Barbara Ann Karmanos Cancer Institute

The Institute

The Barbara Ann Karmanos Cancer Institute (KCI) is a unique, urban-based center of research, patient care and education, dedicated to the prevention, early detection, treatment and eventual eradication of cancer.  Its objective is to apply new science to improve how we treat cancer.

KCI annually receives more than $20 million in research funding from the National Cancer Institute (NCI), nearly $18 million in additional peer reviewed funding and $9.2 million in non-peer reviewed funding.  Karmanos gains additional support from the Department of Defense, the American Cancer Society, Susan G. Komen for the Cure, private trusts and foundations, and generous donors.

The Institute operates one of the only Phase I Clinical Trials Program in Michigan, and is one of only 16 research institutes in the nation to participate in the National Cancer Institute’s Cancer Therapy Evaluation Program (CTEP).  CTEP funds an extensive national program of cancer research, and sponsors clinical trials to evaluate new anti-cancer agents.

Research at Karmanos is done in conjunction with programs for cancer patients, their families and the community as a whole.  In addition to scientists, technicians and support personnel, KCI’s staff includes social workers, nurses and physicians.  It provides home and outpatient health care and rehabilitation, as well as many other social services to cancer patients and their families.  Health education, early detection and cancer control programs bring to the public the latest information and techniques, kept up-to-date by close collaboration with the KCI’s Research Division. 

The Research Division

The Karmanos research program includes basic laboratory, epidemiological, and translational research, which connects laboratory scientists at KCI to bedside physicians and clinical researchers in our neighboring medical institutions.

Karmanos’ scientific leadership emphasizes creative and multidisciplinary approaches to cancer investigative work, based on fundamental and applied peer reviewed research.  Researchers are encouraged to engage in inter-institutional research projects, to travel to scientific meetings and symposia, and to participate in professional societies and organizations.

Karmanos Cancer Institute conducts research in three areas: laboratory, clinical and population-based research.  The five research programs within these three areas focus on breast cancer, developmental therapeutics, molecular biology and genetics, population studies and prevention, and, proteases and cancer. 

Research programs in epidemiology are focused on the industrial and racial diversity of metropolitan Detroit.  An important local and national resource for cancer research is maintained by the Epidemiology program: the population-based Metropolitan Detroit Cancer Surveillance System.  This cancer reporting system has provided information about the occurrence of new cancers and about changing cancer patterns in Detroit’s tri-county population since 1969.  It is a founding participant in the National Cancer Institute’s cancer reporting system for the United States – the SEER program.  Karmanos Cancer Institute’s local cancer surveillance system provides nearly half of the national data on cancer in the African American population and covers the largest industrial complex in the national program.

 

PROGRAMS OF THE CENTER

Regular interaction among the programs of the center through seminars, joint projects and core facilities produces not only a cooperative environment, but also a broadness of scope necessary for present-day training in the discipline of Cancer Biology.

Breast Cancer Program Overview

The Breast Cancer Program at the Barbara Ann Karmanos Cancer Institute is an integrative and comprehensive program spanning basic and translational research. The program focuses on the study of mechanisms involved in tumor progression and tumor growth. The MCF10 model of human premalignant, progressive proliferative disease and a number of SUM breast cancer lines representing multiple genomic backgrounds, are used by members for preclinical studies to determine mechanisms of growth promotion, acquirement of invasive characteristics, and resistance to therapeutic agents. Early detection, development of HER2 targeted vaccines, and assessment of early response to therapeutic interventions are also high priority goals of program members. 

Specific aims for the breast cancer program include:

1. Elucidating the genomic and proteomic changes involved in the progression from normal to malignant breast epithelium;
2. Unveiling molecular mechanisms by which extracellular signaling molecules such as growth factors and extracellular matrix components regulate specific cellular processes;
3. Identification of subsets of oncogenes that are activated in distinct subsets of breast cancer;
4. Analysis of cell signaling resulting from EGFR and HER2  oncogene activation;
5. Oncogenomic analysis of aggressive breast cancers to allow custom therapy for specific cancers;
6. Developing novel immunological controls of tumor growth involving fine tuned balancing of autoimmunity and anti-tumor activity;
7. Defining further the genetic epidemiology of breast cancer in African Americans;
8. Development of high-throughput analysis of serum antibodies to develop neural networks of markers for early detection.

 

Population Studies and Prevention Program Overview

The Population Studies and Prevention Program conducts research in three major areas:

1. Cancer Etiology and Prognosis, population-based studies of cancer etiology, survival and race/ethnicity related health disparities;
2. Prevention, studies designed to prevent and/or control the development and progression of cancer within this population, and
3. Communication and Behavioral Oncology, understanding the role of communication and behavior in determining how to best improve health care.

 

Goals for the Population Studies and Prevention Program include identifying risk factors for both disease onset and progression, and developing and testing cancer intervention and prevention strategies. 

 

Molecular Biology and Human Genetics Program Overview

The Molecular Biology and Human Genetics Program analyzes the genomic information from studies of organisms from yeast to humans in the discovery and functional analysis of novel genes responsible for cancer predisposition in “high risk” families as well as in sporadic cancers.  Cancer development is associated with a series of changes in cellular genes.  These changes occur as mutations or variations in gene expression in cancer causing genes and in other genes which respond to them.  Genetic alterations provide molecular signatures specific to each tumor type.  Cancer susceptibility genes frequently cause “genomic instability” in which cells develop DNA damage in critical cancer-causing genes such as oncogenes and tumor suppressor genes.  Either germline or somatic mutations affect proteins involved in signal transduction, such as growth factor receptor pathways or transcription factors, leading to changes in gene expression.  Similarly, epigenetic changes can occur in the germ line or in somatic cells.  Studies in human populations at extreme risk for cancer can be applied to the general population in which the genetics of cancer risk is subtler.

This Program currently focuses on the mechanisms of genomic instability, chromatic structure, cell cycle checkpoint control, transcriptional regulation of signal transduction, and post-translational control mechanisms.  The Program utilizes cell lines and whole animals to model the genetic mechanisms leading to precancerous cells, the molecular signatures of precancerous lesions, and the critical genetic evens in the progression of these cells to neoplasia.  Because of the extensive body of genetic information on DNA repair genes and growth control mechanisms in model organisms, this Program applies the genetics of yeast and mouse model systems to understand human gene structure and function.  The Program is analyzing the human homologues of well-characterized DNA repair and checkpoint genes for their role in genetic and sporadic human cancers.  These genetic mechanisms will provide useful molecular targets for early detection, chemoprevention and chemotherapy.  This body of knowledge also provides a novel approach to cancer risk determination in special populations.

There are 39 scientific members participating in one or more of the research interests within this program.  The specific aims the Molecular Biology and Human Genetics Program include:

1. Analyzing mechanisms of genomic instability, DNA repair and cell cycle control as germline and somatic genetic events;
2. Applying mechanistic lower eukaryotic models to cancer relevant genes and processes;
3. Determining genetic networks of regulatory mechanisms of transcriptional and intracellular signaling in the development of human tumors, and
4. Translating genomics/proteomic technology to clinical problems.

 

Developmental Therapeutics Program Overview

The Developmental Therapeutics Program leads the Karmanos Cancer Institute’s effort in developing, understanding and testing new treatments for cancer.  The Program is involved in the synthesis of new compounds directed at specific targets, as well as the refinement of newly identified compounds.  These compounds are initially studied using in vitro systems and animal models prior to testing by the Phase I Clinical Trials multidisciplinary team.  The Program develops new agents and approaches to be studied in clinical trials.

The Program uses new approaches to understanding and improving tumor response to chemo-and radiotherapy, which includes studies of drug pharmacodynamics and the analysis of pathways of drug metabolism and resistance in normal tissue and tumor samples.  The Program is also expanding the use of novel non-invasive imaging approaches (PET, MRI) that measure tumor growth, perfusion and drug kinetics, and is evaluating these approaches in phase II and phase III trials. This research is conducted as part of investigator-initiated trials at Karmanos, as part of multi-center studies and in national trials through numerous cooperative groups.

While the basic goals of the Program remain constant, the focus and approaches used by the Program have evolved over time.  In the past, large-scale screening of natural products and inventories of compounds played a large role in the Program.  Efforts at drug screening are now directed at studying improved analogs developed by researchers as part of structure-function studies.  At present Karmanos investigators focus on obtaining a better understanding of drug pathways and finding ways to improve the prediction of response.  A better understanding of the mechanism of action will help to tailor therapy to individual patients.  Part of this effort also involves the development of new imaging modalities to speed the assessment of drugs in the pipeline.  Using PET, MRI and US, Karmanos scientists are testing new drugs to gain a rapid measure of their metabolic effects and what is the best schedule and route.  Imaging is being used to measure the distribution of drugs and improved mechanism of delivery.  Such technologies are vitally important in determining if a drug has promise or should not be considered for further study. Because of the expense and time involved in bringing a new therapy to the clinic, the Program has four specific aims:

1. Identifying significant and novel molecular entities for preclinical and clinical development;
2. Improving therapies and obtaining a better understanding of the mechanics of therapeutic action;
3. Developing improved imaging techniques to assess tumors and their response to treatment, and
4. Demonstrating that Institute approaches lead to significant improvement in patient response and survival in the Clinical Trials Program.

 

Proteases and Cancer Program Overview

The Proteases and Cancer Program at the Barbara Ann Karmanos Cancer Institute concentrates on four major areas of research:

1. The tumor microenvironment, including tumor/host interactions, and how it alters proteolysis,  and the impact of this on antiprotease therapies;
2. The mechanisms (gene to protein) that regulate activation and inhibition of proteases, and how can they be used to develop more efficacious inhibitors or alternative anti-protease strategies in vivo;
3. Proteases and their endogenous inhibitors, and how they function in normal developmental and non-cancerous pathological processes, with the goal of identifying new therapeutic targets, and
4. Identifying the critical proteases and their functions in cell death and differentiation.

 

The Proteases and Cancer Program currently studies proteases of the five endopeptidase classes.  In terms of protease inhibitors, program members are performing structure-function analyses on endogenous protease inhibitors (e.g., tissue inhibitors of matrix metalloproteinases, plasminogen activator inhibitor-1, maspin and cystatins), designing and testing known and novel synthetic inhibitors for matrix metalloproteinases, cysteine (calpain and cathepsin) and aspartic HB-EGF (annexin II heterotetramer, caveolae). 

The Program directs its translational efforts toward developing novel protease inhibitors as potential therapeutic agents, determining whether interactions that may modulate protease-associated functions might serve as novel targets for therapeutic intervention, and developing novel methods and probes for in vitro and in vivo imaging of protease activity.  There are four collaborative subprograms which explore these research areas, with considerable crossover among the subprograms and other Programs.

 

Bench to Bedside

Karmanos also conducts translational research which seeks to interface laboratory scientists with Karmanos physicians and clinical researchers. The Institute's scientific leadership emphasizes creative, multidisciplinary approaches to cancer investigative work, based on fundamental and applied peer reviewed research. The Institute's senior scientific staff is actively encouraged to engage in inter-institutional research projects, to travel to scientific meetings and symposia, and to participate in professional societies and organizations.