2013 Dixon Translational Research Grant Awards Announced
NUCATS and the Northwestern Memorial Foundation are pleased to announce the 2013 Dixon Translational Research Grant awardees. The Dixon Translational Research Grants are awarded to Northwestern investigators for highly innovative, multi-disciplinary clinical and translational research collaborations that accelerate the identification and implementation of new treatments to improve human health. There were three different categories of awards this year:
Project Title: Ipilimumab and Gemcitabine for Advanced Pancreas Cancer: A Phase Ib Study
Award Amount: $25,000
Pancreatic cancer is the 4th leading cause of death in the United States and, despite advances, continues to have poor prognosis and an overall 5 year survival rate of 3-5%. There is an urgent need to overcome this aggressive disease by developing alternative and complementary modalities of therapy. Pancreatic tumors are highly immunogenic, encouraging immune intervention as a complement to conventional chemotherapy. However, little is known about the immune pathology of cancer, which is a prerequisite for design of effective immune therapies. This proposal will take advantage of a Phase1b investigator-initiated clinical trial to elucidate defects in systemic immunity and response to a potent immune stimulating reagent in inoperable pancreas cancer patients. In this trial, patients will be treated with standard gemcitabine chemotherapy in combination with ipilimumab, a human anti-CTLA4 antibody. We will investigate immune parameters in peripheral blood and tumor specimens and evaluate clinical benefits produced by this combination therapy as compared to treatment with gemcitabine alone. This investigation will provide important insight into the immune pathology of pancreatic cancer and the mechanism of action of ipilimumab. The knowledge gained will help shape the rationale for future targeted immune therapy of pancreas cancer.
Project Leader: Daniela Menichella, MD, PhD, Department of Neurology
Project Title: CXCR4 Chemokine Receptor Signaling in Painful Diabetic Neuropathy
Award Amount: $25,000
Diabetes affects 25.8 million people in the USA. Neuropathic pain is a debilitating affliction present in 26% of diabetic patients. Despite this significant impact and prevalence, the molecular mechanisms underlying neuropathic pain in diabetes are not known and current therapies are only partially effective. Given that Chemokine Stromal-cell-derived-factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) signaling has been implicated in the pathogenesis of neuropathic pain in animal models, I tested the hypothesis that SDF-1/CXCR4 signaling has a role in neuropathic pain in High Fat Diet (HFD)-induced diabetic mice. I demonstrated that administration of a selective CXCR4 antagonist AMD3100 reverses neuropathic pain in HFD-induced diabetic mice. Furthermore Dorsal Root Ganglia (DRG) sensory neurons, acutely isolated from HFD-induced diabetic mice, display enhanced SDF-1 induced calcium influx. On the basis of these exciting preliminary results, the goal of this application is to further establish that chemokine SDF-1/CXCR4 signaling in DRG nociceptive neurons has a crucial role in neuropathic pain in diabetes. The overall impact of this proposal is a better understanding of the molecular underpinnings of neuropathic pain in diabetes. Furthermore, these studies will serve as the template for drug development of this currently intractable and widespread debilitating affliction.
Project Leader: Laura Rasmussen-Torvik, PhD, MPH, Department of Preventative Medicine
Project Title: The association of targeted exonic variants and post-surgical weight loss
Award Amount: $25,000
The incidence of bariatric surgery is increasing, but there is variation in long-term weight loss after the procedure. With the recent presentation of exome sequencing project results, the location and frequency of many population-level exonic variants is now known. Preliminary studies have suggested that rare population-level exonic variants in one gene detected through obesity GWAS, MC4R, are meaningfully associated with weight loss after bariatric surgery. We propose to use funds from the Dixon Young Investigator Award to genotype all population-level exonic variants in genes surrounding the 32 loci identified in the largest GWAS of obesity to date in participants of NUGene who have undergone bariatric surgery. In NUgene, we estimate that there are 370 patients with DNA samples who have undergone bariatric surgery, most more than 5 years ago. Electronic health records will be used to assess patterns of weight loss after surgery. Advanced statistical modeling will be used to determine which variants are associated with post-surgical weight loss. Genetic testing for any variants predictive of long-term weight loss could potentially be implemented in the near term, to help patients in their decision making process before surgery and to help tailor long-term follow-up care for those choosing to undergo surgery.
Project Leader: Qiang Wen, MD, PhD, Department of Medicine, Division of Hematology/Oncology
Project Title: Developing MLN8237 as a therapeutic agent for myeloproliferative neoplasms
Award Amount: $24,324
Myeloproliferative neoplasms (MPNs) comprise a group of clonal hematological malignancies that include essential thrombocytosis (ET) and primary myelofibrosis (PMF). Megakaryocytes in patients with ET are hyperproliferative and that those in PMF fail to undergo normal differentiation or polyploidization. Currently, there are no effective therapies that offer the possibility of clinical/molecular remission or cure for ET and PMF. We performed a high throughput screen and identified small molecules, including dimethylfasudil (diMF), which induce polyploidization and proliferative arrest of malignant megakaryocytes. diMF blocked the growth of primary human acute megakaryoblastic leukemia (AMKL) blasts both in vitro and in vivo, a disease in which the malignant megakaryoblasts are hyperproliferative and fail to undergo polyploidization. Multi-approach target identification showed that Aurora kinase A is the key target of diMF. MLN8237, a selective inhibitor of Aurora kinase A, increases polyploidization, expression of megakaryocyte differentiation markers, and apoptosis of murine and human megakaryocytic cell lines and primary cells including those that express MPLW515L, the activating mutation in ET and PMF. Here we propose the study of efficacy of MLN8237 in MPN patient samples and in a murine model of MPN. The study may lead to a clinical trial of MLN8237, which is under intensive clinical studies in multiple cancers. (back to top)
Project Title: Antibacterial Surgical Sealants for Enhanced Healing of Biofilm-Infected Wounds
Award Amount: $50,000
Chronic wounds associated with several medical conditions affect a startling portion of the population. For example, the number of people suffering from diabetes worldwide has been estimated at 350 million. Up to 25% of diabetic patients will develop chronic foot ulcers, which are at high risk for infection and can lead to amputation. While antibiotics have the potential to lessen the complications associated with infections, bacterial evolution and adaptation can render these compounds useless. Bacterial biofilms further complicate management of wounds due to increased treatment resistance and inhibition of wound closure. Chitosan, a non-antibiotic biopolymer, has shown tremendous promise as a biomaterial due to its wound-healing properties and pH-dependent antimicrobial behavior. In this project, we propose to test the ability of a novel, antibacterial hydrogel in promoting wound healing in infected and non-infected models. This medical sealant is based on a hydrogel composed of poly(ethylene glycol) and chitosan that has been modified to contain permanent positive charges. In vitro assays and in vivo models will be used to determine the efficacy of this material in killing bacteria, disrupting biofilms, and enhancing wound healing.
Project Leader: Melina Kibbe, MD, Department of Surgery, Division of Vascular Surgery
Project Title: A Novel Therapy to Treat Atherosclerosis
Award Amount: $50,000
Cardiovascular disease due to atherosclerosis remains the leading cause of death in the United States. Percutaneous interventions to treat atherosclerotic plaque induce mechanical or thermal injury to the vessel wall, which stimulates the development of neointimal hyperplasia and results in arterial restenosis. The objective of this study is to evaluate a new methodology in a preclinical animal model to reduce atherosclerotic plaque burden without inducing mechanical trauma to the arterial wall. Our paradigm-shifting technology is based on a safe method of digesting the atherosclerotic plaque in situ through the use of a specialty double balloon occlusion catheter we will develop. We hypothesize that a digestion solution containing agents that specifically target the components of plaque will dissolve and digest the plaque in situ within a clinically relevant timeframe. The specific aims of this proposal are to: 1) design and fabricate a specialty double balloon occlusion catheter to deliver our therapy to the vasculature in vivo, and 2) evaluate the safety and efficacy of our therapy in a preclinical atherosclerotic animal model. Overall, this therapy has the potential to have an enormous impact in the clinical arena, given the number of percutaneous interventions that are performed annually to treat atherosclerosis.
Project Leader: Josh Levitsky, MD, MS, Department of Medicine, Division of Gastroenterology and Hepatology
Project Title: Delayed Chimerism Induction in Liver Transplants with Bioengineered Marrow Cells
Award Amount: $50,000
There is a great need to develop strategies to facilitate safe, effective withdrawal of immunosuppression in liver transplant recipients. The induction of donor-specific tolerance through durable chimerism while avoiding GVHD would be transformational. We have developed a protocol that reproducibly induces tolerance in living donor kidney transplant recipients. Fifteen highly mismatched kidney recipients were conditioned and transplanted with G-CSF-mobilized donor hematopoietic stem cells processed to retain tolerogenic CD8+/TCR- graft facilitating cells (FCRx). Many have developed durable chimerism and weaned off immunosuppression without GVHD. However, this simultaneous approach does not translate well to ill patients undergoing liver transplantation, where a delayed approach with reduced conditioning would be safer and more practical. This Dixon Innovation Award proposal will test a delayed tolerance approach using a preclinical rat liver transplant model for which we have demonstrated success in a similar kidney/tissue transplant model. The goal is to evaluate the efficacy of the delayed approach in achieving tolerance and to determine if reduced intensity conditioning has similar efficacy with less toxicity in liver recipients—to prepare for more tolerable clinical applications. These findings will be immediately translated to a phase 2 NIH grant submission for delayed tolerance induction utilizing FCRx in human liver transplantation.
Project Leader: Kevin McVary, MD, Department of Urology
Project Title: A Novel "Smart Stent" for Treatment of Obstructive Uropathy
Award Amount: $50,000
Obstructive uropathy is structural or functional hindrance of normal urine flow that affects both adults and children and leads to progressive renal dysfunction if untreated. One of the hallmarks of obstruction is elevated pressure in the urinary tract which can initiate a cascade of inflammation and altered renal blood flow that leads to fibrosis and irreversible kidney damage. Ureteral obstruction, a subset of this group, is treated primarily with ureteral stenting. Unfortunately, it is unclear when these stents need to be changed for patients that have chronic obstruction, leading to early and frequent stent changes every 3-4 months for patients with chronic obstruction at a hospital charge of approximately $3,000 with a trip to the operating room and exposure to ionizing radiation. To reduce the frequency of stent changes and a more accurate monitoring of the kidney and bladder health, we are working toward a "Smart Stent", that is a minimally-invasive solution for monitoring intrarenal pelvic pressures to indicate the functional status of the stent, thus allowing the clinician to know when it is appropriate to change the stent. It does so without the use of ionizing radiation, and furthermore provides early real-time clinical data. The new device is a self-monitoring and diagnostic tool able to measure pressure in different points of the genitourinary (GU) tract and the pressure difference between the renal pelvis and the bladder. It can monitor pressure trends and its readings from the kidney would indicate if alternative treatments should be considered. Immediate cost-savings benefits would be accrued with reduced trips to the OR for unnecessary and expensive procedures by reducing the uncertainty associated with the time of stent changes. The smart stent works with a passive wireless tag. This means that it does not contain a battery or other energy source; the power is supplied by the reader under the form of magnetic induction. We strongly believe that the smart stent will be a powerful diagnostic tool not provided with present technology which will provide clinicians with data to guide the treatment of obstructive uropathy. (back to top)
Project Title: Sleep Disturbance and Metabolic Syndrome
Award Amount: $297,052
Sleep disturbances affect nearly 25% of the general population and nearly 50% of patients with cardio-metabolic disorders. Growing evidence indicate a strong link between insufficient sleep and increased risk for cardio-metabolic disorders. In this application, we propose to employ novel clinically applicable technology using sound waves to stimulate deep slow wave sleep (SWS), the stage of sleep that is most closely linked to cardio-metabolic function. This represents an exciting technological breakthrough because the acoustic system can be adapted to an individual’s sleep pattern. We hypothesize that enhancement of SWS will improve cardio-metabolic function in adults with disturbed sleep. The specific aims are: 1) To determine a dose and duration of stimulation required to achieve a 10% increase in SWS in middle age and older adults; and 2) To determine the effect of the stimulus on cardio-metabolic function in patients with sleep disturbance and increased risk for cardiometabolic disorders. The project proposes an innovative interdisciplinary approach that capitalizes on Northwestern Medicine's strengths of its sleep, cardiovascular and metabolic clinical and research centers to discover novel treatments for the interacting epidemics of sleep disorders and metabolic syndrome, and to establish a unique interdisciplinary center of excellence that combine these clinical and research programs. (back to top)