Adherex is focused on the discovery and development of novel therapeutics to address important unmet medical needs in cancer. Our focus is two-fold: 1) developing product candidates from our broad intellectual property portfolio of cell adhesion and cell signaling molecules known as cadherins; and 2) developing oncology product candidates that either enhance the effectiveness of (chemoenhancers) or protect against the side effects of (chemoprotectants) certain cancer drugs.
In the ongoing battle against cancer, there is a continuing need for more effective and safer treatments. To address this need, researchers have been focusing on developing drugs that target specific molecular differences between tumors and normal tissues, attempting to target the tumors and leave normal tissues relatively undamaged. These drugs are collectively called “molecularly-targeted therapeutics.” Marketed oncology drugs such as Avastin®, Herceptin® and Gleevec® fit into this category.
At the same time, the medical community and patients have sought drugs that will either enhance the anti-tumor activity of certain chemotherapies or assist them in dealing with the side effects that occur with many of today’s treatments, particularly chemotherapy.
Adherex’s clinical and preclinical drug candidates are being developed to address some of these unmet medical needs. Each of these drug candidates will compete in different segments of the cancer marketplace: molecular targeting, chemoenhancement and chemoprotection.
Molecular Targeting
Adherex is developing compounds that target cadherins, cell adhesion and cell signaling molecules crucial to the development of cells into tissues, organs and organisms. Agents that target and inhibit cadherin function have the potential to attack the progression of cancer at two distinct points:
- Direct targeting of cadherins expressed on cancer cells may disturb cadherin-mediated signaling, leading to apoptosis (death) of cancer cells.
- Cadherin inhibitors may exploit the inherent structural weaknesses of the tumor vasculature, causing angiolysis (disruption of blood vessels) and tumor damage.
Adherex's lead biotechnology compound, ADH-1, targets N-cadherin, a protein present on certain tumor cells and established tumor blood vessels. ADH-1 is currently in clinical development in a combination program with a range of chemotherapeutic to investigate in man the synergistic effects noted in our preclinical models. At the end of 2006, the Company also completed patient enrollment in our single-agent Phase Ib/II and Phase II clinical trials of ADH-1.
As many tumors become more aggressive, invasive and malignant, researchers have found that N-cadherin is expressed in greater amounts making it an important target for developing anti-cancer treatments. Early, well-differentiated carcinomas primarily express E-cadherin, like the epithelial cells from which they are derived. E-cadherin functions to establish and maintain the integrity of the polarized, tightly adhesive epithelial monolayer. However, poorly differentiated, highly invasive carcinomas frequently lose their primary E-caderin expression, and N-cadherin is over-expressed instead. This change in primary cadherin expression causes the epithelial cells to lose their tightly adherent, polarized and well-defined shape and become loosely adherent, flattened and migratory. Such cadherin switching promotes properties such as dedifferentiation, local invasion and metastasis, leading to a poor prognosis.
While ADH-1 has a single molecular target, N-cadherin, we believe its anticancer effect results from two distinct mechanisms of action - apoptosis and tumor vessel angiolysis. N-cadherin appears to act as a tumor survival factor. In cell culture studies, inhibition of N-cadherin binding between tumor cells has been shown to cause apoptosis of these tumor cells, we believe as a result of disrupting the cadherin-regulated cell survival signals.
ADH-1 also appears to disrupt the blood vessels needed for cancerous tumors to grow and flourish, with hemorrhaging having been noted in both our clinical and preclinical studies. We believe the mechanism for this disruption is either a competitive inhibition of the binding of cadherins between the endothelial cells of the tumor blood vessel wall or apoptosis in tumor cells that form part of the blood vessel wall, each leading to leakage and rupture of these vessels. The latter involves the phenomenon known as tumor "mosaicism," in which tumor cells form a portion of the vascular wall (along with the endothelial cells). Induction of cell death of these tumor cells would result in tumor vascular disruption.
Chemoenhancement
Chemoenhancers are drugs that enhance the effectiveness and tumor killing properties of chemotherapeutic agents. Our portfolio includes eniluracil, an oral dihydropyrimidine dehydrogenase (DPD) inhibitor that was previously under development by GSK for oncology indications. Adherex is developing eniluracil is to improve the therapeutic value and effectiveness of 5-fluorouracil (5-FU), one of the world’s most widely-used oncology agents. Eniluracil inhibits DPD, the first enzyme involved in the breakdown of 5-FU, by covalently binding to the enzyme and irreversibly inactivating it. The resulting effect on 5-FU breakdown is profound - the half life of 5-FU is increased 20-fold - from less than 15 minutes to up to five hours.
Chemoprotection
Chemoprotectants are drugs that protect against the toxic side effects caused by some chemotherapies. We are developing sodium thiosulfate (STS) to reduce or prevent the hearing loss in children often associated with platinum-based chemotherapies. Our portfolio also includes NAC, which has shown activity in protecting against the bone marrow toxicity seen with certain chemotherapies.
