Relapse or Remission?
Pharmacogenomics Draws the Fine Line

Shortly after chemotherapy treatment, how does a doctor know if a cancer has responded favorably or not to the treatment, or if a patient is destined to develop drug toxicity — before it is too late?

Recent work in the field of pharmacogenomics is moving toward reducing that perplexity and making treatments more individualized for patients. Researchers present their latest advances today at the 2003 American Association for the Advancement of Science (AAAS) Annual Meeting.

The difference between slating a patient for a bone marrow transplant and staying on course with chemotherapy can depend on observations at the gene level in a patient, says William Evans of the St. Jude Children's Hospital. Diagnosing a sickness, or identifying a new molecular target for developing a new drug therapy, can be performed more effectively and efficiently, through DNA chip technology, according to Evans, whose latest clinical trial work indicates that gene expression profiling and detection of host genetic polymorphisms will someday be the "norm" for developing personalized medical treatment and care for diseases. His recent genomic studies discriminate between patients with childhood acute lymphoblastic leukemia (ALL) who relapse after treatment, and those who are on their way to cure.

Leukemia is a "constellation of diseases at the molecular level," Evans says, because this cancer of the blood and bone marrow has many different subtypes. This makes treatment challenging, and one out of five childhood ALL patients cannot currently be cured. Now, analysis at the molecular level "is about how we're using both the host genome and the tumor genome to diagnose patients and determine the appropriate intensity of therapy," Evans says. Work in pharmacogenomics, where functional genomics and molecular pharmacology merge, would help patients at high risk for relapse, while also reducing toxicity from unnecessary chemotherapy.

The healthy cells and tumors cells of a patient each have distinct genomes, or DNA sequences, but the "regions" of the genetic terrain that interests scientists are similar. These are the sequence sections that contain the inherited genetic variation, and the DNA sequence mutations in the tumor.

DNA chips, or gene chips, allow researchers to study the expression, or transcription, of multiple genes at the same time, into RNA. To develop new ways to diagnose a person's inherited response to disease or drug, Evans has been working on developing new kinds of DNA chips carrying the whole human genome. "We're beginning to have DNA arrays that eliminate splice variants," Evans says. Because there is variation in human genetic information, there is also inherited variation in a person's drug absorption. This also has to be considered along with the gene expression of the cancerous cells. Combined, these would key clinicians in on how to optimize the selection or doses of drugs, at a molecular level, instead of relying on traditional pathology tools, such as flow cytometry and karyotyping.

"We now know those molecular abnormalities translate into a different signal of gene expression. This gene expression translates into prognostics," Evans says. "Most recently, they're telling us about how the drugs are working either given alone or in combination. Now, we're starting to look inside the cell at a genomic level and see what's going on, why some patient's cells are escaping effects of drugs."

In Evans' clinical trials, he is studying the complexity of how single drug treatments or a therapeutic method affect patient and cancer cell gene expression, but he is also working towards understanding how gene expression is impacted when patients are given a multiple-treatment regime. In other words, the kinds of RNA that are produced from the DNA code of life are different in all these scenarios, and the sum of the parts does not necessarily equal the whole. This information paves the way for identifying new molecular targets to see why some cells are resistant or why others are cured, and Evans is doing ongoing work with patients to develop more custom-tailored care for children with ALL.

"I think using gene expression profiling to evaluate the tumor and molecular diagnostics to determine host genotypes, are going to be the norm," Evans says of the future of personalized drug therapy.

14 February 2003