An increasing number of therapies targeting tumors that have proteins called epidermal growth factor receptors (EGFR) sitting on their surface are already being used in the clinic or are in late stages of development. For example, Herceptin is an established treatment for certain types of breast cancer and Erbitux and Vectibix are in use for other types of cancer. An additional drug called matuzumab is in phase II clinical trials.
Three years ago, Kate Ferguson, PhD, Assistant Professor of Physiology, and colleagues determined the precise molecular details of how Erbitux, a colorectal and head and neck cancer drug, binds to its target on cancer cells. EGFR drugs halt cell proliferation by blocking EGFR's molecular doorway, keeping hormones from binding and signaling tumor growth. X-ray crystallography provided a snapshot of the interaction between Erbitux and the extracellular component of the cancer cell's receptors.
As is characteristic of many epithelial cancers - such as cancers of the colon, head and neck, breast, ovary, lung, and pancreas - the surface of cancer cells possess abnormally high levels of EGFR. In a cancer cell, an extracellular hormone binds to the outer piece of EGFR, and causes the inside part to kick off a series of reactions that signal the cancerous cell to replicate and divide.
In the present study, published in Cancer Cell, Ferguson and Merck colleagues found ??“ again using X-ray crystallography -- that matuzumab binds in a different place from Erbitux. Their binding does not overlap, and they can bind to EGFR at the same time.
???These findings imply that a combination therapy using both types of EGFR drugs could be developed and tested,??? says Ferguson. ???This has important implications for the clinical use of matuzumab and for developing new therapies that target EGFR.???
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Chang and first author David Wong, MD, PhD, postdoctoral scholar, began to answer the question of how cancer stem cells originate by comparing genetic activity in embryonic stem cells with the activity in normal adult stem cells. They found a large group of genes that were active only in embryonic cells. They then looked at which genes were active in cancer stem cells and found that the pattern resembled that of embryonic stem cells.
The finding was a surprise, given that once embryonic stem cells become committed to forming adult cells, such as skin, brain or blood, they were thought to forever deactivate those embryonic genes. Instead, Chang said this work suggests that when those adult cells become cancerous, they turn those embryonic genes back on.
The group also noticed that the genes active in both embryonic and cancer stem cells are controlled by a few biological master regulators. One of those genes, called Myc, has also been shown recently to help convert normal skin cells into embryonic-like cells.
By activating two genes in addition to Myc in normal skin cells, those cells were transformed into what appeared to be cancer stem cells. When transplanted into laboratory mice, the cells formed tumors, one hallmark of a true cancer stem cell.
From here, Chang and Wong hope to learn more about how these genes activate a cancerous state. "Our particular interest is in using this approach to find the mechanism that turns a normal cell into a cancer stem cell," said Chang, who is also the Kenneth G. and Elaine A. Langone Scholar of the Damon Runyon Cancer Research Foundation.
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