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2010 Prouty Pilot Project Awards

The following Cancer Center research projects in the basic, clinical, and population sciences received Prouty Project funding for one year.

Prouty Pilot Project awards support the development of creative new cancer research and the initial data needed to apply for national funding.

Project: "Melanoma-specific T central memory cells for use in clinical trials"

Principal Investigator: Marc Ernstoff, MD
Co-Principal Investigators: Mary Jo Turk, PhD
Ed Usherwood, PhD
Zbigniew (Ziggy) Szczepiorkowski, MD, PhD

Research Summary: Human metastatic melanoma provides an excellent human model in which to explore high dose IL-2 based therapies. This year, an estimated 53,600 cases of melanoma and 7,400 deaths will occur in the USA. The overall survival of MM patients remains dismal with a median survival of 7-12 months. Treatment to date has had little effect on survival. Prolonged survival in a minority of MM patients is most frequently seen in high dose IL-2 treated individuals. New immunological therapies provide the best strategy for successful treatment of metastatic disease. The work proposed here will allow us to pursue additional NIH funding for clinical trials.

Project: "Developing anti-tumor immune response against ovarian cancer using Toxoplasma"

Principal Investigator: Steven Fiering, PhD
Co-Principal Investigators: David Bzik, PhD
Jose Conejo-Garcia, MD, PhD

Research Summary: "The crucial missing aspect of successful ovarian cancer therapy is the elimination of relapse after initial treatment. One potential therapeutic approach to prevent ovarian cancer recurrence would be to complement current therapeutic approaches for the primary tumors with an immunotherapy that stimulates an effective antitumor immune response to block recurrence over the long-term. This proposal explores a novel tumor vaccine approach to developing the antitumor immune response against recurrent ovarian cancer."

Project: "Clinical relevance of lipoprotein lipase and dietary fat uptake by breast cancers"

Principal Investigator: William Kinlaw, MD

Research Summary: "…this work may provide valuable biomarkers in the near term, and disclose a novel set of therapeutic targets in the medium term. Moreover, the elucidation of a mechanistic link between diet and breast cancer outcome may have therapeutic and public health implications as well."

Project: "A pilot study to explore the possible association between insulin glargine (Lantus) use and cancer."

Principal Investigator: Stephen Liu, MD, PhD
Nancy Morden, MD, PhD
Co-Principal Investigators: Murray Korc, MD
Jonathan Skinner, PhD

Research Summary: Patients with Type 2 diabetes mellitus have an increased risk of colon, breast, and pancreatic cancer. The contribution of insulin treatment to the elevated cancer risk remains largely unknown. As insulin and insulin growth factor-1 (IGF-1) have been shown to be growth factors for tumors in vitro, it is possible that exogenous insulin administration could alter the insulin-IGF-1 axis and promote the progression of malignant cells in vivo. Compared to human insulin, glargine has greater IGF-1 receptor activity in cancer cell lines and thus may have greater potential for tumor promotion in diabetic patients.

In July 2009, several European studies were published that examined the association of glucose lowering medications and cancer risk in diabetic patients. Overall, no definitive conclusions could be drawn from these studies but certain sub-group analyses suggested treatment with glargine insulin was associated with increased risks of certain types of cancers.

This combination of basic science evidence, inconclusive but suggestive population based studies, and the large number of patients currently treated with glargine insulin, have prompted concern among clinicians and patients. In this pilot study, we propose to further explore the possible association between glargine insulin and cancer through a retrospective cohort study of diabetic patients enrolled in Medicare Parts A, B and D.

Project: "Setting the stage for health eating: A pilot study to develop materials for an innovative web-based program for young children"

Principal Investigator: Meghan Longacre, PhD

Research Summary: The overarching goal of this proposal is to develop and evaluate specific elements of a novel, interactive Web Show to encourage healthy eating patterns among young children. To achieve this goal, we propose an innovative partnership with an experienced team of creative visual and performance artists to develop a compelling, research-informed live performance puppet show prototype, called “Gabriel’s Kitchen,” for pre- and early-elementary school aged children. We will adopt a social marketing approach to build positive connections with healthy foods and present them as humorous, exciting and irresistible.

Through the current pilot study, we aim to: develop and evaluate the script, storylines, and themes; develop and evaluate two-dimensional character depictions; create costumes, puppets and sets, and evaluate a live stage performance; and develop an animated prototype of the interactive web show. A community panel of children in grades 3-5 from two distinct geographic locations will provide ongoing character and storyline feedback throughout the development process. The live performance show will be performed and tested with a total of 60-120 children. Multimethod evaluation incorporating both quantitative observation data and qualitative open-ended data will test children’s receptivity to specific performance elements. Dartmouth Film Study students will use the evaluation results to create an initial prototype for the interactive web show. Results from the current study will be used as pilot data to inform a large-scale funding proposal to fully develop the interactive web show and test its effectiveness at improving children’s healthy eating behaviors.

Project: "Breast cancer risk-associated SNPs impact transcription factor recruitment"

Principal Investigator: Mathieu Lupien, PhD

Research Summary: Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths in North American women. Current screening approaches include profiling for risk-associated single nucleotide polymorphisms (SNPs). These correspond to single base pair differences in the genome of individuals that significantly increase their likelihood of developing breast cancer. While this approach is useful for geneticists, it is currently under-exploited clinically because no function is ascribed to any of the eighteen breast cancer risk-associated SNPs. This is due to the fact that risk-associated SNPs typically map to non-coding genomic regions, which excludes their role in protein sequence alterations. Hence, no specific treatment can be offered for personalized medicine. In the long-term, our results will pave the way for the development of newer approaches directed against SNP-associated (single nucleotide polymorphisms) mechanisms in breast cancers.

Project: "A novel platform for cell-based cancer therapeutics"

Principal Investigator: Charles Sentman, PhD

Research Summary: We propose to use allogeneic cells from healthy donors as a source of effector cells. To make tumor-specific effector cells that do not cause graft-vs-host disease, we will express a tumor specific receptor, such as chNKG2D, and remove the endogenous T cell receptor by inhibiting mRNA components for the TCR/CD3 complex. This technology will allow cell-based therapy to go from being a process to being a product. A product that can be created in advance, tested, controlled, stored until needed, and infused into many different patients. Advantages include a much lower cost of therapy, immediate availability for patients, high quality anti-tumor effector cells, and a treatment for patients that are unable to generate autologous effector cells. This platform can be used with a variety of tumor targeting receptors allowing a means to target many types of cancer.

Project: "A strategy for targetig pluripotent cancer stem cells"

Principal Investigator: Michael Spinella, PhD
Co-Investigators: Vincent Memoli, MD
Ethan Dmitrovsky, MD

Research Summary: We propose that DNMT3B may be both a molecular target and biomarker of 5-aza sensitivity in EC and that low dose 5-aza treatment has the potential to be the first “targeted” therapy for TGCTs. This knowledge has the potential to result in more effective use of 5-aza and other epigenetic drugs alone, or in combination with conventional therapies, to advance cancer patient care. This work will contribute to our understanding of how targeting epigenetics regulates the biology of pluripotent cancer stem cells.

Project: "MicroRNAs in delineating prognostic risk groups in chronic lymphocytic leukemia"

Principal Investigator: Gregory Tsongalis, PhD
Co-Principal Investigators: Prabhjot Kaur, MD
Deborah Ornstein, MD
Co-Investigators Larry Dumont, PhD
Claudine Bartels, PhD

Research Summary: MicroRNAs are expressed in a tissue-specific manner and they have been implicated in the pathogenesis of several human cancers including chronic lymphocytic leukemia (CLL). Our study aims to validate the utility of a microRNA profile in the prognosis of CLL patients as it is the most common form of leukemia found in the Western world. CLL is a disease of the elderly and this indolent disorder can evolve into an aggressive lymphoma with a very variable clinical outcome. In this proposed study, we will validate the claims that specific miRNAs can be used as prognostic indicators in CLL by profiling CLL cases for miRNA expression using the FlexmiR v2 miRNA assay (Luminex, Austin, TX) and correlating these findings to traditional pathology correlates for CLL.

Project: "Vitiligo induction as post-surgical adjuvant therapy for melanoma"

Principal Investigator: Mary Jo Turk, PhD
Co-Principal Investigator: Marc Ernstoff, MD

Research Summary: Memory T cell responses are believed to be crucial for long-term immunity to cancer, but little is known about forming durable memory to tumor antigens that are also self-antigens. We hypothesize that the key to long-term tumor protection lies with the induction of acceptable autoimmunity against the normal tissue counterpart of the tumor. The proposed research will determine the extent to which autoimmunity leads to better T cell memory against cancer. If successful, it will also generate a broad platform for induction of long-lived tumor protection post-surgery. These studies employ melanoma as a model system, but findings will apply to other excisable solid tumors in cases where tissue-specific autoimmunity is acceptable (e.g. breast, prostate, ovarian cancer). These studies have immediate and obvious relevance to cancer. We will apply vitiligo (autoimmune melanocyte destruction) inducing therapies for the innovative purpose of post-surgical tumor immunotherapy, and investigate these therapies from the novel perspective of their effects on long-lived T cell memory. Immunotherapy for the treatment of minimal residual disease is a pragmatic concept with enormous potential which has been drastically understudied.