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New Progress in Matching Cancer Patients to Drugs

By Jeffrey Norris, UCSF Science Cafe | April 17, 2007

Breast cancers differ from one another and from tumors that arise in other tissues. A drug that is life-saving for one cancer patient may fail in another with a tumor that originated in the same organ. But it's tough to match the patient to the best treatment.

"We don't have indicators for the vast majority of drugs to predict who should be getting them," says Joe Gray, PhD.

Gray, associate laboratory director for life and environmental sciences at the Lawrence Berkeley National Laboratory (LBNL) and co-leader of the breast cancer program for the National Institutes of Health-designated UCSF Comprehensive Cancer Center, is working with many collaborators to improve this state of affairs.

Continued success in the collaborators' studies of cancer cells and human tumors will lead to smarter use of existing drugs. The research also should result in better informed development of new pharmaceuticals, and in the identification of potent cancer-fighting combinations of drugs.

Already, Gray's team has used molecular biology to re-categorize breast cancer in illuminating ways, and has identified subsets of breast tumors that are the most likely to recur soon after surgery -- despite ongoing treatment.

Gray and colleagues discussed their latest results during several talks and a press conference at the annual meeting of the American Association for Cancer Research on April 14-17.

Elusiveness of "Magic Bullets" for Cancer
Historically, the goal of cancer pharmaceutical research, despite limited success, has almost always been to develop drugs that thwart a broad spectrum of cancers while sparing normal tissue.

This is no trivial problem. Genetic abnormalities that accumulate in successive generations of cells drive cancer. The mix of abnormally acting and abnormally produced proteins that arise from these genetic changes has much to do with whether tumor cells succumb to or resist treatment.

Even when treatment is effective initially, a tumor's tendency to genetically mutate often enables it to engender cells that escape death and regrow.

Cells from different tumors often differ in the biochemical pathways they favor to help them survive, grow and spread. And cancers can change course biochemically in an evasive response to treatment, with different tumors adapting in different ways.

As a result, the goal of developing a single drug that acts as a roadblock on an indispensable biochemical pathway used by all cells in all tumors has long remained elusive.

New Approach to Cancer Drug Development Evolves
In general, new drugs for cancer that are tested in broad-based clinical trials have continued to provide little overall survival benefit. Even so, many of these drugs substantially improve outcomes for a minority of patients.

Pharmaceutical company leaders have started to rethink their approach, with an aim to develop drugs designed to more effectively target tumors with specific characteristics.

Many biochemical pathways that play a role in cancer are governed in part by proteins that already have been identified. And many of these biochemical outlaws have been targeted for drug development.

For instance, extra copies of the gene called HER2 are abnormally present in the cells of between 20 percent and 30 percent of breast tumors. HER2 is targeted by a drug called Herceptin, made by Genentech. A decade ago Gray and UCSF colleague Daniel Pinkel, PhD, developed a quick lab test to determine whether a tumor has amplified HER2. Herceptin normally is used only when tumors test positive for HER2.

Microarrays Reach the Mainstream
In more recent years, researchers have been developing the capability to obtain information simultaneously on many different genes or gene products obtained from cells.

One goal is to identify patterns of gene activation or inactivation that help predict how aggressive or deadly tumors are likely to be, and to ratchet up post-surgical therapy accordingly.

Gene activity in fresh tumor tissue now can be measured with a microarray "chip," essentially many thousands of lab tests on a glass slide.

The MammaPrint -- a microarray developed through cancer genetics research conducted by Laura van't Veer and colleagues at the Netherlands Cancer Institute -- became the first microarray to be approved for sale in the US as a clinical lab test earlier this year. MammaPrint, which measures activity of 70 selected genes, is used to help gauge cancer severity in women diagnosed with small breast tumors that have not yet spread to lymph nodes.

(Note that in November 2007 the UCSF Comprehensive Cancer Center was renamed the UCSF Helen Diller Family Comprehensive Cancer Center.)

Read more at Jeffrey Norris, UCSF Science Cafe