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Newly Established Organization Presents Data on Advancing Compounds at AACR
SAN DIEGO, CA, USA | April 11, 2008 | Ortho Biotech Oncology Research & Development (ORD), a unit of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., will announce results from studies of three innovative compounds - Hdm2, c-Met, and HDAC inhibitors - here at the American Association for Cancer Research (AACR) 2008 Annual Meeting.
"ORD is a new research and development organization that unites the biotechnology and pharmaceutical oncology efforts of several Johnson & Johnson companies with the goal of transforming cancer into a chronic or curable disease," said William Hait, M.D., Senior Vice President and Worldwide Head of Ortho Biotech Oncology Research & Development. "The new organization harnesses broad, multi-disciplinary capabilities and expertise in order to prioritize existing and emerging opportunities, align cancer treatment with modern cancer biology and improve patients' lives."
ORD's scientific approach to cancer examines the cancer cell and the surrounding tissue, or microenvironment. Previously, researchers often studied cancer as collections of malignant cells growing in isolation, but now understand cancer cells depend on interactions with the surrounding tissue to survive, grow and metastasize. ORD seeks to identify compounds which can inhibit or block the interaction cancer cells have with the surrounding tissues, which compromises the cancer's ability to survive.
The organization will combine the microenvironment disruptive agents (MDAs) resulting from this approach with classic treatments that directly target cancer cells. MDAs represent one of the most promising areas of drug discovery, and ORD has a pipeline of several investigational MDAs, including some of which are first-in-class and first-in-clinic.
Pre-clinical data presented at this year's AACR meeting demonstrate evidence of broad-spectrum, anti-tumor activity for three new compounds. These compounds selectively target specific pathways and influence the interaction between cancer cells and the microenvironment to induce cancer cell death. The presentations include:
- JNJ-26854165, a first-in-class, first-in-clinic Hdm2 inhibitor which induces apoptosis (programmed cell death) in a number of cancer cell lines, and restores function of the p53 tumor suppressor protein through a novel mechanism of action; the compound is in phase I studies for non-small cell lung cancer and prostate cancer. (Oral abstract No.1592)
- JNJ-26481585, a novel, second-generation pan-Histone Deacetylase (HDAC) inhibitor with anti-tumor activity against solid and hematological malignancies, which interferes with expression of genes that control cancer cell proliferation, angiogenesis and metastasis; phase I trials are ongoing. (Oral abstract No.2444)
- JNJ-38877605, a small molecule that selectively and potently inhibits the c-Met receptor tyrosine kinase (c-Met RTK) pathway that regulates inhibition of signaling from the microenvironment to block cancer cell development and metastasis; based on promising pre-clinical properties and clean toxicity profile of JNJ-38877605, ORD has advanced this potent and uniquely selective c-Met inhibitor into clinical evaluation in multiple metastasized malignancies. (Poster abstract No.4837)
"These new agents are just a few of the novel compounds from our pipeline that we hope may lead to the control of cancer," Dr. Hait said. "The scientific community is attempting to identify all the genetic abnormalities within cancer cells; this has yielded a finite number of treatment opportunities. The scientific approach of ORD has the potential to generate new opportunities to improve cancer care."
About Our Compound Targets
Human Double Minute 2 (Hdm2)
The Hdm2 oncogene is activated in cancers through various mechanisms, including gene amplification and deletion of upstream tumor suppressors. Hdm2 over-expression induces tumor formation, and Hdm2 levels correlate with sporadic tumor incidence in humans(i). Hdm2 promotes tumor cell proliferation by associating with cell cycle regulatory proteins, modulating their activity and stability. Key examples include p53, p73, E2F1 and HIF1a(ii),(iii). This positions the Hdm2 protein as an attractive target for the development of anti-cancer agents.
Histone Deacetylase (HDAC)
DNA in chromatin is wound around proteins called histones. HDACs are a family of enzymes that influence gene expression through selective regulation of chromatin structure. Inappropriate gene expressions, due to changes in chromatin structure, are a hallmark of cancer. HDAC inhibitors aim to normalize chromatin structure, thereby restoring the activity of genes which inhibit proliferation, angiogenesis and metastasis(iv).
c-Met Receptor Tyrosine Kinase (c-Met RTK)
Receptor tyrosine kinases (RTKs) are cell surface receptors that regulate many key processes including invasive growth and cell survival. The c-Met RTK pathway has been shown to be specifically important in regulation of cell migration and invasion, cell proliferation, survival and angiogenesis. Deregulation of c-Met RTKs has been implicated in the development and progression of numerous human cancers. The c-Met RTK inhibitors prevent receptor activation and thus inhibit tumor cell development and metastasis(v),(vi),(vii),(viii).
About ORD
Ortho Biotech Oncology Research & Development (ORD) is a new research and development organization dedicated to oncology, hematology and supportive care. ORD partners closely with Ortho Biotech Products, L.P. and Janssen-Cilag companies worldwide to bring oncology treatments and supportive medicines to patients around the world. ORD is headquartered in Raritan, N.J., and has facilities throughout Europe and the United States.
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(ii) Levine, A J; Hu, W; Feng, Z. The P53 pathway: what questions remain to be explored? Cell Death and Differentiation; 2006, 13(6), 1027-1036.
(iii) Toledo F, Wahl GM. MDM2 and MDM4: p53 regulators as targets in anticancer therapy. International Journal of Biochemistry & Cell Biology; 2007, 39(7-8):1476-82.
(iv) Johnstone, RW. Histone deacetylase inhibitors: novel drugs for the treatment of cancer. Nature Reviews Drug Discovery; 2002, 1, 287 - 299.
(v) Lesko, E and Majka, M. The biological role of HGF-MET axis in tumor growth and developmentof metastasis. Fron Biooscie; 2008, 13: 1271-80.
(vi) Sattler, M and Salgia R. c-Met and hepatocyte growth factor; potential as novel targets in cancer theray. Curr Oncol Rep; 2007, 9 (2) 102-8.
(vii) Boccaccio C, and Comoglio, PM. Invasive growth; a MET driven genetic programme for cancer and stem cells. Nat Rev Cancer; 2007, 6(8) 637-45.
(viii) Peruzzi, B and Bottaro, DP. Targeting the c-Met signaling pathway in cancer. Clin Cancer Res; 2006, 12(12) 3657-60.
SOURCE: Ortho Biotech |
