There are over 1,000 molecular targets linked to some aspect of neoplasia currently in preclinical or clinical development or on the market. Among the approximately 500 novel molecularly targeted agents that have been evaluated in clinical trials (multitargeted agents may appear in several groups), there are multiple distinct agents addressing some of the most extensively validated oncology targets, among them:

• 41 agents targeting the vascular endothelial growth factor (VEGF) pathway
• 20 agents targeting the ErBb family (EGFr, HEr2, etc.)
• 13 agents targeting the Aurora kinase family
• 11 histone deacetylase inhibitors (HDAC)
• 13 agents targeting PDGF/PDGFr
• 11 agents targeting various heat shock proteins (Hsp)
• 10 drugs targeting various cyclin-dependent kinases (Cdk)
• 10 agents targeting c-Met
• 10 agents targeting IGF/IGFr
• 10 agents targeting FLT-3
• 9 agents targeting c-Kit

Subscribers, to access comprehensive profiles of these agents, please log in and click on the links on the subscriber home page of nm|OK.

Also, a partial list of specific tumor-related molecular targets is presented in a recent press release at PRNewswire.com. Profiles of all of these agents are in nm|OK and may be viewed by entering the target designation in the Target field in the New Drug module Query Screen.

A team at M. D. Anderson Cancer Center (Houston, TX), led by Isaiah J. Fidler, DVM, PhD, and Mien-Chie Hung, PhD, professor and chair of the Department of Molecular and Cellular Oncology, discovered an unexpected role of EGFr that protects cancer cells from starving. This additional role may explain the limited efficacy of EGFr inhibitors in the clinic. Drugs that only block EGFr's activation by growth factors, i.e. its tyrosine kinase activity, result in response rates in only 10% to 20% of patients with various malignancies.

The M. D. Anderson team reports (Weihua Z, etal, Cancer Cell, May 2008;13(5):385-93) that in human cancer cells, the function of kinase-independent EGFr is to prevent autophagic cell death by maintaining intracellular glucose level through interaction and stabilization of the sodium/glucose co-transporter 1 (SGLT1). EGFr protects SGLT1 from destruction by the cell's proteasome complex. Autophagy is thought to be a second type of programmed cell death, with the first being apoptosis.

Because of cancer cells' high metabolic rate, they require more glucose to fuel their activities than do normal cells. Inhibition of the kinase activity of EGFr does not interfere with its SGLT1 stabilizing activity, allowing cancer cells to maintain their intracellular glucose levels. In order to address EGFr's role in preventing cancer cells from accessing glucose, it is necessary to interfere with the receptor per se rather than its activation. Therefore, it may be necessary to knock down both EGFr's glucose-related role and its growth-inducing kinase activity in order to attack epithelial malignancies that make up 80% of all neoplasms. Blocking EGFr itself is expected to induce cancer cell death by self-cannibalization.

In their research, when the M. D. Anderson team addressed the expression of EGFr and not its kinase activity, they found that blocking the receptor's expression with small interfering RNA (siRNA) killed prostate cancer cells. Similar results were obtained in breast cancer and colon cancer cells. The cells did not die from apoptosis but rather of autophagy during which a cell under stress or lacking nutrients consumes part of its cytoplasm and other organelles to survive. Over the long term, this autophagy leads to cell death.

When glucose levels were measured in two sets of prostate cancer cells, one treated with a tyrosine kinase inhibitor, and the other with EGFr knocked down by siRNA, glucose levels were unaffected by the tyrosine kinase inhibitor but fell by 50% in the cells with blocked EGFr. Similar results were obtained in breast and colon cancer cells. Increasing the level of glucose in the medium that held the cells halted autophagic cell death. In seeking glucose transporting proteins, the investigators found that when EGFr was knocked down in a cell, levels of SGLT1 also fell, as did glucose levels, resulting in autophagic cell death.

This research was supported by grants from the National Cancer Institute (NCI), including M. D. Anderson's Specialized Program of Research Excellence (SPORE) in prostate and breast cancer.

Numerous agents blocking the tyrosine activity of EGFr have been investigated preclinically and/or clinically. Currently, 6 agents targeting EGFr have been approved and are on the market and 14 separate agents are in active clinical development. Also, many others are in preclinical development.

The nature and activity of EGFr are described in great detail in the Targets in Oncology module of nm|OK.

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