Fighting breast cancer from new angles

(Press-News.org) ORLANDO, Fla. — August 3, 2011 — In their lifetime, women have more than a 12 percent risk of being diagnosed with breast cancer. 1 This week, research on novel approaches to breast cancer treatment is being presented at the Era of Hope (EOH) conference, a scientific meeting hosted by the Department of Defense Breast Cancer Research Program (BCRP).

Existing breast cancer treatments don't work for everyone, and alternative methods and delivery systems for breast cancer treatment are critical to saving and improving patient lives. New approaches to be presented at Era of Hope include research that explores using reconstituted "good" cholesterol as a drug delivery model as well as a study looking at a heat-activated drug delivery system using peptides to target tumors.

"The Department of Defense Breast Cancer Research Program is proud to support the investment into early and new science that can potentially improve and enhance the lives of breast cancer patients," said Captain Melissa Kaime, M.D., Director of the Congressionally Directed Medical Research Programs (CDMRP), under which the BCRP is managed. "The Era of Hope conference provides an opportunity for investigators to share the results of their research and collaborate about next steps, ultimately striving to make a significant impact in the lives of breast cancer patients."

Thermally Targeted Delivery of a c-Myc Inhibitory Peptide in Vivo Using Elastin-like Polypeptide
Principal Investigator: Gene Leflore Bidwell, III, PhD, University of Mississippi Medical Center

Surgery, along with chemotherapy and radiation are traditional treatment methods for breast cancer, but the harm to normal tissue, tumor metastasis and resistance to treatment can hinder a successful outcome. Thus, it is critical to identify alternative targeted approaches that reduce undesired side effects. Researchers at the University of Mississippi Medical Center developed a polypeptide (CPP-ELP-H1) that is responsive to heat and inhibits breast cancer cell growth by blocking the activity of c-Myc, an oncogenic protein.

The polypeptide is comprised of cell-penetrating peptide (CPP) and elastin-like peptide (ELP). When administered systemically, ELPs remain soluble and are cleared from circulation at normal body temperature. But at the tumor site, where mild heat is applied externally, ELP aggregates and accumulates. The CPP then facilitates entry into the tumor cells, where H1, an inhibitory peptide, blocks c-Myc activity.

Researchers administer the therapeutic peptide attached to the thermally responsive ELP carrier systemically by IV injection. The heating and cooling process is repeated several times, and each time more drug carrier accumulates in the heated tumor tissue and enters the tumor cells. The net result is called "thermal targeting." In the study's mouse breast cancer models, investigators noticed up to three times more drug in a heated tumor relative to an unheated one, following injection of the same amount of drug intravenously. At the dose used with mice, there was a 70 percent reduction of tumor volume when using thermal targeting compared to unheated controls or controls lacking the H1 peptide. For use in the human clinical setting, mild focused heat can be applied using a technique called high intensity focused ultrasound (HIFU). This technology is rapidly developing and is actively researched by other groups. In its most sophisticated form, the HIFU technology is combined with imaging via MRI. HIFU can be used for "image guided" delivery of the heat to much defined target volumes, and MRI can accurately monitor the tissue temperature.

"What's novel about our work is we're developing a carrier for peptide therapeutics," said Dr. Gene Leflore Bidwell of University of Mississippi Medical Center. "Peptides are easier to rationally design for a specific target than small molecules are. You can design peptides to modulate pathways of interest for certain types of breast cancer, but the problem with peptides is they need carriers to be made into good drugs. We generated a carrier to do that using thermal targeting, so the carrier we use specifically responds to heat."

Selectively Targeted Therapeutics for Breast Cancer
Principal Investigators: Andras Lacko, PhD and Nirupama Sabnis, PhD, University of North Texas Health Science Center, Fort Worth

In the United States, six percent of women with breast cancer already have metastatic disease at the time of diagnosis.2 Despite improved response rates to currently available treatments, drug resistance continues to be an issue. A multi-site study was conducted to investigate a highly innovative approach for selectively targeting breast cancer by using biocompatible nanoparticles.

Researchers developed a novel drug delivery model utilizing synthetic and reconstituted high-density lipoprotein (rHDL) or good cholesterol nanoparticles that is uniquely effective in selectively encouraging cancer cells to accept therapeutic treatments. The anti-cancer agent used in the study was siRNA directed against the STAT-3 transcription factor and focal adhesion kinasse (FAK). 3 The drug carrying the nanoparticles was 20 times more efficient in suppressing the growth of breast cancer cells than the drug on its own, and in vivo studies in mice led to the suppression of the growth of human breast tumors by more than 70 percent. The system targets malignant cells and tumors via the scavenger receptor type B1 (SR=B1). The normal function of the SR-B1 receptor includes the extraction of cholesteryl esters from high density lipoproteins (HDL). This receptor has been shown to be markedly overexpressed in malignant cells and tissues, apparently because of their need for excess cholesterol due to their high proliferative rates. Researchers have found the SR-B1 receptor is also the major gateway for the entry of anti-cancer drugs into malignant cells. During the study, the accumulation of the siRNA (delivered via the rHDL nanoparticles) was undetectable in nearly all normal tissues, while it was substantial in tumor tissue, suggesting the selective drug delivery to tumors via rHDL is feasible.

"This novel drug delivery system has the potential to be compatible with most of the commonly used chemotherapy agents," said Dr. Andras Lacko of University of North Texas Health Science Center, Fort Worth. "This is a selectively targeted model, so cancer cells are reached, and normal cells are spared. We hope to contribute to what could bring patients a more effective therapy with reduced side effects."

Therapeutic Eradication of DCIS Progenitor Cells
Principal Investigator: Lance A. Liotta, MD, PhD, George Mason University

The true malignant nature of ductal carcinoma in situ (DCIS), breast cancer that begins inside the milk ducts 4, remains unclear, and therefore, it is often considered difficult to treat. A collaborative study led by Dr. Lance A. Liotta of George Mason University with Dr. Kirsten Edmiston of Inova Health System and Virginia Espina of George Mason University was conducted to answer the question: When does the propensity for breast cancer invasion first begin? Researchers also sought to investigate the potential of autophagy, a cell survival mechanism used by DCIS malignant progenitor cells growing within the breast duct, as a novel target for treating this type of disease.

In this study, an initial culture sample of fresh human DCIS lesions was shown to elicit cells with full malignant, or cancerous, properties in an animal model. Some of these cancerous properties include invasion, spheroid formation, and the ability to produce more tumors or tumorigenicity. Treatment with a lysosomotropic inhibitor of autophagy (chloroquine phosphate [CQ]) reversed all the invasive and tumorigenic properties, induced cell death and eliminated genetically abnormal cells from the organ culture.5 The mechanism of the suppression was the inhibition of autophagy. Findings indicate that the malignant cells are surviving within the breast duct by using autophagy to digest cell components in lysosomes and generate energy.6 Lysosomotropic inhibitors 7 work by modifying lysosomal function and reducing the cell survival mechanisms employed by malignant cells.

"Based on our findings, we are testing the safety and effectiveness of CQ in patients with DCIS," said Dr. Lance Liotta. "This trial will investigate the applicability of autophagy as a novel treatment target for DCIS, and if successful, could provide a neoadjuvant therapy option for this difficult to treat disease and a new approach to prevent breast cancer by killing preinvasive lesions."

### About the Era of Hope The Era of Hope (EOH) conference joins scientists, clinicians and breast cancer advocates committed to advancing research on the prevention, detection, diagnosis and treatment of breast cancer. From August 2-5, 2011 in Orlando, Florida, the EOH will feature prominent scientists and clinicians with presentations of recent remarkable advances in breast cancer research funded by the Department of Defense Breast Cancer Research Program (BCRP). This research challenges paradigms and pushes boundaries to identify innovative, high-impact approaches for future breast cancer research and discoveries. The EOH conference is recognized as one of the premier breast cancer research conferences, and this year marks the sixth conference of its kind. The EOH will bring together more than 1,600 BCRP awardees, advocates, and invited speakers in an atmosphere of collaborative thinking in the fight against breast cancer. The EOH is a unique opportunity for advocates and expert scientists from different fields and research areas to discuss unanswered questions, share ideas, identify promising directions in breast cancer research, and develop collaborative partnerships. The conference will unveil innovative research and discoveries that are essential to ultimately eradicating the disease. For more information about the EOH, please visit https://cdmrpcures.org/ocs/index.php/eoh/eoh2011. Follow the Era of Hope conference on Twitter @EraofHope. About the Congressionally Directed Medical Research Programs In the early 1990s, the breast cancer advocacy community launched a grassroots effort to raise public awareness for the crucial need of increased funding in breast cancer research. Beginning in fiscal year 1992 (FY92), Congress appropriated $25 million for breast cancer research to be managed by the Department of Defense. The following year, Congress continued to respond to the advocacy movement and appropriated $210 million for breast cancer research, marking the beginning of the Congressionally Directed Medical Research Programs (CDMRP). The CDMRP represents a unique partnership among the public, Congress and the military. Because of continued and expanded advocacy efforts, the CDMRP has grown to encompass multiple targeted programs spanning cancer research, military medical research, and other disease, injury or condition specific research. The CDMRP has received $6.525 billion in appropriations from its inception through FY11 and more than 10,000 awards have been made across 25 different programs through FY10. For more information about the CDMRP, please visit http://www.cdmrp.army.mil.

1 http://www.cancer.gov/cancertopics/factsheet/detection/probability-breast-cancer 2 http://www.medscape.com/viewarticle/725148 3 Shahzad MM, Mangala LS, Han HD et al. 2011. Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles. Neoplasia 13:309-319. 4 http://www.breastcancer.org/symptoms/types/dcis/ 5 Espina V, Mariani BD, Gallagher RI, Tran K, Banks S, Wiedemann J, Huryk H, Mueller C, Adamo L, Deng J, Petricoin EF, Pastore L, Zaman S, Menezes G, Mize J, Johal J, Edmiston K, Liotta LA. 2010. Malignant precursor cells pre-exist in human breast DCIS and require autophagy for survival. PLoS One 5(4):e10240. 6 Espina V and Liotta LA. 2011. What is the malignant nature of human ductal carcinoma in situ? Nat Rev Cancer 11(1):68-75. 7 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090357/