Success Stories Fall 2014

Rosemary Akhurst, PhD
Professor In Residence, Helen Diller Family Comprehensive Cancer Center and Department of Anatomy, UCSF; Director, Preclinical Therapeutics Core Facility, Helen Diller Family Comprehensive Cancer Center, UCSF

“Optimizing preclinical mouse models for testing novel cancer immunotherapies”.

The RAP funding will jump-start this new collaborative initiative, generating pivotal data for obtaining future NCI funding in this arena. It will help provide a suitable preclinical model for testing novel immunotherapeutics that could be utilized by the UCSF community at large through the NCI-sponsored HDFCCC Preclinical Therapeutics Core facility

The ability to eradicate a malignant cancer once it has metastasized to distant sites remains one of the greatest challenges in oncology, and one most likely to be resolved using immunotherapy. Recent clinical successes with drugs, such as pembrolizumab and nivolumab that block the immune checkpoint have ushered in an exciting era in oncology. This capacity to reactivate tumor immune rejection has shown enormous promise, although many challenges remain. Some human tumor types, for unknown reasons, are refractory to this form of immunotherapy and only a fraction of cancers are fully responsive even in responding tumor types, such as melanoma. It is increasingly clear that combinations of immunotherapeutic drugs, with each other or with targeted small molecules, will be required for optimal patient responses, and the ability to predict or follow robust patient responses by development of biomarkers has yet to be achieved. Development of better mouse models that truly reflect human cancer is essential in order to address critical issues to improving clinical translatability of immunotherapy. The Akhurst lab has formed a team with the labs of Allan Balmain and Max Krummel to investigate the superiority of a chemically-induced mouse model for testing novel immunotherapeutics, based on the observations that such tumors are far more similar to human tumors than those that appear in genetically-engineered models of cancer. Specifically, chemically-induced tumors share with human tumors the extensive spectrum of single nucleotide mutations that increase tumor antigenicity, making the tumor available to immunotherapy. This novel model will be used to investigate the development of biomarkers of response and drug resistance to FDA-approved immunotherapies, as well as novel immunotherapies based on TGFb blockade.

Chloe Atreya, MD, PhD
Gastrointestinal Cancer Specialist
Helen Diller Family Comprehensive Family Cancer Center

RAP funding for Audio-Based Mindfulness Meditation Intervention for Colorectal Cancer Patients and Caregivers will support our goal to help current patients live as well as possible, for as long as possible, and to support their loved ones, whilst we continue to strive for advances in cancer prevention and treatment. A diagnosis with metastatic cancer is associated with high levels of distress in both patients and caregivers. In-person mindfulness programs are an effective means to reduce psychological distress and improve quality of life among cancer survivors, but are not practical for patients receiving ongoing chemotherapy or their caregivers. To address the need for mindfulness interventions tailored to patients with advanced cancer, we will develop an audio-based mindfulness intervention and evaluate its feasibility, acceptability and efficacy in Helen Diller Family Comprehensive Cancer Center (HDFCCC) patients with metastatic colorectal cancer and their caregivers. We will first establish patient and caregiver perceptions of audio-based mindfulness training via two focus groups among 8-10 patients and 8-10 caregivers. We will ask participants about intervention content, duration/frequency, and delivery; and perceived barriers/benefits to engaging in and adhering to mindfulness training. Focus group feedback will guide refinement of the intervention. We will then conduct an 8-week single arm study among 22 HDFCCC patients with metastatic colorectal cancer undergoing chemotherapy and 22 caregivers. Positive results from this study would provide the foundation for a definitive trial to evaluate delivery of a simple and inexpensive mindfulness intervention to reduce distress and improve quality of life, generalizable to all patients receiving chemotherapy and their caregivers.

Abigail Batchelder, MD, PhD, MPH
Postdoctoral Scholar
Osher Center for Integrative Medicine
School of Medicine

Innovative low-resource approaches are needed to optimize the benefits of treatment as prevention (TasP) among HIV+ substance users, who experience profound health disparities that amplify onward transmission risk. This RAP award will be used to develop, refine and conduct an open pilot to assess the feasibility and acceptability of an emotion regulation intervention targeting emotional barriers to HIV-related self-care among active substance users, such as internalized stigma and shame. The first phase will involve multicomponent in-person sessions that utilize transdiagnostic approaches (e.g., positive affect-focused emotional regulation, mindfulness and self-compassion) to target emotional, cognitive and behavioral barriers to HIV self-care behaviors among HIV+ substance users. The second phase will use an innovative personalized bi-directional text message platform to extend the intervention benefits by sending personalized positive self-reappraisal text messages in response to mood queries. This project will be instrumental in developing a relatively low-resource intervention strategy to address unmet emotional barriers to optimal HIV-care among individuals who are actively using substances. The resulting intervention has the potential to address unmet barriers to self-care along the HIV care cascade including retention in care, antiretroviral treatment adherence and persistence, and ultimately viral suppression.

Audrey Brumback, MD, PhD
Assistant Professor of Neurology & Pediatrics
Division of Child Neurology

Autism is associated with many genetic mutations, but how these diverse genetic changes translate into autistic behavior is unclear. I am trying to understand how different genetic defects associated with autism cause common changes in the brain’s electrical activity, and how those changes in electrical signaling contribute to autistic behavior. My preliminary results show that a specific population of neurons in the prefrontal cortex is less excitable in autism models than in typically developing mice.

The first aim of my proposal is to use in vivo calcium imaging to measure the activity of this specific population of neurons during social behavior. Because these cells are less excitable in the autism models, I predict that their activity will be decreased during social behavior. Then, as my second aim, I will use optogenetic techniques to activate and inhibit this specific population of neurons while the mouse is engaged in social behavior. I will compare results from multiple models of autism so that I can determine how distinct genetic changes converge on this specific synaptic circuit, and how modifying activity within that circuit may restore normal social function.

The skills I will acquire during the RAP award period will help me support a future R01 application using optogenetic tools to study the effects of manipulating clinically-relevant neuronal circuitry in mouse models of autism.

Bruno Biagianti, MD
Postdoctoral Fellow
Department of Psychiatry

As a physician scientist, I am interested in developing novel therapeutic interventions for schizophrenia. My long-term goals are to pursue an academic career in psychiatric neuroscience, incorporating insights from the bedside and performing clinical and basic research. I hope to use breakthroughs from neuroscience and insights from clinical experience to inform my cognitive clinical research. This RAP award would provide vital funds to support the development of CLIMB, a mobile platform that disseminates cutting edge treatments for schizophrenia (including cognitive training, automated CBT, computerized neuropsychological assessments and virtual group therapy) to individuals with schizophrenia remotely using tablets. This award would provide vital funds to support this promising study, which will be an important training vehicle for me to learn about digital health research for schizophrenia. Data from this project will generate preliminary knowledge about the impact of CLIMB on psychotic symptoms, neurocognitive functioning and quality of life. These data will also form the basis for larger grant applications, which will be an important next step in my career development. Findings from the study will set the stage for a pilot RCT that will determine the efficacy of CLIMB in improving functional outcome and quality of life in schizophrenia compared to treatment as usual. This RAP award will provide the support that would further promote my independent research career.

Myriam M. Chaumeil, PhD
Assistant Researcher
Department of Radiology and Biomedical Imaging

The goal of this RAP project is to develop an innovative neuroimaging method that can provide unprecedented information on a specific type of immune cells, namely macrophages, in Multiple Sclerosis (MS). More precisely, the method developed in this project will help differentiate between macrophages that contribute to formation of lesions (so called M1 macrophages), from the ones that promote regeneration and repair of the damaged tissues (M2 macrophages). Knowing the status of macrophages inside an MS lesion – or in the entire brain and spinal chord – would be of high interest for diagnosis, prognosis and development of new therapeutic strategies aiming at switching the macrophages from M1 to M2.

To date, the method of choice for monitoring and diagnosing MS in the clinic is Magnetic Resonance Imaging (MRI). Whereas MRI provides images of the brain structure, new imaging methods are now capable of looking at the brain function, and more precisely at metabolism. This project proposes to use, to our knowledge for the first time in MS, one of these methods, namely hyperpolarized (HP) 13C MR spectroscopy (MRS), to look at macrophage status. HP 13C MRS will be used to measure arginase and glycolysis in a preclinical MS model. The knowledge of glycolysis and arginase measured by HP 13C MRS will indicate which macrophage population is present in the different regions of the brain (M1 or M2).

This pilot study is really important, as to date, there are no available methods to differentiate between M1 and M2 macrophages in vivo, namely without altering the tissue. The knowledge of macrophage status (M1 or M2) will also serve as a basis for development, optimization and monitoring of response to innovative M2-inducing therapies. Furthermore, this project could further our understanding of the role of macrophages in the disease development.

Valy Fontil, MD
Postdoctoral Scholar
Center for Vulnerable Populations at SFGH

Hypertension is the most important treatable risk factor for cardiovascular death, yet it is inadequately treated in nearly half of at-risk adults in the United States. Community health centers (CHCs) provide care to a disproportionate share of vulnerable populations who are at highest risk for uncontrolled hypertension. Translating successful practice-based interventions to improve hypertension control at CHCs has proven difficult. This RAP award will provide start-up funds to enable utilization of rigorous implementation science approaches to adapt a multi-modal practice-based hypertension management intervention from Kaiser Permanente (KP), implement it at 12 CHCs in the San Francisco Department of Public Health Community Health Network (CHN), and evaluate its impact on hypertension control at the clinic level. Our findings could show that implementation of a KP-like hypertension management program can be successfully implemented in resource-limited, community healthcare settings to achieve improved rates of BP control in high-risk populations vulnerable to health disparities. Lessons learned from our robust evaluation can be applied to dissemination of similar interventions in other CHCs.

Moses Obimbo, MD
Department of Human Anatomy and Department of Obstetrics and Gynecology,
University of Nairobi, Kenya is the beneficiary of the International mentored Scientist Award Program in HIV/AIDS.

Dr. Obimbo will be mentored by Professor Susan Fisher and Professor Craig Cohen of University of California San Francisco (UCSF). He has proposed a translational study that will correlate HIV status of mothers who deliver preterm infants with several aspects of placental architecture this partly forming part of his work at Ob/Gyn and further research on the same subject. The goal of this study is to understand whether HIV affects placental architecture and inflammatory status in cases of preterm birth, in order to better understand the strong recognized association between HIV+ status and preterm birth. This award will enable him meet the cost study, cost of travel and stay while at UCSF. It is expected that findings from this study will form basis for future and advanced studies in this area. He is grateful to the UCSF community for this offer.

Vasant A. Salgaonkar, PhD
Associate Physicist
Thermal Therapy, Radiation Oncology

The RAP pilot grant, awarded for developing an MR-guided hyperthermia platform, will be instrumental in kick starting my career as an independent scientific researcher. My research interests are focused on technology development for minimally invasive therapy, image-guided interventions, and targeted drug delivery. Successful completion of the proposed project will allow me to further clinical hyperthermia and thermal therapy research at UCSF. Currently energy-based therapies are being investigated for several exciting applications such as cancer ablation and hyperthermia, cardiac ablations, enhanced ocular drug delivery, targeted chemotherapy with temperature sensitive liposomes, stimulation of immune response, and bone/joint/disc healing. I will be able to continue investigating these avenues by utilizing this RAP award as an excellent platform for major funding from federal and private agencies. The RAP grant will allow me to expand by network of collaborators, perform scientifically and clinically exciting research, secure additional funding, and further my career prospects.

May Sudhinaraset, PhD
Assistant Professor
Epidemiology & Biostatistics

Documenting DREAMers: Exploring Barriers and Challenges in Health Access among Undocumented Asian and Pacific Islanders in Northern California

Currently there are 1.8 million undocumented young people in the US who are eligible for a new federal program that grants them the right to live and work lawfully in the US. These individuals are known as the “DREAMers.” While the Affordable Care Act will expand health coverage to over 32 million individuals, it will purposefully exclude 11.7 million undocumented immigrants – including DREAMers. California is an exception, where low-income DREAMers are now eligible to receive health coverage through the state’s Medi-Cal program. California therefore offers a unique opportunity to study this growing but hidden population to determine how expansion of state funding will influence their health utilization patterns. Despite these DREAMers being a major public policy interest, there is a critical knowledge gap regarding who these people are and their health behaviors. Furthermore, while the majority of the migration literature in the US focuses on Latinos, there is tremendous heterogeneity across immigrant groups – including within Asian and Pacific Islanders (APIs). In fact, a significant demographic shift is occurring where APIs are now the fastest growing immigrant population in the US. Despite this, there is a dearth of information on API immigrants, particularly young immigrants. Building upon a study on Latino DREAMers, this study will be the first to investigate the health status and utilization patterns of undocumented APIs living in Northern California, and will compare and contrast Latino and API DREAMers to understand cross-national health inequities. Findings will inform health policy interventions for undocumented immigrants

Dmitri A. Young, PhD
NIMH Clinical Services Research Fellow
UCSF Trauma Recovery Center

Childhood trauma occurs at high rates and is associated with increased physical and psychological health risks over the life course. Considerable evidence implicates childhood trauma in the development of posttraumatic stress disorder (PTSD) and hypothalamic-pituitary adrenal (HPA) axis dysregulation. However investigations focusing on glucocorticoid levels have yielded inconsistent results. Heterogeneous responses to childhood trauma suggest underlying genetic differences in phenotypic expression. The single nucleotide polymorphisms (SNP) of the FK506-binding protein 51 (FKBP5) gene, associated with HPA axis functioning, has emerged as a consistent correlate of a variety of psychological distress symptoms in survivors of childhood trauma. However, past research has focused on FKBP5, childhood trauma, and PTSD symptoms in previously traumatized individuals, but not acutely traumatized individuals. Some laboratory studies have assessed the effect of FKBP5 risk alleles on HPA reactivity to an artificial trauma, but it is unclear how FKBP5 and childhood trauma interact when an individual is acutely traumatized. Furthermore, research on childhood trauma and HPA dysregulation has yielded conflicting findings. It is possible that investigating gene x environment interactions on phenotypic traumatic stress response in acutely traumatized individuals would aid in resolving these ambiguities and yield potentially clinically relevant findings. We hypothesize that interactions between FKBP5 and childhood trauma may be associated with elevated PTSD symptoms and HPA axis dysfunction. Therefore, we 1) aim to assess whether the interaction between FKBP5 SNPs and childhood trauma is associated with elevated PTSD symptoms in acutely traumatized individuals and 2) assess whether the interaction of FKBP5 SNPs and childhood trauma is associated with differences in HPA axis functioning before and after acute trauma. In addition to resolving the aforementioned inconsistencies, results from this proof-of-concept RAP proposal have the potential to further the personalize mental healthcare in community settings by using biomarkers in addition to other standard clinical data.