Seven common myths about cancer debunked.

ZURICH -- Recent advances in cancer genetics have fueled the push for targeted therapeutics--and are standing the field of oncology on its head, Dr. Levi A. Garraway said at the annual meeting of the European Society for Dermatological Research.

"Think of cancer as a disease of the genome leading to abnormal activation of oncogenes and inactivation of suppressor genes," he said.

Dr. Garraway, who is with the Dana-Farber Cancer Institute and Harvard Medical School, Boston, is credited with major advances in the understanding of the biology of melanoma. He led an international team that discovered that the melanocyte master regulator MITF (microphthalmia-associated transcription factor)--which normally regulates melanocyte differentiation and survival--is also a lineage survival oncogene figuring prominently in metastatic melanoma (Nature 2005; 436:117-22). MITF thus provides an important new potential therapeutic target in a disease that has seen precious little therapeutic progress in decades.

He described and then debunked seven widely held myths about cancer biology and therapy:

1. Cancer is common. Certainly true in terms of patient numbers, but at the cellular level--and again, thinking about cancer in cellular and molecular terms is proving extremely fruitful--the notion that cancer is common is a myth. Indeed, at the cellular level, cancer is exceedingly rare.

Take the example of acute myelogenous leukemia. There are 2,000-3,000 new cases annually in the United States. That means, by a back-of-the-envelope calculation, there is one cancer cell for every 100 quadrillion normal bone marrow cells nationwide per year, he said.

"The question to ask in terms of understanding the genetic basis of cancer is not 'why is cancer so common?' But 'why is it so rare at a molecular level?'" the oncologist said.

2. Cancer cells grow more rapidly than normal cells. Not more rapidly, as a rule, but inappropriately. When oncologists obtain bone marrow samples from patients with acute myelogenous leukemia several weeks after administering induction chemotherapy to obliterate both normal hematopoietic progenitor cells and leukemic cells, what they see under the microscope, provided there has been a remission, is recovery of the normal marrow. Leukemic cells are still present--several more cycles of chemotherapy are required for cure--but they have been outpaced by the faster-growing normal cells.

3. Expression of an activated, cancer-causing oncogene such as BRAF in normal epithelial cells causes them to grow more rapidly. Melanocytic nevi provided the first in vivo demonstration of what is now a well-established general phenomenon: Expression of an oncogene allele in a normal cell typically results in cell death or irreversible growth arrest.

Eighty percent of nevi possess the activated BRAF point mutation. Moreover, BRAF mutation is present in more than one-half of melanomas. Yet fewer than 1 in 1,000 moles will progress to melanoma. In the majority of cases, oncogene expression triggers activation of tumor suppressors, resulting in a phenomenon called oncogene-induced cell senescence (N. Engl. J. Med. 2006;355:1037-46).

4. Oncogenes harbor gain-of-function somatic mutations that are sufficient to transform normal cells into malignant ones. It is now clear that cancer involves a multistep path. In most cases no single genetic alteration is sufficient to cause malignancy.

The two key phenomena involved in the development of cancer are insensitivity to the normal breaks in the cell division cycle and indifference to exogenous growth factors. If cells are able to bypass the oncogene-induced cell senescence roadblock, they undergo cellular crisis, which is marked by telomeric dysfunction, genomic instability, and massive cell death. Only a few cells survive this crisis. They emerge from the turmoil with stabilized telomeres, giving the cells limitless replicative potential and resistance to apoptosis.

But even then they are still not cancer. They must go on to develop the other hallmark of malignancy: the ability to invade normal cells and metastasize, Dr. Garraway explained at the symposium, which was sponsored by Galderma.

5. Conventional chemotherapy works by selectively killing dividing cells. Actually, chemotherapeutic agents work by a variety of mechanisms having in common the induction of apoptosis. Yet evasion of growth arrest and apoptosis is hardwired into the carcinogenic process-it is a hallmark of cancer. This explains why chemotherapy is generally ineffective in advanced cancer.

6. The optimal form of cancer therapy is defined by a malignancy's anatomic origin. That's how cancer clinics have always been set up. But this ignores the fact that key genetic derangements don't always respect anatomic boundaries.

For example, Herceptin (trastuzumab) started out as an effective therapy for breast cancers marked by HER2 overexpression. But there is mounting evidence that Herceptin is also effective in lung cancers and colon cancers featuring HER2 overexpression.

"There's a paradigm emerging where we think of cancer in terms of the critical molecular alterations that occur in a tumor. Anatomy is important in terms of predicting the frequency of these alterations, but it may not necessarily be the trump card that it is right now in terms of determining how patients are to be treated," Dr. Garraway continued.

At present, guidance of patient care based upon critical genetic alterations is occurring in clinical trials; Dr. Garraway predicted it will increasingly work its way into daily practice.

"We can already see this by the example of Gleevec, which is effective against cancers involving BCR-ABL mutations, KIT mutations, PDGFR-alpha mutations. These are the criteria we use to decide whether the cancer is going to respond to Gleevec. We don't necessarily use the observation of what type of cancer it is," he explained.

7. Cancer genomic alterations are too complicated and the genomic instability is too great to yield good therapeutic targets. There has been skepticism all along, but it has gradually diminished over time in the face of Gleevec and other therapeutic success stories.

Moreover, powerful tools for the cost-effective identification of novel therapeutic targets have emerged as a spin-off from the Human Genome Project. For example, Dr. Garraway and coworkers have developed a system that uses high-density single nucleotide polymorphism arrays to screen a sample of a patient's tumor DNA for 238 known mutations in 17 of the best-established oncogenes at a cost of about $65. The resultant information could someday soon be used to guide rational individualized cancer therapy (Nat. Genet. 2007;39:347-51).

BY BRUCE JANCIN

Denver Bureau