September 1, 2008 (Vol. 28, No. 15)

Nina Flanagan

Biomarkers Are Being Leveraged at All Stages of Development as well as During Treatment

The identification and validation of biomarkers involved in cellular pathways has led to the development of targeted therapies for various cancers. This, in turn, has changed the paradigm of early drug discovery, patient selection for clinical trials, the road to FDA approval, and projected market potential. Many in the field say that diagnostics and drug development must occur simultaneously, as the diagnostic will be required for patient selection.

One could argue that personalized medicine is already here. Some examples include Gleevec, Herceptin, and Erbitux, all target specific cell receptors involved in cell-signaling pathways that lead to cancer.

“It’s illogical to think of developing one drug to treat a certain cancer,” points out Joseph Nevins, Ph.D., Barbara Levine University professor of breast cancer genomics at Duke University Medical Center ( “What’s needed are strategies for patients that don’t respond to current cancer therapies or to new developing drugs,” he explains.

Dr. Nevins will be one of a number of speakers at AACR’s (American Association for Cancer Research) “Third International Conference on Molecular Diagnostics in Cancer Therapeutic Development” to be held later this month in Philadelphia.

“Ultimately,” Dr. Nevins adds, “what truly personalized medicine is about is to get to the point where you profile a patient’s tumor and select the combination of drugs that best match that individual’s profile.”

Prediction and Chemotherapy

Researchers now have the tools to gain insight into an individual’s biology, which is “completely changing the road map of drug development and the way in which doctors think about cancer,” says Steve Shak, M.D., CMO at Genomic Health.

Genomic Health is already commercializing a test called Oncotype DX® that predicts the benefits of chemotherapy, as well as the likelihood of breast cancer recurrence in early-stage disease. In the past year, both ASCO and NCCN (National Comprehensive Cancer Network) have included it in their guidelines, as the only test for breast cancer. In addition, most insurance companies will now cover its cost.

The company estimates that 35,000 to 40,000 assays will be conducted this year. “All this has led many to ask if personalized medicine, the use of multigene assays, is the future. It really is the present,” says Dr. Shak.

He points out that, for a test to be successful, it must pass through multiple challenges such as: developing and identifying the right genes, conducting the right studies to provide evidence that the test is valid and clinically useful, and meeting the needs of clinicians. Additionally, it is key to have sufficient reimbursement that provides enough resources for the development of new tests.

His group is also working on tests for targeted therapies like Erbitux. They recently reported, along with other research teams, on the detection of mutations in Kras that predict the likelihood of benefit from Erbitux.

“Most treatments for cancer are targeted, we just need to incorporate diagnostic tests in order to most effectively and most widely use them,” Dr. Shak explains. “Now that there are many more options in oncology, it’s even more important that we’re able to select among those options more intelligently, based on the individual biology of the tumor.”

Dr. Nevins’ group as well, has developed a series of gene expression signatures based on biomarkers to predict sensitivity and resistance to various commonly used chemotherapies. “We evaluate whether we can achieve better response rates by selecting a drug based on a genomic signature versus random selection, which is currently what’s done.” Ongoing clinical trials in breast and lung cancers at Duke are designed so that treatment is not interrupted.

Dr. Nevins reports that his group continues to develop a large series of signatures to predict the efficacy of about 20 to 30 different drugs. The next step, he says, is fine-tuning the assays to understand how to apply them and use them most effectively. “Certainly, five years from now, it will be commonplace.”

Monitoring Tumor Response

Researchers at NeuroSurvival Technologies developed a compound, 18-F-ML-10, which can recognize cells undergoing apoptosis. This small molecule PET tracer is ammendable to fluoratine attachment and penetrates and accumulates in cells in the very early steps of the apoptosis process.

“Preclinical animal studies have shown that it is selective and universal to any situation in the body where apoptosis is occurring, regardless of the apoptotic stimuli,” according to Anat Shirvan, Ph.D., vp of R&D.

The Phase I study showed that the compound was able to identify physiological apoptosis in the testes of healthy volunteers. In the Phase II evaluation, it was able to identify pathological apoptosis in patients with acute ischemic stroke. The company has an IND to conduct a multicenter trial in the U.S. in people with brain metastases treated with high doses of radiation.

“The compound allows one to see during radiation treatment at a very early stage whether the radiation destroyed the tumor or perhaps extended past the tumor into healthy tissue,” explains Dr. Shirvan. “This allows the radiologist to re-adjust the next dose and/or readjust the alignment so it focuses directly on the tumor.”

This also provides information early enough so that alternative treatments like additional radiotherapy, chemotherapy, or surgery may be considered.

Current imaging methods like MRI and CT cannot be done until two months after radiation treatment to the brain. Additional applications for the marker include cerebrovascular diseases, acute infarct in other organs, solid organ transplantation, and atherosclerosis.

Lung Cancer Drugs

Researchers at Dana Farber ( have discovered that about 10% of advanced lung cancer patients have sensitizing mutations within EGFR, enabling an 80% response rate to Tarceva, leading to survival of two to three years versus only 10 months in a cohort of unselected patients. “These mutations tend to occur more frequently in women, nonsmokers, and adenocarcinomas,” states Bruce Johnson, M.D., professor of medicine at Harvard Medical School ( and director, Thoracic Oncology Program, Dana Farber Cancer Institute.

His group is currently working to discover additional abnormalities that may have potential for targeted agents. Two examples include mutations in oncogenes (BRAF) and translocations (the EML-4 gene), both present in about 2% of lung cancers.

“We’re trying to find mutations present in about five percent of lung cancers, characterize them, and then use agents in early phases of clinical trials to treat those patients,” states Dr. Johnson. “It’s our goal to expand the number of patients so that we can target agents up to 25 percent over the next five to ten years.”

Dr. Johnson says they have identified eight different genes they are trying to characterize within newly diagnosed lung cancer patients. “We think we’ll treat all patients with mutations in EGFR with Tarceva, but the other mutations, we believe, will have agents we can use further down the line after conventional treatment.”

Preclinical studies showed that Tarceva not only inhibited growth in tumors with EGFR mutations it also caused apoptosis. His group is ready to test this in clinical trials.

There are many more mutations to identify and characterize, but Dr. Johnson says they will stay focused on ones for which drugs already exist or for those new drugs which are being developed. “We anticipate adding to those eight genes as time goes on.”

Developing Prognostic Tools

Finding prognostic markers and choosing the right therapy once disease has been identified remains one of the main challenges for the clinical development of molecular diagnostics in oncology, according to Walter Koch, Ph.D., vp, global research. “These are unmet clinical needs that we and others are trying to address, and the challenges for prognostic versus predictive biomarkers can be very different.”

Once biomarkers are discovered, they have to be validated in independent cohorts. The resulting data must substantiate that the markers provide clinically useful information that predicts patient outcome. “Challenges with this scenario include the fact that there aren’t many sets of cohorts, and most samples banked over the past decades come from clinical endpoints not designed to answer a diagnostic question but rather safety and efficacy questions,” Dr. Koch reports.

Roche Diagnostics is currently working with Plexxikon on a therapy-selection marker for melanoma. It is a BRAF kinase inhibitor that targets a specific mutated form, V600E, present in 70% of melanomas.

In drug development itself, Roche has established a new organizational structure to include biomarker discovery and validation in all its programs. “We have the right tools in diagnostics to provide clinically important information and can apply them in clinical trials from the beginning to the end,” Dr. Koch states.

“When a companion diagnostic is necessary and helpful in selecting and stratifying patient populations, we can more easily register drug and diagnostic together. This is a fundamental change from the endpoint of how a physician goes about treating a patient, and also for the drug development process. You start with the notion that you may have a smaller potential market.”

The biggest challenge to reaching the goal of personalized medicine, according to Nancy Simonian, M.D., CMO, Millennium Pharmaceuticals: The Takeda Oncology Company, is the science: trying to understand what are the most critical pathways driving cancer cells to proliferate.

This has led to a change in the approach of clinical studies, especially patient selection. “If you knew your drug was only going to work in a subset of patients who had a specific abnormality in cancer that you can detect, you would only enroll those patients.” But, she adds, that the endpoints of clinical trials have remained the same—clinical efficacy and a positive benefit-to-risk ratio. “Ultimately, I think companies will have to develop their drugs with a companion diagnostic.”

Dr. Simonian says there is an increasing role of various biomarkers early in cancer drug development. “Early on, in first-in-human trials, we collect tumor biopsies before and after the drug candidate is given, to measure target pathway inhibition.” The company is using this approach in studies of a small molecule inhibitor of the Aurora-A kinase.

“The reason is to prove early on in development that you are hitting your target and effecting downstream pathways, which is very important for decision making and dose selection.” In drug development, this represents a move away from pushing the drug to toxicity to, instead, show that the compound is hitting its target and effecting pathways. “As a result, there is more assay development early on, which is later translated to the clinic,” concludes Dr. Simonian.

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