervene with MCC patients, providers, and leadership. We are particularly interested in targeting Hispanic breast cancer patients because they are the largest minority group in San Diego County, the region served by the MCC.
The Duke Cancer Institute and the College of Veterinary Medicine at N.C. State University formed a Comparative Oncology Consortium (COC), taking advantage of their expertise and national leadership in their respective disciplines and their geographic proximity. The goals are to collaborate in pre-clinical and clinical cancer research activities in order to advance our understanding of both cancer causation (a high incidence of specific cancers in specific dog breeds provides opportunities to identify new cancer susceptibility genes and environmental factors in cancer causation) and of behaviors and genetics of specific tumor types, as well as to coordinate clinical trials in humans and canines so that novel therapies can be tested in both settings, with information gained in one setting informing the other. In addition to response outcomes of these cancer therapies, the ability to use biomarkers and pharmacology in the canine models can be a novel addition to the characterization of these new cancer therapies and these insights could result in significant enhancements of clinical trial designs (including dosing, scheduling, and combination therapies) when these treatments are tested in human clinical trials. Cost savings and improved clinical trials design would help encourage pharmaceutical companies to use the canine models as part of the assessment process and would benefit the canine patients by giving them access to these novel therapies.
Funded in partnership with WWE in honor of Connor’s Cure
Medulloblastoma is the most common malignant brain tumor in children. There are four distinct forms of this tumor based on its gene profiles, and a form known as Group 3 medulloblastoma is the most aggressive and deadly, which accounts for 25%-30% of all medulloblastoma. Each medulloblastoma group has distinct abnormal gene expression that determines how it creates, grows, and spreads tumors. Changes in gene behavior, like overexpression or underexpression, are controlled by what is called epigenetics. Fortunately, we know how to manipulate epigenetics with drugs. Dr. Hu and his colleagues found two epigenetic components that play important roles in controlling gene expression in tumor. Interestingly, these two epigenetic components seem to work together: when one component is suppressed, the other increases, and vice versa. A gene called MYC is very active in many cancers including Group 3 medulloblastoma. In this project, Dr. Hu’s team will characterize these two epigenetic components to understand more precisely how they work, particular in controlling MYC expression, even further, they will test in the lab whether “drugging” these epigenetic factors can halt the growth and spread of medulloblastoma tumors. If this hypothesis is proven, it may be possible to use these drugs in combination to treat this devastating childhood cancer.
The goal of “Campaign to Improve Access to Clinical Trials” at The University of Arizona Cancer Center (UACC) is to increase the clinical trial access to a diverse population in Arizona. Dr. Pavani Chalasani, Breast Cancer Disease Oriented Team Leader, will oversee the campaign to improves access by involving the breast multidisciplinary team, patient navigators and physician liaisons to develop educational materials and outreach programs. Patients and community physicians will be targeted through proposed outreach programs by developing targeted educational materials. Materials and training will be provided to introduce and educate about clinical trials to patients early by various members of their cancer team. The goal of this campaign is to become a model for other disease teams and cancer centers to implement to improve clinical trial enrollment.
First year of this Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Robin Lail
Triple negative breast cancer (TNBC) is breast cancer that lacks HER2 and ER/PR receptors. Because most treatments are based on having these markers, TNBC is hard to treat. Additionally, TNBC often spreads to the brain (brain metastasis), which is even harder to treat. Radiation therapy (RT) is a standard local therapy for TNBC brain metastases; however, survival is less than 6 months.
Immune cells (found throughout the body) fight invaders like viruses, bacteria and cancer. However, cancer cells are highly adept at hiding from immune cells. Immunotherapies are being tested to help immune cells fight cancer better. There have been promising results using immunotherapies to treat brain metastases. We have shown that TNBC brain metastases have a higher number of immune cells called tumor infiltrating lymphocytes (TILs) compared to TNBC in breasts. More importantly, we found that patients with a higher number of TILs in their brain metastases live longer. Adding RT to immunotherapies can help immune cells to fight cancer. We will use mouse models to test this strategy, which will lead to a clinical trial in humans. We expect immunotherapy will also treat cancer inside and outside of the brain at the same time, which will improve the lives of patients facing this disease. We also want to find more signals in brain metastases (biomarkers) that will guide selection of the right immunotherapy for each patient. New biomarkers will help us treat the right patient, at the right time, in the right way, with immunotherapies.
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.
