gpawelski
03-01-2008, 03:42 AM
Targeted therapy halts the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells. The drugs are effective in about 10-15% of patients. The drugs work specifically in patients whose cancers contain mutations in a gene that encodes the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) or some other pathway.
The EGFR stands at the origin of a major signaling pathway involved in the growth of breast cancer. Two of the four receptors in this pathway, epidermal growth factor receptor type 1 (HER1) and epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErbB2), are promising targets for new treatments.
In about 20% of patients with breast cancer, the tumor overexpresses HER2. Herceptin, a humanized monoclonal antibody that targets the extracellular domain of HER2, is effective as adjuvant therapy and as treatment for metastatic disease in patients with HER2-positive breast cancer.
Tykerb, an orally administered small-molecule inhibitor of the tyrosine kinase domains of HER1 and HER2, has antitumor activity when used as a single agent in patients with HER2-positive inflammatory breast cancer or HER2-positive breast cancer with central nervous system (CNS) metastases that are refractory to Herceptin. This finding is important because HER2-positive tumors frequently spread to the CNS, where the tumor is sheltered from Herceptin and most chemotherapeutic agents.
Other targeted therapies also show great promise in the treatment of breast cancer. Avastin is a monoclonal antibody against the vascular endothelial growth factor (VEGF). Tumors can be effectively controlled by targeting the network of blood vessels that feed them. Tumor growth is dependent on angiogenesis. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.
Although these targeted therapies are initially effective in certain subsets of patients, the drugs eventually stop working, and the tumors begin to grow again. This is called acquired or secondary resistance. This is different from primary resistance, which means that the drugs never work at all. The change of a single base in DNA that encodes the mutant protein has been shown to cause drug resistance.
Initially, tumors have the kinds of mutations in the EGFR or VEGF gene that were previously associated with responsiveness to these drugs. But, sometime tumors grow despite continued therapy because an additional mutation in the gene, strongly implies that the second mutation was the cause of drug resistance. Biochemical studies have shown that this second mutation, which was the same as before, could confer resistance to the EGFR or VEGF mutants normally sensitive to these drugs.
It is especially interesting to note that the mutation is strictly analogous to a mutation that can make it tumor resistant. For example, mutations in a gene called KRAS, which encodes a signaling protein activated by EGFR, are found in 15 to 30 percent of certain cancers. The presence of a mutated KRAS gene in a biopsy sample is associated with primary resistance to drugs. Tumor cells from patients who develop secondary resistance to a drug like Tarceva after an initial response on therapy did not have mutations in KRAS. Rather, these tumor cells had new mutations in EGFR. This further indicates that secondary resistance is very different from primary resistance.
All the EGFR/VEGF mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if one drug is better or worse than some other drug which may target this. There are differences. The drug has to get inside the cells in order to target anything.
EGFR/VEGF-targeted drugs are poorly-predicted by measuring the ostansible targets, but can be well-predicted by measuring the effect of the drug on the "function" of live cells.
Literature Citation:
PLoS Medicine, February 22, 2005
Eur J Clin Invest 37 (suppl. 1):60, 2007
The EGFR stands at the origin of a major signaling pathway involved in the growth of breast cancer. Two of the four receptors in this pathway, epidermal growth factor receptor type 1 (HER1) and epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErbB2), are promising targets for new treatments.
In about 20% of patients with breast cancer, the tumor overexpresses HER2. Herceptin, a humanized monoclonal antibody that targets the extracellular domain of HER2, is effective as adjuvant therapy and as treatment for metastatic disease in patients with HER2-positive breast cancer.
Tykerb, an orally administered small-molecule inhibitor of the tyrosine kinase domains of HER1 and HER2, has antitumor activity when used as a single agent in patients with HER2-positive inflammatory breast cancer or HER2-positive breast cancer with central nervous system (CNS) metastases that are refractory to Herceptin. This finding is important because HER2-positive tumors frequently spread to the CNS, where the tumor is sheltered from Herceptin and most chemotherapeutic agents.
Other targeted therapies also show great promise in the treatment of breast cancer. Avastin is a monoclonal antibody against the vascular endothelial growth factor (VEGF). Tumors can be effectively controlled by targeting the network of blood vessels that feed them. Tumor growth is dependent on angiogenesis. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.
Although these targeted therapies are initially effective in certain subsets of patients, the drugs eventually stop working, and the tumors begin to grow again. This is called acquired or secondary resistance. This is different from primary resistance, which means that the drugs never work at all. The change of a single base in DNA that encodes the mutant protein has been shown to cause drug resistance.
Initially, tumors have the kinds of mutations in the EGFR or VEGF gene that were previously associated with responsiveness to these drugs. But, sometime tumors grow despite continued therapy because an additional mutation in the gene, strongly implies that the second mutation was the cause of drug resistance. Biochemical studies have shown that this second mutation, which was the same as before, could confer resistance to the EGFR or VEGF mutants normally sensitive to these drugs.
It is especially interesting to note that the mutation is strictly analogous to a mutation that can make it tumor resistant. For example, mutations in a gene called KRAS, which encodes a signaling protein activated by EGFR, are found in 15 to 30 percent of certain cancers. The presence of a mutated KRAS gene in a biopsy sample is associated with primary resistance to drugs. Tumor cells from patients who develop secondary resistance to a drug like Tarceva after an initial response on therapy did not have mutations in KRAS. Rather, these tumor cells had new mutations in EGFR. This further indicates that secondary resistance is very different from primary resistance.
All the EGFR/VEGF mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if one drug is better or worse than some other drug which may target this. There are differences. The drug has to get inside the cells in order to target anything.
EGFR/VEGF-targeted drugs are poorly-predicted by measuring the ostansible targets, but can be well-predicted by measuring the effect of the drug on the "function" of live cells.
Literature Citation:
PLoS Medicine, February 22, 2005
Eur J Clin Invest 37 (suppl. 1):60, 2007