Prouty Pilot Projects 2006
Supporting new ideas is essential to innovative cancer research. Norris Cotton Cancer Center’s Prouty Pilot Projects play a pivotal role in helping promising scientists gather the preliminary data necessary to develop fertile new ideas. All cancer discoveries--from investigating cancer’s basic biology to creating effective treatments and methods of prevention--begin with an idea that is nurtured and supported.
Over $137, 000 in proceeds from the Prouty Bike Ride and Fitness Walk currently support 25 innovative pilot projects chosen by the directors of the six major research areas at Norris Cotton Cancer Center: cancer control, cancer epidemiology and chemoprevention, cancer mechanisms, molecular therapeutics, immunology and cancer immunotherapy, and radiobiology and bioengineering. Each project was chosen for its promise and scientific rigor.
Alexi F. Kisselev, PhD
Pharmacology/Toxicology
Design and Synthesis of Site-specific Proteasome Inhibitors
Proteasomes function like trash recycling machines in mammalian cells. They break down damaged and unneeded proteins and generate the building blocks for the synthesis of new proteins. Protein breakdown by proteasomes occurs at three active sites. Dr. Kisselev’s research explores the differences between these sites in order to generate drugs and drug combinations that are more potent and less toxic than the drug Velcade, a proteasome inhibitor that is used in the treatment of multiple myeloma and other cancers. Velcade works by temporarily blocking the action of two of three active sites. Research suggests that combining Velcade with a drug that inhibits the third site may be therapeutically beneficial. Because there are no inhibitors of this third site that can enter cells, Dr. Kisselev is synthesizing these molecules and testing their effects on laboratory cultures of cancer cells.
| Bassem Zaki, MD | Alan Eastman, PhD |
| Radiation/Oncology | Pharmacology/Toxicology |
Prediction of Chemoradiation Sensitivity and Resistance of Rectal Tumors (Radio)
The majority of patients at Norris Cotton Cancer Center with stage III rectal tumors are treated with chemotherapy plus radiation for 5-6 weeks. After an additional 6-8 weeks, the remaining tumor is surgically removed. Some patients have a dramatically positive response and can go on to have an increased life expectancy. But some patients do not respond as well. Drs. Zaki and Eastman are analyzing tumor tissue for several markers that they hypothesize impact patient response. Their focus is on proteins involved in repair of DNA damaged by chemotherapy, since preliminary results suggest that many rectal tumors may have a defect in this pathway.
| Burton L. Eisenberg, MD | William B. Kinlaw, MD |
| Deputy Director, Norris Cotton Cancer Center | Endocrinology |
| Surgical Oncology |
Differentiation Therapy for Liposarcoma: A Tissue Culture Model
Liposarcoma is a poorly-characterized malignant tumor that arises from fat tissue. The current therapeutic options for affected patients are poor. Drs. Eisenberg and Kinlaw are comparing the pattern of gene expression in liposarcoma cells with normal adipocytes, and seeing if agents that cause preadipocytes to change into fully differentiated adipose cells exert similar effects on liposarcoma. Their overall hypothesis is that fostering differentiation of the liposarcoma cells enhances their susceptibility to being killed by drugs that damage the ability of the cells to make fat.
| Constance Brinckerhoff, PhD | Alan Eastman, PhD | James DiRenzo, PhD |
| Biochemistry | Pharmacology/Toxicology | Pharmacology/Toxicology |
Diagnosis and Treatment of Basaloid Cancers of the Breast
Drs. Brinckerhoff, Eastman and DiRenzo are investigating changes in normal breast cells that make them become cancerous. Using mice with a deficient immune response, which allows them to accept human cells without rejecting them, the investigators are changing the DNA in normal cells and then determining if the changes cause cancer. If the cells are cancerous, can they invade and metastasize to other organs.
Barbara Conradt, PhD
Genetics
Identifications of Essential Genes with a Pro-apoptotic Function
Deregulating apoptosis, or programmed cell death, can lead to cancer in humans. Pioneering genetic studies with apoptosis in the nematode worm Caenorhabditis elegans resulted in the identification of key components of apoptosis, the function of which is similar in worms and humans. Dr. Conradt is using C. elegans to identify new factors that might have a role in apoptosis. She is searching for factors essential for C. elegans viability and that promote apoptosis.
| Charles N. Cole, PhD | Wendy Wells, MD |
| Biochemistry | Pathology |
Micro RNAs in the Etiology and Diagnosis of Breast Cancer
Micro RNAs are a new class of RNA. Unlike messenger RNA (mRNA), which codes for proteins, micro RNAs do not. They regulate target mRNAs by binding to them and preventing translation. Dr. Cole is examining the pattern of micro RNAs expressed in normal and malignant mammary cells and in sections from normal breast and breast tumors, hoping to gain insight into the types of genes involved in breast cancer. Micro RNA expression patterns may also have diagnostic or prognostic value.
| Patricia Ernst, PhD | Nancy Speck, PhD | Albert Erives, PhD |
| Genetics | Biochemistry | Biology |
Cooperation Between Runx1-CBFb and MLL in Establishing and Maintaining Hematopoiesis.
Dr. Ernst is gathering preliminary data to examine the relationship between Runx1-CBFβ and MLL in the development of hematopoietic stem cells. Both MLL and Runx1-CBFβ are essential for the development of blood cells, and both proteins can cause childhood leukemia when altered. Preliminary data demonstrate that both Mll mutant and Runx1 mutant animals fail to develop hematopoietic stem cells during fetal development. Dr. Ernst’s hypothesis is that both proteins work together to first establish and then maintain definitive hematopoiesis, or blood cell development. These studies will clarify the genetic pathways required to establish steady-state blood development, which are likely the same pathways deregulated in leukemia.
Hilary White, PhD
Microbiology and Immunology
Neuroendocrine Regulation of CD8+ T Cells at the Tumor Site
Immune cells, in particular CD8+ T cells (CTL) normally kill tumor cells. But using a mouse model of ovarian cancer, Dr. White found that corticotropin releasing hormone (CRH), the master stress hormone, is critical for the ability of ovarian carcinoma cells to kill CTL that infiltrate the tumor site. Blockade of CRH action was found to rescue CTL from destruction. Research with human ovarian tumor samples indicates that this stress hormone system is important in human disease as well. Dr. White is continuing her investigate into the role of CRH in ovarian cancer.
Charles L. Sentman, Ph.D.
Microbiology and Immunology
Chimeric NKG2D as Immunotherapy for Ovarian Cancer
A healthy immune system has the potential to attack specific cancer cells while leaving nearby normal cells intact. But cancer cells can interfere with a patient's normal immune response. Dr. Sentman’s research is investigating new ways to protect immune cells against cancerous cells by modifying a specific immune receptor molecule, called a chimeric receptor. Using primary ovarian tumor cells, he hopes to discover if modifying a patient's own immune cells with the new receptor allows the immune cells to recognize and attack the tumor cells.
Jose Conejo-Garcia, PhD
Microbiology and Immunology
Treatment of Ovarian Carcinoma with Cytotoxic Lymphocytes Redirect Against Vascular Leukocyte
Dr. Conejo-Garica’s research team has unveiled an indispensable role for a population of leukocytes in ovarian cancer vascularization. These cells, called Vascular Leukocytes (VLCs), are massively recruited to the tumor microenvironment, where they are transformed into endothelial-like cells. Dr. Conejo-Garcia proposes that depletion of ovarian carcinoma-infiltrating VLCs should result in the collapse of tumor vasculature. Since solid tumors cannot grow in the absence of blood vessels, impeding vascularization stops tumor growth and eventually leads to tumor death.
Brent L. Berwin,
Microbiology and Immunology
Stimulation of Host Immunity Against Tumor Cells via HSP Based Adjuvants
There is currently no successful immunological method for preventing or treating ovarian cancer. Dr. Berwin is investigating a substance that stimulates the production of an antibody, called antigens, specific to ovarian tumors, and methods to stimulate immunological responses against these antigens in order to create an anti-tumor immune response. He is also researching cell surface markers on ovarian tumors in order target these cells for immunological eradication.
Angeline S. Andrew, PhD
Community and Family Medicine
Epidemiologic Factors and Epidermal Growth Factor Receptor (EGFR) Pathway Activation
The epidermal growth factor receptor (EGFR) has become an important drug target for lung cancer therapy. Some lung tumors have alterations in this receptor that may help doctors predict how well these drugs work. The cause of these alterations remains unknown. Using data collected by the New England Lung Cancer study, Dr. Andrew is investigating possible causes by identifying exposures that occur along with alterations in lung tumors.
David J. Robbins, PhD
Pharmacology/Toxicology
Uncovering Molecular Pharmacologic Targets of Hedhehog Signaling in Cancer
Approximately 25% of all human tumors require Hedgehog (Hh) signaling, which is a family of molecules that control development, to maintain tumor cell viability. Identifying markers of Hh dependence for use in clinical diagnosis and developing potent therapeutic Hh inhibitors have become important goals in the treatment of diverse human tumors. Dr. Robbins is identifing diagnostic markers of these Hh-dependent cancers.
| Vincent A. Memoli, MD | Angeline Andrew, PhD |
| Pathology | Community and Family Medicine |
The Relationship of Carcinogen Exposure and Alterations in the EGFR Pathway in Patients with Lung Cancer
Drs. Memoli and Andrew are collecting patient lung cancer tissue samples which will be used to construct a tissue microarray that will be used to study the expression of EGFR, a growth factor receptor that plays an important role in lung cancer. They will use the DNA mircoarray to look at the expression of EGFR, Cyclin D1 expression, and related molecular markers involved in an important transcription pathway. These findings will be correlated with epidemiological information collected by the New England Lung Cancer Study.
Madeline A. Dalton, PhD, MPH
Pediatrics
Feasibility of Obtaining Biological Samples from Children Enrolled in an Ongoing Follow-up Study
Dr. Dalton is conducting a longitudinal survey of 2,500 adolescents and their parents to examine individual, family, and environmental influences on adolescent overweight, physical activity, and dietary patterns. Her pilot study is assessing the feasibility of obtaining biological samples from female adolescents participating in the study. Dr. Dalton’s long term goal is to measure steroid hormones and insulin growth factors on the full sample of adolescent girls to better understand the interrelationships between dietary patterns, physical exercise, growth, overweight, and age at menarche, and to evaluate whether these factors influence long term breast cancer risk.
Sonya Dal Cin, PhD
Norris Cotton Cancer Center, Postdoctoral Fellow
Cigarette Craving in Response to Depictions of Movie Smoking: A Pilot Study Using fMRI
Researchers here have shown that the more a teen sees smoking in movies, the more likely that teen is to try smoking. Watching smoking in movies might also influence adult smokers. Research has shown that when smokers see other people smoking or when they see pictures with smoking in them (a smoking cue), they experience an increased desire for cigarettes (craving). It is also known that smoking cues create an activation pattern in the brain. Dr. Dal Cin uses functional MRI technology to monitor the brain’s reaction to seeing smoking in movies. If smoking in movies produces the same kind of activation pattern as other smoking cues, then watching movie smoking might make it harder for people to quit, or could lead to cravings that cause a person who has quit to start smoking again.
Raine L. Riggs
Psychiatry
Sleep and Immune Function in Breast Cancer Survivors
This study is a first step toward identifying a relationship between sleep and immune functioning in breast cancer survivors. Dr. Riggs is comparing immune functioning between three groups of breast cancer survivors, including a group of good sleepers, a group of poor sleepers, and a group of insomniacs, and a group of good sleepers without a history of cancer. He believes that breast cancer survivors with disrupted sleep have greater disruptions in immune functioning than women with normal sleep. If this relationship is confirmed, future research will focus on how disrupted sleep and immune functioning impact quality of life and whether treatments for sleep disruption can improve immune functioning.
| Susan Tanski, MD | Stephen K. Liu, MD, MPH |
| Pediatrics | Preventive Medicine |
Promoting NRT in the Physician's Office: Promotional Displays and Quit Kits
Drs. Tanski and Liu are investigating whether placing nicotine replacement therapy (NRT) in the physician’s office increases the proportion of smokers who discuss quitting with their doctor and if it facilitates their attempts to quit smoking. Promotional displays for smoking cessation “quit kits” that containing tips for behavior change, numbers for Vermont and New Hampshire quit lines, and samples of multiple varieties of nicotine replacement therapies, including patches, gum, lozenges, and the nictoine inhaler, will be placed in clinical exam rooms. Researchers are also exploring if giving adults access to multiple forms of nicotine replacement therapy increases experimentation and utilization of nicotine replacement therapies, and ultimately, smoking cessation attempts.
Monit S. Kasibhatla, MD
Radiation Oncology
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Ellen L. Smith, ARNP, MSN
Hematology/Oncology
Psychometric Evaluation of Peripheral Neuropathy Measurement Approaches
Chemotherapy-induced injury to the nerves that supply sensation to the arms and legs, called peripheral neuropathy (CI-PN), is a common and distressing side effect of neurotoxic chemotherapy. The absence of simple, clinically useful, and scientifically sound neuropathy assessment approaches has contributed to a scarcity of knowledge regarding the prevalence and associated negative consequences of CI-PN. Dr. Smith’s research is collecting evidence that simplified approaches to neuropathy and associated neuropathic pain measurement are useful. Research aimed at improving symptom awareness can culminate in a patient-centered environment where symptoms can be easily reported, assessed, and ultimately controlled. Better symptom assessment could create future intervention research targeting chemotherapy-induce CI-PN prevention and treatment.
Petra Lewis, MB BS
Radiology
MRI Screening of the Contralateral Breast among Patients with Recently Diagnosed with Breast Cancer
Breast MRI can be an effective screening tool for breast tumors that may not have been detected by a mammogram or a physical exam. A contralateral breast MRI (done of the opposite breast of a woman with known one-sided breast cancer) is currently performed on all newly diagnosed breast cancer patients at Norris Cotton Cancer Center prior to their surgery on the known cancer. Dr. Lewis is exploring a number of questions. How many additional procedures (repeat scans and biopsies) are done as a result of contralateral MRI findings? How do these procedures affect the timing of surgery? Do they have an impact on patient distress? How many contralateral MRI’s result in the detection of additional cancer? Dr. Lewis’s study will help clarify whether the benefits of contralateral MRI screening on all new breast cancer patients justifies the burden, risks, and stress of the procedure.
Kenneth Meehan, MD
Director, Bone Marrow Transplant Program
CD8+ T Cells Transduced with a Chimeric NKG2D Protein: Future Treatment for Myeloma Patients
Dr. Meehan’s research hopes to demonstrate that a specific protein (NKG2D) that directs and enhances killing of tumor cells can be put into T cells from myeloma patients to specifically kill myeloma cells. The long term goal is to infuse these T cells with the protein into myeloma patients, following high dose chemotherapy and stem cell transplantation.
Ian Baker, DPhil
Thayer School of Engineering
Magnetic Hyperthermia for Cancer Treatment
Using heat to kill cancer cells has shown promise in the laboratory. In humans, however, the amount of heat needed to kill cancerous tissue can cause overheating of surrounding, healthy tissue. Dr. Baker is studying the use of iron oxide nanoparticles to heat and destroy individual cancer cells, without damaging surrounding healthy cells.
Marvin M. Doyley, PhD
Radiology
Targeted Ultrasonic Imaging:
The ability to deliver nanoparticles in a targeted manner to extravascular sites hitherto inaccessible to ultrasound contrast agents presents a new opportunity that would enhance the therapeutic and imaging capabilities of ultrasound. Dr. Doyley’s hypotheses is twofold: 1) that the availability of nucleation promoting agents based on nanobubbles would enhance the therapeutic utility of gas bubble activation and transient cavitation, and 2) the availability of echogenic nanostructures will considerably widen the range of applications for molecular imaging methods based on ultrasound. He is examining two specific aims: 1) develop methods for enhancing the therapeutic efficacy of acoustic cavitation in vivo by manipulating the nucleation process, and 2) assess the feasibility of detecting and treating metastatic tumors in local and distant lymph node by employing targeted nanodroplets in combination with acoustic cavitation. The work proposed represents a unique synthesis of existing and novel ideas that should address many of the current problems associated with creating nanometer size gas bubbles, and provide new information/documentation concerning the therapeutic utility of acoustic cavitation.
