BACKGROUND

Breast cancer is mostlikely to become fatal when cancerous cells metastasize, or spread, to other parts of the body. In fact, more than 90% of cancer mortalities are due to cancer that has metastasized. Although breast cancer shows a propensity to spread to the bone, very little research has been conducted on the mechanisms of metastasis and ways to minimize or prevent this occurrence.

Dr. Danny Welch, a Professor of Pathology at the University of Alabama, Birmingham and the Director of NFCR's Center for Metastasis Research, is a leading scientist in cancer metastasis research. Since 1996, he has led a team of researchers attempting to identify which genes in our body suppress metastasis and how their metastasis-suppressing function is regulated by other parts of the biological system. A more complete understanding of the metastatic process would facilitate more effective medical intervention to prevent or treat metastasis. This would particularly benefit patients with later-stage breast cancer.

THE CHALLENGES

Even after successful removal of a primary tumor, cancer patients still live under the constant fear that a few cancer cells have escaped the surgery, and that these cells may eventually become secondary tumors in other locations of the body. Presently, there has been insufficient research on the root cause of metastasis, which means that there are no effective medical strategies to prevent or stop cancer once it has spread. Although chemotherapy drugs are used to inhibit the cancer metastasis, this form of treatment often leads to debilitating side effects which diminish the quality of life for patients and their families.

There is an urgent need f or better methods to prevent and treat metastasis. Due to the complex nature of this aspect of cancer, extensive research collaboration among scientists is essential to tackle this problem. Critical as it is, research funding in this field is severely limited. Of the $6.2 billion dollars allocated to the National Cancer Institute for cancer research, less than 1% of that budget focuses on research trying to understand the fundamental mechanisms of cancer metastasis. More funds and efforts need to be allocated to this critical cancer research field.

THE OPPORTUNITY

The National Foundation for Cancer Research (NFCR) is a global leader among private charitable organizations dedicated to fighting cancer. NFCR provides the world's best scientists with both "adventure" funding -- to encourage them to explore and discover -- and sustained funding -- to encourage them to translate their discoveries from the lab bench to cancer patients.

In order to address the challenges facing cancer metastasis research, NFCR established the NFCR Center for Metastasis Research in 2001 at The Pennsylvania State University, and elected Dr. Danny Welch, an innovative leader in the field of metastasis research, as the Director of the Center. In 2003, Dr. Welch moved to the University of Alabama at Birmingham and reestablished the Center.

With NFCR funding, Dr. Welch and his team have made great progress on many fronts of cancer metastasis research which has created opportunities for further significant advances in diagnosis and treatment of metastatic cancers.

The following is a list of key published accomplishments by the NFCR Center for Metastasis Research under the leadership of Dr. Welch:

• Discovery of the KISS1 and BRMS1 metastasis suppressor genes.

• Recognition of the first metastasis suppressor pathway in cancer cells (CRSP3/TXNIP/KISS1).

• Discovery that KISS1 and BRMS1 expression results in tumor cell dormancy after cells have seeded secondary (ectopic) sites.

• Utilized fluorescently-tagged tumor cells to study the earliest steps in cancer metastasis to bone for the first time. This method led to discovery that one of the first things tumor cells do when they seed bone is to eliminate bone-forming cells (osteoblasts).

• Defined molecular pathways regulated by BRMS1 (PtdIns(4,5)P2; chromatin-regulated gene expression and microRNA regulation) using genomic and proteomic analyses.

• Contributed to genetic analyses demonstrating metastasis susceptibility as an inherited trait.

SIGNIFICANCE AND IMPACT

The metastasis of cancer cells is the greatest cause of lethality from tumors. Despite this fact, metastasis remains a relatively understudied area with a corresponding lack of understanding of the metastatic process. The research presented above has already provided new insights into the causes and mechanisms of cancer cell metastasis. These discoveries have already stimulated prognostic and therapeutic research in other laboratories:

• Dr. Welch and his team have provided reagents for and participated in dozens of clinical studies which show that KISS1 and BRMS1 have prognostic value for different cancer types.

• The recognition that tumor cell proliferation at secondary sites is regulated by KISS1 and BRMS1 has spurred multiple labs into pursuit of anti-metastatic therapies based upon this concept.

• Center scientists and others have tested chemotherapeutic drugs that have shown efficacy against bone metastasis in pre- clinical models. Some of these drugs are already entering clinical trials.

• KISS1's normal cellular function has been determined to be as a neurotransmitter responsible for initiating pubertal development. This has led to a new class of therapies that affect growth and maturation of many species, including humans.

THE UNIQUENESS of the NFCR APPROACH

Strong Leadership: Center Director Dr. Danny Welch is a pioneering scientist in the field of metastasis research. In 1996, Dr. Welch was among the first researchers to identify a gene in humans that suppresses the spread of melanoma, a potentially deadly form of skin cancer. He and his team have gone on to identify numerous other metastasis-suppressor genes, including genes that block metastasis in breast, prostate, pancreatic, ovarian, and lung cancers. Building upon these discoveries, Dr. Welch is leading a team to determine the mechanisms of how these genes work, how tumor cells acquire the ability to metastasize, why some types of cancer have a propensity to "gravitate" to bone tissue and, importantly, how these discoveries can be rapidly translated into clinical practice.

Innovative Team: Each of the investigators in the NFCR Center for Metastasis Research team led by Dr. Welch has produced significant research, supported by peer-reviewed papers, which forms a foundation for the proposed projects. These projects will focus more closely on the interrelated aspects of cancer metastasis; as metastasis is the proximate cause of 90% of cancer fatalities.

Members in the research team of the NFCR Center for Metastasis Research include Drs. Scott Ballinger, Andra Frost and Douglas Hurst of the University of Alabama, Birmingham; Dr. Andrea Mastro of the Pennsylvania State University; Dr. Daryll DeWald of Utah State University; Drs. Carlton Cooper and Robert Sikes of the University of Delaware; and Dr. Shawn Holt of Virginia Commonwealth University.

Dr. Ballinger's expertise is in mitochondrial function and free radical biology; Dr. Frost is a pathologist specializing in breast cancer and brings many years of clinical experience to the team; Dr. Hurst is a biochemist with expertise in microRNA regulation; Dr. Mastro is a renowned immunologist with interests in the relationship of tumor cells and bone marrow; Dr. DeWald is biochemist and brings his expertise in signaling and classical biochemical techniques to the Center; Dr. Cooper bring credentials in prostate cancer and racial disparities to the Center; Dr. Sikes' expertise is in endothelial biology and prostate cancer. The complementary expertise of all of these investigators is expected to have an important positive effect on the success of the proposed projects as has been proven in their collaborative research efforts outlined in the attached yearly NFCR Progress Reports.

THE OBJECTIVES

Dr. Welch and his team will continue and expand the research as described above. They plan to focus on the following objectives in their research during this year:

• Further define the role(s) of mitochondrial genes in metastasis

• Further characterize the KISS1-fibroblast cellular interactions

• Determine whether mutants of BRMS1 that do not localize to the nucleus are still able to
suppress metastasis

• Establish whether the Gli transcription factor and the sonic hedgehog pathway are involved in Metastasis

• Determine how BRMS1 can affect gap junctional intercellular communication

• Develop and begin initial characterization of genetically engineering mice that over-express or no longer expressing BRMS1

The Lucy Fund for Metastatic Breast Cancer Research

The Lucy Fund for Metastatic Breast Cancer Research is an official fund of the National Foundation for Cancer Research. It's intiated by Lucy Stanovick, a college professor and mother of two who is diagonizedwith stage IV metastatic breast cancer.One year after her diagonosis, Lucy decided to gather her friends, family and community together for a party to celebrate her life and to raise money for breast cancer research. Lucy created the annual "Party 4 Life", an all-day, all-night festival with auction items, games, lunch, dinner and dancing in the Poconos of Pennsylvania, raising over $65,000 so far. 100% of the Lucy Fund goes to support metastatic breast cancer research. The fund is currently supporting the NFCR Center for Metastasis Research, led by Dr. Danny Welch.

To support metastatic breast cancer research and The Lucy Fund, please call 1-800-321-CURE (2873) or fill out the form below. You can also visit Lucy's fundraising page by clicking here.

*For security purposes, we require that your name and address match exactly the information your credit card company has on file. Please fill out billing information below exactly as it appears with your credit card company. If you have any questions, or would like to make your donation over the phone, please contact us at 1-800-321-CURE (2873).