Blocking Cancer Networks

spider web
Image: Flickr - Luc Viatour
The emergence of drug resistance is one of the main causes of failure in cancer treatment and is one reason that cancer drugs are often used in combination. Resistance can also arise during the use of combinations of cytotoxic agents developed by trial and error but researchers at Fox Chase Cancer Center and Georgetown University have now developed a better way of selecting drug combinations based on molecular targets.

The epidermal growth factor receptor (EGFR) is a well validated molecular target and inhibitors are already used clinically for certain types of cancer. The team used siRNA to silence 638 genes known to encode proteins involved in the EGFR signalling network and identified over 60 proteins that can rescue cells in the presence of an EGFR inhibitor. Amongst these were three proteins for which drugs are already being developed: Aurora kinase A, protein kinase C, and STAT3. Aurora kinase A inhibitors are already being evaluated clinically and a trial testing the EGFR inhibitor erlotinib with an Aurora kinase inhibitor in patients with non-small cell lung cancer is being launched. A similar network-centred approach could be used to design other combination therapies to overcome resistance mechanisms in cancer.

Interestingly, the screen did not pick out genes previously linked to resistance to EGFR inhibitors and most of the genes identified were not mutated: KRAS mutations did not appear to be needed for resistance to EGFR inhibitors although patients with KRAS mutations do not benefit from EGFR inhibitors.

The study is published in Science Signaling.

New Regimen for Breast Cancer?

DoxorubicinA recent report suggests that treatment with a combination of two commonly used anti-cancer drugs, doxorubicin and zoledronic acid, may benefit women with breast cancer. Doxorubicin is an anthracycline antibiotic that is widely used in cancer chemotherapy. It is thought to work by intercalating DNA and preventing cell replication.

Zoledronic acidZoledronic acid is a third generation bisphosphonate that is used to prevent fractures in cancer patients with bone metastases. The bone destruction associated with malignancy develops because tumor cells synthesize and release soluble factors that stimulate osteoclasts to resorb bone. The bisphosphonate drugs act by inhibiting osteoclast function.

Zoledronic acid and other bisphosphonates are also used to treat osteoporosis – a single dose of zoledronic acid has been shown to increase bone mineral density for up to a year.

The new study looked at the effects of the two drugs given alone, sequentially , or in combination on the growth of established breast tumours in mice. Alone out of the treatment methods, doxorubicin followed 24 hours later by zoledronic acid almost completely abolished tumor growth in the absence of bone disease. Zoledronic acid has already been shown to reduce the risks of fractures in breast cancer patients with bone metastases and the new study provides hope that new dosing regimens may provide additional benefits.