The importance of being accurate

Molecular diagnostics hold the promise of distinguishing the patients who will respond from those who will not.

Issue: November 1, 2006

ByWilliam N. Hait, MD, PhD

Our ability to accurately select patients for treatments that target specific molecular abnormalities contained within an individual’s cancer cells will be essential for the practice of modern hematology/oncology. Yet, as physicians and scientists we remain frustrated by our inability to predict who will respond to treatment and who will not.

The American Association for Cancer Research, the world’s oldest and largest cancer research organization, convened a special conference in Chicago on Molecular Diagnostics in Cancer Therapeutic Development to help accelerate the process as part of AACR’s commitment to clinical/translational research.

Attendees from academia, industry, government, along with patients and advocates came together to hear the most recent scientific advances. Topics included how to more precisely define an individual’s malignancy, how to identify promising therapeutic targets and how to improve our understanding of the target within the context of the cancer cell. More than 500 people attended the conference, which was chaired by David Sidransky, MD, director of head and neck cancer research at the Sydney Kimmel Cancer Center of Johns Hopkins University, in Baltimore.

William N. Hait, MD, PhD [photo]
William N. Hait

Therapeutic targets

All drugs have targets, but it is the affinity of the drug for the target and the importance of the target to the disease, relative to normal tissues, that defines the therapeutic index — the ratio of efficacy to toxicity. For example, classic chemotherapeutic agents target DNA, the enzymes of DNA synthesis and repair, and microtubules. These targets are present in every cancer cell (and every normal cell), yet only a minority of patients with solid tumors realize a major therapeutic benefit from treatment, whereas everyone experiences the untoward effects. Molecular diagnostics hold the promise of distinguishing the patients who will respond from those who will not, so the latter can be spared the drugs’ toxicities. For example, we now appreciate that tumors harboring mutations or deletions in the p53 tumor suppressor gene are less likely to respond to DNA damaging drugs than those whose tumors retain p53 wild-type function. Yet, these tumors without p53 function appear to retain responsiveness to microtubule stabilizing drugs like the taxanes and epothilones.

chart Similarly, drugs that target molecules that are more specific for malignant cells do not always work. For example, trastuzumab (Herceptin, Genentech), which targets the HER-2/neu oncogene, is only effective against about 25% of patients whose breast cancers overexpress this target. The results with epidermal growth factor receptor (EGFR) antagonists, including those that target the tyrosine kinase domain of the receptor, are even more limited despite the presence of the target in virtually all patients receiving the drug. The astute clinical observation that non-smoking women of Japanese descent, who often presented with bronchoalveolar non-small cell lung cancer responded best to gefitinib (Iressa, AstraZeneca), led to the understanding that a critical activating mutation in the catalytic domain of EGFR identified those individuals who would benefit greatly from this class of drug.

A second clue comes from the extraordinary efficacy of imatinib (Gleevec, Novartis). The drug’s target, BCR/ABL, is present in all patients with chronic myelogenous leukemia whose cells harbor the 9:22 reciprocal chromosomal translocation commonly known as the Philadelphia chromosome. In the early, chronic phase of this disease, over 90% of patients are likely to achieve a meaningful clinical benefit. However, as the disease moves into its more ominous accelerated and blast crisis phases, the response to imatinib dramatically declines. We now appreciate that this change in efficacy has to do with the ability of cancer cells to mutate the BCR/ABL gene in ways that resist the effects of imatinib, and to accumulate other defects that abrogate response despite a robust drug-to-target interaction. Molecular diagnostics defined the critical mutations in the BCR/ABL oncogene and led to the creation of second generation drugs that are more “irresistible,” ie, they work in the presence of many of the common mutations.

Logical approach

Despite the overwhelming logic of this approach, the conference also highlighted the significant hurdles to implementation. Some examples include the difficulty in obtaining fresh, or adequately preserved tissues, the ability to standardize highly accurate molecular diagnostic tests and the identification of predictive biomarkers that can serve as surrogates to accelerate the drug discovery process. It will be our ability to overcome these barriers that will ultimately define the length of time it will take to realize the promise of modern molecular biology, genomics, proteomics and pharmacogenomics as they relate to the FDA’s Critical Path initiative.

The AACR plans to continue its support of this critically important translational research through its collaboration with the European Organization for the Research and treatment of Cancer and the NCI, in their joint Molecular Targets and Cancer Therapeutics Meeting. The meeting will be devoted to topics such as the use of predictive biomarkers to accelerate drug discovery, and it will be held in Prague, Czech Republic, this month. The AACR will further support these research efforts at its next annual meeting from April 14-18, 2007, in Los Angeles.

For more information:

William N. Hait, MD, PhD, is Professor of Medicine and Pharmacology and Chair of the Cancer Institute of New Jersey in New Brunswick. He is also section editor of HemOnc Today’s Breast Cancer section and president-elect of the American Association for Cancer Research.