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Cephalon Oncology research is focused on understanding and directing the molecular mechanisms of cell survival. By uncovering the cell signaling pathways that command a cell to survive and divide — or, conversely, to die — Cephalon Oncology is preparing the way for novel therapeutics.
Going further inside the cell
Researchers at Cephalon Oncology use their technical expertise in molecular biology, molecular and behavioral pharmacology, biochemistry, cell biology, tumor biology and chemistry to develop new medicines.
Cephalon Oncology scientists look deep inside the cell to understand what biochemical mechanisms play a role in cell survival and cell death. With research in cell signaling pathways, kinase inhibition, apoptosis and angiogenesis, the company is committed not only to identifying novel pathways for regulation of cell survival and death, but also to exploiting inhibitors or activators of these pathways for therapeutic use against human disease.
Selectively targeting pathways critical to the growth and death of cancer cells
All living cells sense and respond to their environment by means of mechanisms known as cell signaling pathways. These mechanisms are part of a complex system of communications that govern basic cellular activities and coordinate the actions of cells. Before researchers can understand the behavior of cells and how that behavior impacts the health of the whole organism, they must first understand cell signaling.
Signal transduction pathways are under intense investigation at Cephalon Oncology. It refers to the movement of signals from outside the cell to inside. One way cells move signals is through the exchange of phosphates. The workhorses in these phosphate transfers are a group of specialized signaling molecules called protein kinases.
With the help of kinases, signal transduction pathways govern a myriad of biological processes at the cellular level, including growth regulation, growth control and apoptosis. When there is a defect in the kinase, or a defect in the transfer of phosphates, the molecular pathways leading to cell survival or cell death are altered and disease can be the result.
Blocking the signaling pathways implicated in cancer
Kinase inhibition refers to the use of orally active, small molecule drugs to block the signaling pathways implicated in disease. Since virtually all cellular processes involve some sort of phosphate transfer, kinases play a central role in many cellular functions. But it's the fact that kinases are involved in the signal transduction pathways that mediate cell survival and cell death that makes them important targets for therapeutic intervention at Cephalon Oncology. The ability to modulate the activity of kinases by developing small molecule drugs may allow Cephalon Oncology researchers to slow the growth of cancerous tumors.
The proprietary orally active, small molecule kinase inhibitors being developed by Cephalon Oncology scientists are different from large molecule, antibody-based inhibitors being developed to target kinases. The distinction between small and large molecules is significant because a protein's permeability of tumor blood vessels varies. Small macromolecules may be able to penetrate the vascular wall more quickly and easily than large macromolecules.1
Our researchers screen these molecules for activity against our existing and emerging targets to identify promising therapeutic candidates. Currently, one of Cephalon Oncology's proprietary kinase inhibitors is undergoing human testing to evaluate its safety and efficacy.
CEP-701 (lestaurtinib), is a compound currently in clinical development for acute myeloid leukemia (AML) at Cephalon Oncology. In vitro studies show CEP-701 selectively inhibits the survival pathways that block apoptosis by inhibiting FMS-like tyrosine kinase 3 (FLT3). FLT3 mutations are the most prevalent genetic alterations in AML, found in approximately one third of patients. Targeting these mutations by inhibiting the tyrosine kinase activity of FLT3 is cytotoxic to cell lines as well as the primary AML cells that harbor the mutations. Study results show that FLT3 inhibition is associated with clinical activity in those AML patients with FLT3 mutations and suggest CEP-701 should be further studied as a potential targeted therapy for the disease.2, 3
Click here for more information on the clinical study of CEP-701.
Restoring the natural process of programmed cell death
Apoptosis, a molecular process also known as programmed cell death, is the body's natural way of eliminating unneeded or abnormal cells. The process, mediated by a group of protease enzymes called caspases, may be blocked in cancer cells, allowing cell proliferation.
TRISENOX® (arsenic trioxide), the standard of care in relapsed/refractory acute promyelocytic leukemia (APL), induces apoptosis via caspase activation in leukemic cells, resulting in complete remission.4
Click here for full prescribing information including Boxed Warning.
TRISENOX actually has multiple proposed mechanisms of antileukemic activity, which are currently under investigation. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. Cell differentiation and apoptosis are mediated by both PML/RAR-alpha-dependent and -independent antileukemic effect.5
TREANDA® (bendamustine hydrochloride) for Injection is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.
Click here for more information on the clinical study of TREANDA.
Inhibiting the blood vessel development underlying tumor growth
Investigations into the signaling mechanisms of cell survival and cell death also have led to significant contributions by Cephalon Oncology scientists in the area of angiogenesis. Angiogenesis, or blood vessel formation, occurs in the healthy body for healing wounds and for restoring blood flow to tissues after injury or insult.
Cancer growth and spread is facilitated by an increase in this new blood vessel development (angiogenesis). Research at Cephalon Oncology, therefore, is focused on identifying signal transduction pathways involved in aberrant angiogenesis and developing kinase inhibitors to block those pathways.
To date, the company has synthesized a number of proprietary small molecules that are potent and selective inhibitors of the VEGF receptor kinase, which is a known contributor to the survival of capillary cells.
Another anti-angiogenic target under investigation at Cephalon is the Tie-2 receptor kinase. The Tie-2 receptor kinase works in concert with the VEGF receptor systems to form new blood vessels. Several of these molecules have demonstrated ability to slow the growth of certain experimental tumors when used in vivo and therefore represent an exciting new area of potential clinical development.
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