WCC News - December 2012
Local Group Awards Second Seed Grant for Breast Cancer Research Initiative
The Wilmot Cancer Center’s donor-driven Breast Cancer Research Initiative has awarded its second $25,000 seed grant to a URMC researcher. At a gathering held last month at the headquarters of Constellation Brands, the group awarded a grant to Regine Choe, Ph.D., whose lab focuses on diffuse optical methods based on near-infrared light illumination, which offers great potential for detection of breast cancer and monitoring the efficacy of treatments.
In 2011, a group of Rochester-area women with the desire to give back to their community came up with an idea for raising funds to support breast cancer research. They dubbed their endeavor the Breast Cancer Research Initiative - the very first seed grant award for breast cancer research at the James P. Wilmot Cancer Center.
The group is led by Carol Mullin, Megan MacKenzie, and Josephine Trubek, and has grown to more than 25 members, many of whom are breast cancer survivors. They meet two to three times a year to discuss the newest research discoveries – inviting Wilmot physicians and scientists to present to them - and talk about their own experiences in dealing with the disease.
Through their personal contributions, the group raised $25,000 during its first year alone, and has now exceeded $70,000. Constellation Brands, Inc., has also lent support to the program, agreeing to match future donations to the initiative up to $25,000. To date, two seed grants of $25,000 each have been awarded to Wilmot researchers. Helene McMurray, Ph.D., received the first grant, which is being used to support her research efforts in finding cancer cell-specific vulnerabilities in breast cancer.
Philanthropic seed grants are extremely important, enabling scientists to launch promising research initiatives and helping them generate results and data that help qualify them for larger government or foundation funding to support their next phase of study. These funds are pivotal and very difficult for young researchers to acquire. The group’s mission is to raise $25,000 every year, making this an annual award.
“It’s because of the advances in breast cancer research and treatments over the last decade that I am here today, and this is just one small way I can give back and show how grateful I am for the care I received,” says Mullin.
Investigators Gather for First Wilmot-Roswell Park Collaborative Science Workshop
Generous local philanthropy has enabled seed funding for collaborative cancer research projects involving investigators from both the James P. Wilmot Cancer Center and the Roswell Park Cancer Institute in Buffalo with the goal to foster strong interactions between both institutions. Two rounds of grants were awarded competitively in mid 2011 and early 2012 to a total of 16 research teams. All 16 teams met November 9 in Rochester for the first progress report and discussions. Over 50 scientists and physicians discussed their mostly inter-disciplinary work from a large variety of fields. Examples of some of the most exciting new developments arising from these collaborations are summarized below:
Lymphoma Translational Research
Francisco J Hernandez-Ilizaliturri MD1, Paul Barr MD2, Seema Bhat MD1, Steve Bernstein MD2, Cory Mavis MS1, Myron S. Czuczman MD1, Carla Casulo MD2, Jennifer Kelly PhD2, and Jonathan Friedberg MD2. 1Roswell Park Cancer Institute, 2James P. Wilmot Cancer Center,
Acquired resistance to treatment of cancer cells hinders the clinical outcome in a significant number of patients with non-Hodgkin lymphoma (NHL). Despite currently available treatments, approximately 70,130 new non-Hodgkin lymphoma (NHL) cases and 18,940 deaths have been estimated in the United States for 2012. Scientific efforts must now be focused not only in defining the pathways developed by lymphoma cells to evade immunochemotherapy, but also to develop novel therapeutic strategies to overcome it. As a result, a group of Wilmot and RPCI investigators formed a collaborative group aimed to: 1) define key signaling pathways relevant to the development of therapy resistant in B-cell lymphoma; 2) pre-clinical evaluation of novel agents targeting relevant pathways; 3) identification and validation of biomarkers that predict response to a particular targeted agent(s) investigated; and 4) translate results of our pre-clinical modeling studies into rationally design clinical studies. The group has identified several key regulatory proteins suitable for therapeutic targeting of Mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). These include
the Mammalian Target of Rapamycin (mTOR), the ubiquin-proteasome system (UPS) components, histone deacetylases (HDAC), and members of the Bcl-2 and inhibitory of apoptosis proteins (IAP) protein families. Current plans are to expand innovative approaches to target the B-cell receptor signaling/mTOR pathway and to move pre-clinical studies results into a Phase I/II clinical trial for relapsed/refractory lymphoma patients to be opened in both institutions.
Bone Marrow Microenvironment in Human Hematological Malignancies
Kelvin Lee, MD (RPCI), Eunice Wang, MD (RPCI), Craig Jordan, PhD (WCC/URMC).
The research seeks to understand the central elements of the bone marrow microenvironment that support the survival and resistance to therapy of human hematological malignancies. The significance of the work proposed arises from the observation that most of the hematologic malignancies are critically dependent on interactions with the bone marrow (BM) microenvironment (ME) for survival, even in advanced and end-stage disease. These interactions thus represent potentially important therapeutic targets, and when interdicted may result in tumor cell killing through mechanisms that are completely different than (and complementary to) conventional cytotoxic chemotherapies. However, the specific cellular and molecular components involved in the human BM ME - cancer cell interactions are largely unknown. Nor do we understand with any certainty how the ME modulates the hematologic cancer cell, how the cancer cell modulates the ME, and relatedly how the cancer “grows” the essential supportive niche beyond the normally tightly regulated number/size to allow for disease progression.
Project 1. Role of marrow vasculature and oxygenation in hematopoietic cancers (Project Leader, Eunice Wang, MD) hypothesizes that the vascular microenvironment in the bone marrow plays a critical role in supporting the survival and expansion of malignant hematopoietic cells. This has been well defined in the solid tumors but largely unexplored in the hematological malignancies. Furthermore, leukemic cell adaption to hypoxia may serve to protect them against chemotherapy-induced cell death.
Project 2: Marrow microenvironment role in the therapeutic response of cancer stem cells (Project Leader, Craig Jordan, Ph.D) hypothesizes that the bone marrow microenvironment influences the survival of cancer stem cells (CSCs, in leukemia and multiple myeloma) upon challenge with therapeutic agents. While a CSC “niche” has been postulated by many reports based on normal hematopoiesis, the understanding of what this niche is and how such a microenvironment could regulate survival of CSCs is extremely limited.
Project 3: The tumor-supportive immune microenvironment in the bone marrow (Project Leader, Kelvin Lee, MD) hypothesizes that since the hematopoietic malignancies are immune cell cancers, the essential components of their supportive microenvironment are normal immune cells that are not performing their immunological function - but rather are acting as stroma as traditionally defined.
Cooperation Response Gene Signature as a Prognostic Indicator for Recurrent Disease in Prostate Cancer
Justin Komisarof1, Laurel Newman1, James Mohler2, Carl Morrison2 and Hartmut Land1
James P. Wilmot Cancer Center1 Rochester, NY and Roswell Park Cancer Institute2 Buffalo, NY
One of the central goals for the molecular analysis of cancer is the development of rational approaches to identifying effective prognostic indicator systems for predicting disease progression and/or treatment response. Identification of patients at high-risk of disease recurrence or treatment failure will allow early application of adjuvant therapies for cancer. Prostate cancer is unique in that an estimated 50% of men newly diagnosed in the U.S. are over-treated due to inability to distinguish the indolent from lethal phenotype. Discovery of relevant bio-markers should include differential gene expression signatures. Due to complexity of cell regulation, gene expression signature selection has been based on correlative information, mostly biased by cell type identity and indiscriminate of functional relevance of the chosen gene set to the cancer phenotype. They presented data suggesting that a gene signature based on cohorts of genes essential to the cancer phenotype, termed cooperation response genes (CRGs), can identify the aggressive phenotype of prostate cancer and enable robust stratification of treatment outcome. This was made possible by a previous discovery in the Land laboratory demonstrating that genes synergistically deregulated in response to cooperation between oncogenic mutations, i.e. CRGs are dramatically enriched for critical drivers of the cancer cell phenotype, and the availability of the invaluable RPCI Pathology Resource Network with its large biorepository of cancers with clinical annotation of long-term follow-up.
Micro-environmental Interactions Between Lung Adenocarcinomas and Host Cells
Yasmin Thanavala PhD (RPCI) and Richard Phipps PhD (JPWCC/UR)
The microenvironment promotes and shapes the growth of malignant cells. Within the tumor microenvironment, a dynamic crosstalk exists between the malignant cells and the host cells, including immune cells. There is a significant body of literature detailing the mechanism by which various mediators alter the tumor microenvironment. However, there are several gaps in our understanding of how this milieu influences the interaction between tumor cells, stromal cells, and immune cells. Understanding the factors that comprise this milieu and its impact on tumor growth and cancer therapies has emerged as a major area of investigation. This collaboration is designed to address how two important inflammatory mediators in the respiratory tract impact on the host response and affect lung cancer growth. Cigarette smoke is itself an inflammatory mediator, and it further induces pulmonary inflammation by damaging the respiratory epithelial barrier, thereby facilitating repeated infections. These infections along with cigarette smoke exposure, establish a milieu of chronic inflammation in the lungs of smokers. Most models of respiratory inflammation simply evaluate the impact of either smoke exposure or infection alone, neglecting that the combination of several inflammatory mediators creates a unique microenvironment that may have an additive effect on both lung adenocarcinoma growth and on the function of the host’s cellular response to the malignancy. Their hypothesis was that chronic smoke exposure prior to chronic infection would lead to an elevated inflammatory response that would create a pro-malignancy environment in the lungs.
The studies revealed that exposure to smoke followed by repeated respiratory infections severely compromises various arms of both innate and adaptive immunity. The general pattern is one of increased inflammation but decreased anti-microbial response. Thus, we find augmented lung inflammation with an influx of more macrophages and neutrophils and less lymphocytes into the airways as enumerated in the BAL. Increased levels of pro-inflammatory cytokines were also found in the BAL in the mice subjected to the dual inflammatory insults. Impairment of adaptive immunity was supported by the result that smoke exposed mice made less antibodies and T cell responses to key antigens on the bacteria with which they were infected. Their studies have direct clinical implications for treating respiratory infections and vaccinating against respiratory infections in smokers and patients with COPD. In ongoing experiments, we are now evaluating how chronic pulmonary inflammation affects the frequency and severity of lung adenocarcinomas in transgenic mice that develop lung adenocarcinoma via a conditionally activatable allele of oncogenic K-ras.
Genomics of the Neoplastic Progression of Barrett’s Esophagus
Irwin Gelman, Ph.D. (RPCI) and Jeffrey Peters, MD (Wilmot)
Barrett esophagus (BE) is defined as a metaplastic process where the esophageal stratified squamous epithelium is replaced by intestinalized columnar epithelium. These changes are thought to be caused by chronic gastroesophageal reflux disease (GERD) and evidence confirms that BE is the most important risk factor for the development of esophageal adenocarcinoma (EAC). Despite a low incidence of neoplastic progression (0.5-1.0% annually), the risk of a Barrett's patient developing EAC is 30-125 times higher than the general population and this cancer is the most rapidly increasing cancer in the Western world. BE likely progresses to EAC in a stepwise pattern similar to that of colon cancer, with progressive dysplasia mediated by accumulated genetic mutations. Newer data suggest that metaplasia without goblet cells may represent a precursor to BE since this still predisposes to cancer development. The five-year survival for EAC limited to the mucosa is 83-90%, whereas it is less than 15% for advanced disease. While early diagnosis clearly improves prognosis, patient survival would be enhanced by the prevention of EAC or the ability to identify high risk BE populations. Attempts to identify genomic markers of progression have been confounded by small cohort groups and by failure to isolate pre- and neoplastic cells by techniques such as laser capture microscopy (LCM).
Both Wilmot and RPCI have active BE surveillance and treatment programs. BE, dysplasia and EAC samples, as well as genomics data obtained and analyzed at each center will be shared so as to better develop an early BE genomics signature that might predict progression to malignancy. The Wilmot group focuses on DNA changes such as single nucleotide polymorphisms (SNP), mutations or copy number variations (CNV), the RPCI group focuses on next-gen-based assays to detect differential gene expression, exon use variation and some gene mutations/translocations, using techniques such as RNA-, exome- or miRNA-seq. Wilmot has a unique bank of columnar cell metaplasia with or without goblet cells, whereas RPCI has a significant bank of high-grade dysplasias (HGD). The bases for the Wilmot-RPCI collaboration include: i) larger numbers of BE cases available to both groups, insuring greater probability of identifying patients with neoplastic progression, ii) sharing of biopsy samples for complementary genomic analyses, iii) sharing best-practice standard operating procedures (SOP) for the isolation of BE, HGD, or EAC DNA/RNA by laser capture microdissection (LCM), and iv) sharing unique sample banks (HGD and BE +/- goblet cells).
Gary Morrow, Ph.D., M.S., Receives 2012 Davey Memorial Award for Outstanding Cancer Research
Gary Morrow, Ph.D., M.S., received the 2012 Davey Memorial Award for outstanding cancer research, presented November 15 during the James P. Wilmot Cancer Center’s 17th annual Scientific Symposium. The annual symposium celebrates the leading-edge cancer research of University of Rochester Medical Center physicians and scientists. Morrow’s presentation, Three Decades of Paradigm Shifts in Cancer Control: An Eyewitness View, presented an overview of the huge gains made in helping cancer patients control many of the sometimes debilitating side effects of cancer treatment.
Over the span of a 36-year career, Morrow has made landmark contributions to research related to cancer survivorship and symptom management. As the head of Community Clinical Oncology Program (CCOP) Research Base at the Wilmot Cancer Center, Morrow has helped position the University of Rochester Medical Center and its multidisciplinary team of investigators at the forefront of cancer control research.
The CCOP program at URMC is part of a national network of clinical research programs that develops, conducts, monitors, and evaluates clinical trials and trains researchers. Oncologists and patients look to the CCOP network to inform their decisions on care and treatment, with a particular focus on side effects of cancer therapy such as fatigue, insomnia, shortness of breath and nausea. The UR CCOP has been in existence since 1983, making it a leading resource in the country. It was the first CCOP Research base funded in a cancer center in the U.S.
In addition to his personal achievements related to helping improve the lives of cancer survivors, he has been instrumental in the development and training of a new generation of scientists dedicated to the same pursuits. For his effective leadership role in mentoring more than 50 young professionals in medicine and science, Morrow in April received the Distinguished Research Mentor Award for 2012 from the Society of Behavioral Medicine (SBM). The SBM award recognizes those who have shown an outstanding commitment to training and mentoring, resulting in a major impact on the field of behavioral medicine.
Morrow is a professor of Radiation Oncology and professor of Psychiatry at URMC. He has been the principal investigator on eight cancer-control grants, totaling more than $40 million, funded by the National Institutes of Health, American Cancer Society, and Department of Defense, and has presided over or been a member of several cancer review panels and councils. He holds dual undergraduate degrees from the University of Notre Dame and Master’s and Ph.D. degrees in clinical psychology from the University of Rhode Island.
The Davey Memorial Award for Outstanding Cancer Research was established in memory of R. Bruce Davey, who was treated for cancer before his death in 1996. His wife, Linda Wells Davey, and sons, Peter and Jeffrey, created their own significant way to join Rochester’s fight against cancer. Linda Wells Davey served on the Cancer Center Board, dedicated to advancing local research and care, and served as its first chair.
URMC/Wilmot Staff Recognized for Excellence
Luke Peppone, Ph.D. and Michelle Janelsins, Ph.D., researchers in the Cancer Control group at URMC, were awarded Career Development Grants by the American Cancer Society during an event held last month for honorees and donors from the Rochester area.
Sharon Swift RN, outpatient BMT Coordinator, was co-winner of the Federation of Social Workers Human Service Worker of the Year Award for the private sector.
Congratulations to Mike Ellis, MSW, who served as team captain for the Wilmot Cancer Center team that participated in the “Light the Night” fundraiser for the Leukemia and Lymphoma Society. Mike’s team raised more than $3,100.