Showing posts with label STUDY. Show all posts
Showing posts with label STUDY. Show all posts

Monday, February 14, 2011

Breast Cancer Invasion and Metastasis Prevented by Targeting Pro Interface

Recent research from Japan has reported on targeting AMAP1 and cortactin binding bearing an atypical src horology 3/proline interface for prevention of breast cancer invasion and metastasis. "Invasive potentials of carcinomas greatly contribute to their metastasis, which is a major threat in most cancers. We have recently shown that Arf6 plays a pivotal role in breast cancer invasive activities and identified AMAP1 as an effector of GTP-Arf6 in invasion. "Expression of AMAP1 correlates well with invasive phenotypes of primary tumors
of the human breast. We also have shown that AMAP1 functions by forming a trimeric protein complex with cortactin and paxillin," wrote S. Hashimoto and colleagues, Osaka Bioscience Institute.

"In this complex, AMAP1 binds to the src homology 3 (SH3) domain of cortactin via its Pro-rich peptide, SKKRPPPPPPGHKRT. SH3 domains are known to bind generally to the Pro-rich ligands with a one-to-one stoichiometry. We found that AMAP1/cortactin binding is very atypical in its stoichiometry and interface structure, in which one AMAP1 Pro-rich peptide binds to two cortactin SH3 domains simultaneously. "We made a cell-permeable peptide derived from the AMAP1 peptide, and we show that this peptide specifically blocks AMAP1/cortactin binding, but not other canonical SH3/proline bindings, and effectively inhibits breast cancer invasion and metastasis," wrote the researchers.

"Moreover, this peptide was found to block invasion of other types of cancers, such as glioblastomas and lung carcinomas. We also found that a small-molecule compound, UCS15A, which was previously judged as a weak inhibitor against canonical SH3/proline bindings, effectively inhibits AMAP1/cortactin binding and breast cancer invasion and metastasis," the investigators wrote.

They concluded, "Together with fine structural analysis, we propose that the AMAP1/cortactin complex, which is not detected in normal mammary epithelial cells, is an excellent drug target for cancer therapeutics."

ImClone Presents Promising Phase I Data on Two Pipeline Antibodies For Cancer Therapy

ImClone Systems, Inc., (IMCL) announced promising phase I data on two of the company's fully-human, Immunoglobulin G 1 (IgG1) monoclonal antibodies, IMC-1121B and IMC-11F8, at the American Society of Clinical Oncology 42nd annual meeting. The first of these antibodies, IMC-1121B, aims to inhibit the function of a signaling pathway known to play a role in the formation of blood vessels in tumors - a process known as angiogenesis - by blocking the vascular endothelial growth factor receptor-2 (VEGFR-2) from binding to molecules (ligands) that stimulate its activation.

A phase I study was designed to characterize the principal toxicities, dose-limiting toxicity, and maximum tolerated dose of IMC-1121B, as well as assess any preliminary evidence of antitumor activity. To date, a total of 14 patients with advanced cancer have been enrolled in the study at varying dose levels. The most frequent adverse events were anorexia, vomiting, anemia, depression, fatigue, and insomnia. Preliminary results of the study suggest that the toxicity profile of IMC-1121B is distinct from other VEGF pathway inhibitors and that its pharmacokinetic profile is similar to other growth factor receptor pathway antibodies. Further, promising early evidence of antitumor activity was observed, where one patient experienced a partial response and five patients had stable disease. Dose escalation continues and imaging and biological endpoints are in process.

The second antibody, IMC-11F8, is a high-affinity antibody that blocks liganddependent activation of the epidermal growth factor receptor (EGFR). EGFR is part of a signaling pathway that is linked to the growth, development, and survival of many human cancer cells. Studies have shown that the inhibition of EGFR with an IgG1 antibody blocks phosphorylation, resulting in the inhibition of cell growth, the induction of cell death, a decreased ability to form tumor vasculature, and the recruitment of the body's immune defenses to attack cancer cells.

A phase I study is being conducted to determine the safety profile and recommended dose of IMC-11F8. To date, 31 out of 40 planned patients with advanced solid tumors who are refractory to, or have no available, standard therapy have been enrolled at various dose levels. The most frequent adverse events were nausea, vomiting, fatigue, and headache. No infusion reactions were observed. Although a maximum tolerated dose has not been established, IMC- 11F8 has shown activity at two different dose levels.

"These antibodies are among several targeted therapies in development at ImClone Systems that give us a uniquely valuable pipeline within the industry," stated Eric K. Rowinsky, MD, chief medical officer of ImClone Systems. "We are very excited about the antitumor activity demonstrated by both of these compounds at this early stage of testing. Because the proof of principle for both of these antibodies has been well established by commercially available therapies, we are optimistic that phase III testing can begin shortly after phase I is
complete."

The exclusive rights to market IMC-11F8 outside the United States and Canada and coexclusive development rights in Japan belong to ImClone Systems, while commercial rights to the antibody in the U.S., Canada, and Japan fall within the scope of ImClone Systems' commercial agreement with Bristol-Myers Squibb regarding ERBITUX. Commercial rights to IMC-1121B have not been partnered.

HuMax-CD38 Technology Shows Unique Property in Preclinical Studies

Genmab, A/S, announced that HuMax-CD38 was shown to inhibit the enzymatic activity of the CD38 molecule in preclinical studies, which may may contribute to its effectiveness in killing both primary multiple myeloma and plasma cell leukemia cells. HuMax-CD38 is a fully human antibody that targets the CD38 molecule which is highly expressed on the surface of multiple myeloma tumor cells. In previous preclinical studies, HuMax-CD38 was more effective in triggering the immune system killing mechanisms Antibody-Dependent Cellular Cytotoxicity and Complement Dependent Cytotoxicity, than other human CD38 antibodies when tested on multiple myeloma tumors. HuMax-CD38 also potently killed tumor cells from a patient with a CD38/138 positive plasma cell leukemia which was refractory to chemotherapy at the time of analysis. Furthermore, treatment with HuMax-CD38 slowed tumor growth in both preventive and therapeutic settings in SCID mice in animal models.

Multiple myeloma is a cancer of plasma cells and accounts for approximately 1% of all cancers. The incidence of multiple myeloma is 5.2 per 100,000 people corresponding to 15,270 new cases in the U.S. in 2004. In the U.S., approximately 11,000 deaths each year are related to multiple myeloma. At present, no cure is available, and the mean survival is approximately 3 years from time of diagnosis.

"We are pleased with the unique qualities of HuMax-CD38, which continues to show promising results in preclinical studies," said Lisa N. Drakeman, PhD, CEO of Genmab. These data were to be presented by Dr. Paul Parren, vice president, research and technology of Genmab on June 10, 2006 at "The CD38 Ectoenzyme Family: Advances in Basic Science and Clinical Practice" conference in Torino, Italy. Genmab, A/S, is a biotechnology company that creates and develops human antibodies for the treatment of life-threatening and debilitating diseases. Genmab has numerous products in development to treat cancer, infectious disease, rheumatoid arthritis, and other inflammatory conditions, and intends to continue assembling a broad portfolio of new therapeutic products.

Multicenter Validation Ovarian Cancer Biomarker Study

Ciphergen Biosystems, Inc. (CIPH) announced results of a multicenter study evaluating the performance of a set of seven biomarkers for the detection of ovarian cancer. Six hundred seven (607) patient samples taken from five international medical centers were evaluated for each of the seven markers. Two hundred thirty four (234) women had benign gynecologic disease and 373 patients had invasive epithelial ovarian cancer, including 101 with early stage cancer.

All seven biomarkers individually demonstrated statistically significant power to differentiate ovarian cancer patients from women with benign disease, and most biomarkers had p<.00001. As in previous studies, an index derived from the seven markers demonstrated improved specificity for discriminating ovarian cancer from benign pelvic masses, as well as for the detection of early stage cancer.This is the first time that biomarkers discovered through current clinical proteomics efforts have been subjected to a large-scale multi-institutional independent validation study.

The Johns Hopkins Medical Institutions; University of Texas M.D. Anderson Cancer Center; University Hospitals, Leuven, Belgium; Rigshositalet, University of Copenhagen Hospital, Copenhagen, Denmark; University of Kentucky; and Groningen University Medical Center, Groningen, The Netherlands participated in the study. The paper was presented by Dr. Zhen Zhang, associate professor, Department of Pathology, The Johns Hopkins University School of Medicine.

"We are very pleased with the results of this study. Demonstrating the multi-center validity of our markers is a key milestone in the development of a test that can aid in distinguishing women with ovarian cancer from women with benign ovarian tumors," said Gail S. Page, president and CEO. "We have now shown the utility of these markers in large multiinstitutional retrospective studies as well as in prospective studies."

The particular study presented at the ASCO Annual Meeting is part of a comprehensive ovarian cancer program being conducted by Ciphergen in conjunction with leading collaborators at The Johns Hopkins School of Medicine, the University of Texas M.D. Anderson Cancer Center, University College London, and the University of Kentucky. In addition to the ongoing work aimed at developing assays that are designed to distinguish between benign and malignant pelvic mass, Ciphergen has studies underway to target the prediction of recurrence of ovarian cancer as well as to provide additional tools to aid the physician in triaging women considered at high risk of ovarian cancer.

Ciphergen is dedicated to the discovery of protein biomarkers and panels of biomarkers and their development into protein molecular diagnostic tests that improve patient care; and to providing collaborative R&D services through its Biomarker Discovery Center laboratories for biomarker discovery for new diagnostic tests as well as pharmacoproteomic services for improved drug toxicology, efficacy and theranostic assays.