January 2013 - Abstracts
Role of STAT3 signaling in proliferation and survival of DLBCL cells
Jiyong Zhao and Craig Jordan
Diffuse large B cell lymphoma (DLBCL) is an aggressive and the most common type of non- Hodgkin’s lymphoma, accounting for 30% to 40% of lymphoid malignancy. Current therapies, such as R-CHOP, cure approximately 60% of the DLBCL patients.
The remaining patients, however, either do not respond to initial treatment or relapse after initial response, and die of the disease. Therefore, identifying and targeting new vulnerabilities in DLBCL may lead to new therapeutic strategies for this malignancy. STAT3 signaling controls cell proliferation, survival, inflammation, migration and angiogenesis. Aberrant activation of STAT3 has been associated with diverse human cancer types, and it is generally accepted that the activated STAT3 contributes to tumorigenesis. Constitutive STAT3 signaling has also been observed in DLBCL patient specimens, and high STAT3 signaling is associated with worse prognosis of the disease.
Our preliminary results indicate that all subtypes of DLBCL cells require STAT3 signaling for proliferation and survival, extending previous observations that only a certain subtype of DLBCL cells depends on STAT3 signaling for growth. We thus hypothesize that STAT3 signaling is essential for the growth of DLBCL and that targeting STAT3 signaling may represent a promising approach for the treatment of DLBCL. The proposed research seeks to establish a role for STAT3 signaling in the proliferation and survival of DLBCL cells both in vitro and in vivo, and will explore the pathways leading to STAT3 activation. Most importantly, we will evaluate whether targeting STAT3 signaling can be exploited as a potential treatment strategy for DLBCL. Overall, this proposal is designed to obtain sufficient preliminary data to support a new R01 application.
Nonsense-mediated mRNA decay as a molecular filter for apoptotic transcripts
Lynne Maquat, Max Popp, and Damon Runyon
Abstract. Nonsense-mediated mRNA decay (NMD) is a quality control pathway that destroys transcripts bearing a premature termination codon. This proposal seeks to determine how NMD impinges upon apoptosis, a process thought to be impaired in many cancers.
Hypothesis. The overarching hypothesis is that NMD sculpts the transcriptome by pruning those transcripts from the pool of actively translated mRNAs that contain the cis-acting elements (uORFs, alternative exons or introns, etc.) that render them NMD targets. We further hypothesize that the cell is able to actively tune NMD to suit its needs through cleavage of the key RNA helicase UPF1, resulting in a loss of function. Here we seek to expand on the example of apoptosis, particularly in the context of breast cancer. Our belief that cells actively modulate NMD to accomplish different cellular outcomes is a novel and far-reaching concept that in all likelihood will be extended to other examples in the future.
Specific Aims. We have discovered that caspase-mediated cleavage of UPF1 is induced by a diverse array of apoptotic insults in a wide range of species and in a broad collection of cell types, including human breast adenocarcinoma. To investigate the biological significance, we propose the following aims:
Map the site of caspase cleavage in UPF1 by site-directed mutagenesis, and determine how UPF1 cleavage affects NMD activity.
Inventory the apoptosis-specific transcripts affected by UPF1 cleavage (and as a consequence, modulated by NMD) using the Single Nick In Proteome (SNIPer) chemical genetic method and investigate how these changes impact the apoptotic process.
Dyadic Exercise Intervention for Cancer Survivors and Caregivers
Charles Kamen, Gary Morrow, Karen Mustian, Michelle Janelsins, Supriya Mohile, Mohamed Tejani, Jim McMahon, and Charles Heckler.
Overview: Cancer causes psychological distress in both cancer survivors and their non-professional caregivers. Exercise has been shown to reduce distress in survivors through improving immune function; however, few studies have delivered exercise interventions to caregivers and no studies have compared individual interventions to interventions delivered to survivor/caregiver dyads. A standardized exercise intervention, EXCAP©®, has been efficacious in reducing psychological distress among cancer survivors. This intervention has not yet been delivered to survivor/caregiver dyads. We hypothesize that providing EXCAP to survivors and caregivers will reduce distress in both individuals relative to an intervention delivered to survivors alone, both by improving individual immune function and by increasing support within the dyad. Reducing distress in survivor/caregiver dyads has the potential to ameliorate the public health burden of long-term cancer care by improving caregiver functioning. Thus dyadic interventions represent an innovative and patient-centered addition to cancer control research.
Research Design: Dr. Kamen proposes to extend previous work establishing the efficacy of EXCAP (a daily, 6 week, progressive walking and resistance training program) by conducting a two-arm pilot study, randomizing 30 survivor/caregiver dyads (total N = 60; 30 survivors 1-12 months post treatment plus 30 caregivers; 15 dyads per arm) to either an individual EXCAP intervention delivered to survivors (Arm 1) or a dyadic EXCAP intervention delivered to survivors and caregivers (Arm 2). The primary aim will compare baseline to post-intervention change in distress among survivors, caregivers, and dyads in the individual versus dyadic arm; secondary aims will compare change in immune biomarkers and dyadic support between arms.
Multidisciplinary Oncology Research (MORe)
Katia Noyes, John Monson
Abstract: Cancer imposes a tremendous burden on modern society, including morbidity, mortality, and resource utilization, with projected costs of cancer care approaching $157.77 billion in 2020.1 New compelling evidence suggests that cancer patients have better outcomes when managed by well-trained multi-disciplinary specialist groups using standardized management protocols.2-5 Patients managed by multi-disciplinary teams (MDT), especially those associated with Centers of Excellence, have been shown to have oncologically more appropriate management (according to the National Comprehensive Cancer Network (NCCN) guidelines),6 lower rates of readmission, cancer recurrence, and complications, better functional outcomes and satisfaction, and more efficient resources utilization. However, a significant proportion of cancer patients and subsequently survivors in the United States do not receive high quality MDT-based care.7-9
The primary goal of this program is to develop a new collaborative research center with shared research infrastructure to improve quality of cancer patient care and patients outcomes, both clinical (survival, recurrence, readmissions, and complications) and patient-centered (functional status, satisfaction with care, and economic burden of illness) through increased use of MDT-based care. Current and future research areas include, but are not limited to improvement of provider communication, reductions in institutional fragmentation, better alignment between payment and quality disincentives, integration among information systems, and finally, incorporating patient perspective on illness into the process of cancer care.
The center will bring together currently disconnected outcomes research groups at the University of Rochester Medical Center (URMC) and Wilmot Cancer Center (WCC) interested in cancer patients, including Surgical Health Outcomes and Research Enterprise (SHORE), Division of Health Policy and Outcomes, Geriatric Oncology Program, Palliative Care Group, Department of Urology, Cancer Survivorship Program, Center for Community Health, and the Department of Biostatistics and Computational Biology. Establishing shared core research infrastructure with consistent goals and mission will allow a wider range of investigators to develop competitive and successful research projects and proposals in the area of cancer outcomes and quality improvement and respond quickly to RFAs and PAs. In additional, having such an infrastructure will reduce the tremendous inefficiency associated with re-hiring and re-training research staff for individual externally funded projects.
The program of research will utilize existing administrative (such as Hospital Consortium database)10 and clinical (such as National Surgical Quality Improvement Program (NSQIP) database11 and National Cancer Data Base (NCDB)12, URMC and area electronic medical records system (EPIC and RHIO)) databases as well as conducting primary prospective data collection on patient and physician-reported outcomes and preferences. The multidisciplinary
research team includes clinical practice experts (surgeons, urologists, palliative care specialists and medical oncologists with expertise in outcomes research), health services researchers, quality of medical care experts, and public health professionals in close collaboration with University of Rochester, Strong Memorial Hospital, and area leaders in cancer care and quality improvement. Successful launch of the center will build upon our previous studies and facilitate new proposals rapidly and in a cost effective manner, that address the research priorities of the National Institute of Health, Agency for Healthcare Research and Quality (AHRQ), Patient-Centered Outcomes Research Institute (PCORI), Center for Disease Control (CDC), Department of Defense (DoD) and Veterans Administration (VA), Center for Medicare and Medicaid Innovation (CMMI), American Cancer Society (ACS), Clinical and Translation Science Institute (CTSI), State Department of Health (NYS DoH), Excellus/BCBS and private foundations.
Wilmot Cancer Center Program Grant
Noble, McMurray, Hicks, Skinner
Basal-like breast cancer (BLBC) is an aggressive, hard-to-treat cancer, with high rates of metastasis and tumor relapse, and poor long-term survival rates. These phenotypes are associated with a great deal of heterogeneity within the tumor cell population, facilitating cancer cell growth in foreign tissues, and allowing outgrowth of chemo-resistant cells following chemotherapy.
Examples from other disease paradigms, including hard-to-treat cancers as well as management of HIV and tuberculosis, suggest that the most efficacious way to target a heterogeneous, highly mutable population is by combination therapy aimed at core vulnerabilities of the disease entity. But how do you define such a strategy for cancer cells? Existing attempts at developing multi-drug therapies for cancer have focused on combining existing therapeutic approaches with newer therapies targeted at mutated cancer drivers. Although these approaches enable some enhancement of survival, they still have an unacceptably high failure rate, and have not produced significant gains in BLBC patient survival.
Our strategies represent a very different approach to targeting BLBC core vulnerabilities. We target regulatory architectures underlying BLBC transformation, but which are not due to mutational changes in the proteins targeted. At least some of these changes appear to be a consequence of cooperating oncogenes, while others may be regulated in other ways. We find that these key features confer phenotypic changes essential for tumor generation, maintenance and resistance to therapy. Moreover, while these changes appear to be essential in BLBC cells, they often are not essential for the function of non-cancer cells, thus providing cancer-specific targets.
Dissection of these newly discovered vulnerabilities in BLBC provides insight into new kinds of combination therapies based on simultaneously targeting multiple components of the underlying signaling architecture of transformation. Unlike efforts in which the establishment of a new class of compound is required, our focus is almost entirely on repurposing agents approved by the FDA for other purposes. Repurposing exploits the fact that virtually all drugs have multiple targets and activities, harnessing novel activities of compounds for which clinical information already exists. We have obtained substantial evidence to support the feasibility of this approach. As a result, we are now in the unusual position of being able to focus on rational combinations of compounds already approved by the FDA for other purposes or already in use in clinical trials.
New therapeutic approaches to neuroblastoma
Neuroblastoma (NB) represents 7% of all childhood cancers outside the CNS and is responsible for 15% of all childhood cancer deaths. Improvements in treatment have led to a 5-year survival of approximately 70%. Survival varies widely, however, with different age groups and also with different degrees of malignancy and metastasis, with long-term prognosis for older patients being particularly poor. In addition, 30% of survivors demonstrate neurological consequences attributed to age and laminectomy, as well as an increased risk of secondary neoplasms .
Moreover, patients treated with multi-modality therapies are twice as likely as those treated with surgery alone to develop any of a variety of chronic health conditions. Thus, although treatment of NB has certainly improved, there remains an urgent need both to improve treatments and to develop treatments that are less toxic than current therapies.
The foundation of our work: Our cancer studies are focused on: (i) discovery of intervention points that are critical for tumor generation and/or maintenance in tumors of multiple origins; (ii) identification of means of pharmacologically targeting these potential intervention points, and (iii) integration of our discoveries with promising advances from other laboratories so as to further optimize disruption of tumor cell function. All work is carried out with a focus on developing strategies that target tumor cells with minimal toxicity for normal tissue.