Role of Cryptic Activation Site within B1 Integrins in Breast Tumor Growth

Peter Brooks, Ph.D.
Maine Medical Center Research Institute, Scarborough

Recent studies suggest that a group of molecules call Integrins play critical roles in breast cancer and some work has suggested that they may actually reduce the effectiveness of certain types of chemotherapy. Our laboratory has generated an antibody that only recognizes an activated form of these molecules. The unique characteristics of this new antibody (FM155) allow us the opportunity to target these Integrins in a highly selective manner. Thus, we have proposed to evaluate the effects of combining FM155 with chemotherapy to examine whether this unique strategy may enhance the effectiveness of existing therapy for the treatment breast cancer.

MicroRNA Expression during Lung Tumor Progression

Julie Wells, Ph.D.
The Jackson Laboratory, Bar Harbor

Lung cancer is the leading cause of cancer deaths worldwide.  The genes and mechanisms that mediate metastasis, or spread, of pulmonary adenocarcinoma, the most common type of lung cancer, are poorly understood.  The objective of our work is to identify which microRNAs are present and how their abundance and function changes during the progression from early-stage to late-stage pulmonary adenocarcinoma.  MicroRNAs are a class of recently discovered small, regulatory molecules.  Knowledge of which genes and molecular pathways are important during tumor progression will lay the foundation for predicting which lung tumors are likely to become metastatic and for identifying molecules for chemotherapeutic intervention.

Regulation of Hematopoietic Stem Cells by Heparin Binding Domain of IGFBP-2

Anne Breggia, Ph.D.
Maine Medical Center Research Institute, Scarborough

Successful bone marrow transplantation is an important therapeutic option for both blood and solid organ cancers. Increasing the number of stem cells prior to transplantation increases the likelihood of successful transplantation. Insulin-like growth factor binding protein 2 (IGFBP-2) is a potent stimulus for proliferation of mouse and human stem cells. We have made a 13 amino acid peptide of the heparin binding domain unique to IGFBP-2 and will investigate the ability of this peptide to expand the number of stem cells in cell culture and to test the functionality of these cells in mouse models of human bone marrow transplantation. Our ultimate goal is to use this peptide therapeutically for improvement of bone marrow transplant outcomes and to better understand the regulatory cell signaling mechanisms operational in the bone marrow stem cell niche.

Notch Signaling in Medulloblastoma Initiation and Cancer Stem Cell Maintenance

Kyusun Yun, Ph.D.
The Jackson Laboratory, Bar Harbor

According to a recent report by the Center for Disease Control, Maine has the highest incidence rate for brain cancer among the 50 states. This study focuses on medulloblastoma, the most common pediatric brain tumor, with the goal of elucidating the role of the Notch signaling pathway in medulloblastoma formation, maintenance, therapy resistance, and recurrence. We will analyze cancer stem cells (cells responsible for therapy resistance and tumor recurrence) from a new mouse model we generated and medulloblastoma patient samples. We anticipate that our findings will provide new insights into cancer stem cells in medulloblastomas and reveal molecular characteristics of a medulloblastoma subtype, knowledge that can be used to improve diagnosis and patient management strategies.

Computational Pathology: 3-d Analysis of Chromosome Territories

Andre Khalil, Ph.D.
University of Maine, Orono

Although changes in the architecture of the cell nucleus as well as chromatin structure have long been recognized as hallmarks of many cancers the precise architectural transitions that occur during tumorigenesis are essentially unknown. There is a pressing need for new rigorous methods for quantitative measurement of highly detailed microscopy images. The objectives of this proposal are to acquire large amounts of images, to quantitatively measure normal nuclear architecture by combining high-resolution 3D imaging with new image analysis tools and to apply this analysis to probe structural transitions in nuclei during the tumor progression. Realization of these goals will hasten the development of computational pathology approaches that measure structural states of nuclei in patient samples to achieve accurate, early, sensitive cancer diagnoses.

Genetic Chemotherapy: Inducing Leukemia and Lymphoma Cell Self Destruction

Kevin Mills, Ph.D.
The Jackson Laboratory, Bar Harbor

Current standard of care in leukemia and lymphoma treatment often involves intensive, sometimes long-term chemotherapy. Such treatments can be difficult and physically taxing for the patient, and can sometimes last for months or years. One major problem with current cancer treatments is the damage done to otherwise healthy tissues. This can lead to long-term consequences for cancer survivors, including immune system defects, cognitive problems, and new treatment-induced cancers. Most of these devastating side-effects could be potentially mitigated by selectively treating the cancer cells, without affecting surrounding normal cells. This project aims to develop an alternative to standard chemotherapy that we term “genetic chemotherapy” -- in which cancer-specific genetic features could be exploited for cancer cell self-destruction, thus minimizing side effects in non-cancer tissues. If successfully implemented, genetic chemotherapy could improve treatment and survivorship for some leukemia/lymphoma patients by better destroying the cancer cells while simultaneously preserving normal healthy tissues.

Evaluating MicroRNA’s as Prognostic Determinants in Stage II Colon Cancer

Matthew Dugan, D.O.
Maine Center for Cancer Medicine, Scarborough

Early stage colon cancer treated with surgery alone has a small, but real, risk for recurrence elsewhere in the body. Treatment with chemotherapy greatly reduces this risk for a small proportion of patients, but carries other health risks associated with drug treatment. Patients with early stage colon cancer must choose between these alternatives. A test that can determine which early colon cancers have an aggressive tendency (very likely to recur and spread) and those that are unlikely to recur would greatly benefit patients and their oncologists. A recently discovered type of bio-molecule known as microRNA shows promise in distinguishing aggressive from non-aggressive early colon cancers. This work is aimed at developing a predictive test based on microRNA profiles of colon tumors.

Targeting Stromal Cell Interactions to Reduce Prostate Cancer

Calvin Vary, Ph.D.
Maine Medical Center Research Institute, Scarborough

Prostate cancer is the second leading cause of cancer-related death in the United States among men and is the most commonly diagnosed cancer in American males. Endoglin is a constituent of the transforming growth factor-beta receptor signaling system that is involved in prostate cancer cell migration, invasion, and metastasis. In an endoglin-dependent mouse model of prostate cancer previously developed with MCF support, we find that mice that are deficient in endoglin develop prostate tumors that lack supporting stromal cells, which arise from the tumor microenvironment. We will use this model of prostate tumor-stromal cell interaction to study the ability of pharmacologic inhibitors of endoglin function to target the prostate cancer microenvironment.