Key Proteins in Cell Growth

January 24, 2011

" The current approach of molecular targeting is like shutting down 1 station in

a railway network, " he told Medscape Oncology. " This causes some disruption, but

does not prevent the rest of the system from operating. What we need is

something that can close down the whole system, " he says. Dr. Neidle was

speaking last week at the 2010 School of Pharmacy lecture in London.

Molecular targeting has produced useful anticancer drugs, he said, citing as an

example the " spectacular success " of imatinib (Gleevec, Novartis) in the

treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors

(GIST). However, he suggested that this success is unlikely to be repeated for

the more common cancers.

" We now know that a small number of mostly rarer cancers, such as CML and GIST,

are driven by changes in a very few key proteins involved in cell growth, " he

said. " Targeting these proteins is effective, " he conceded. However, most common

cancers are genetically complex, he pointed out, and are often diagnosed when

this complexity has already spun out of control.

There are also multiple pathways of signaling involved, and blocking one pathway

can easily be compensated for elsewhere. " Hitting a single target is unlikely to

halt tumor progression in these cancers, " he said.

As evidence of this, Dr. Neidle cited the relatively small impact that new

targeted therapies have had on the most common cancers, such as colorectal and

breast cancer. The addition of these targeted agents has delayed progression or

improved survival, but often by only a few weeks, and these new drugs are very

expensive.

This has resulted in some of these news drugs not being accepted in the United

Kingdom. A number of these drugs have been deemed not to be cost-effective by

the National Institute of Clinical Excellent (NICE), and thus are not available

on the National Health Service (NHS). These negative decisions have been widely

covered in the lay media, he said, with emotive headlines such as " Life

prolonging cancer drugs to be banned because they cost too much. "

But, in fact, these negative decisions have been in the minority, he pointed

out. NICE has appraised 79 cancer drugs, and 59 of these (75%) have been

approved for use on the NHS.

Nevertheless, the fact remains that many of the new drugs have only a small

impact on the disease. " We need new drugs capable of making a very significant

difference to patients' survival, " he said.

More " Global " Approach

Dr. Neidle advocated a more global approach to cancer-drug development, which

would focus on global differences between normal cells and cancer cells. One

approach would be to focus on telomerase, the universal driver of cellular

immortality, which is activated in more than 85% of all cancers, he said.

Another is the intriguing finding and " long neglected " Warburg effect, first

noted 90 years ago, in which glucose levels are elevated in cancer patients.

" This is now known to be involved in global cancer cell growth regulation, and

has led to excitement and activity over this as a target, " he added.

" The current approach of molecular targeting is like shutting down 1 station in

a railway network, " he told Medscape Oncology. " This causes some disruption, but

does not prevent the rest of the system from operating. What we need is

something that can close down the whole system, " he says.

Dr. Neidle was speaking last week at the 2010 School of Pharmacy lecture in

London.