Harbor Lecture
Mission Possible: Fresh Troops & New Weaponry in the War on Cancer
Cancer occurs when normal cellular processes go awry due to mutations in a person's DNA. Most current cancer treatments are toxic because they destroy not only tumor cells, but also harm healthy cells. To make matters worse, cancerous cells devise solutions to avoid being killed when challenged by drugs, or may acquire "de novo" resistance to a cancer drug before they are even exposed to the drug. Further complicating the search for effective cures is the fact that most cancers are heterogeneous: not all cells in a tumor are exactly alike, and no single drug—the proverbial "magic bullet"—can kill all the cells. Therefore, surgery, radiation, and harsh drug therapies are often used in attempts to eradicate the disease.
There is good news, however. Many cancers, particularly childhood leukemias, are treatable now as never before. Public awareness of the importaance of early detection has also lead to a decline in some forms of cancer. Moreover, new generations of therapies that target known molecular defects in cancer cells are showing promise.
For those cancers that remain a threat, researchers at CSHL have a plan to fight the enemy head on. As part of the Laboratory's Harbor Lecture Series, Scott Lowe, Deputy Director of the CSHL Cancer Center, outlined the Laboratory's strategy to find ways to conquer cancer. Based on a deep understanding of the genes that lead to cancer and cancer progression, the strategy aims to improve current diagnostic techniques and reveal novel theraputic approaches that specifically target cancer cells and are therefore more effective as well as less toxic.
In his October 8 lecture, Cancer: Mission Possible, Scott explained why gene mutations that give rise to cancer are rarely inherited from one's parents, and how, far more often, such mutations occur spontaneously and accumulate during one's lifetime. Next, Scott described three classes of genes that—when altered or "mutated"—set the cell on a course to becoming cancerous.
"Oncogenes" act as dominant genes whose normal function is to promote cell growth, and can be compared to the accelerator of a car. In cancer cells, mutated oncogenes function as a stuck accelerator, promoting abnormal cell growth. The function of "tumor suppressor genes," akin to the brakes of a car, is to stop cells from dividing or kill them outright. In cancer, mutated tumor suppressors act like faulty breaks and are unable to stop cells from dividing. A third class of cancer-associated genes, Scott explained, is the "mutator genes." These genes function in healthy cells as mechanics, repairing whatever cellular machinery needs fixing. In cancer cells, altered mutator genes act as inept mechanics. When mutator genes no longer function to repair broken cellular machinery, including other damaged genes, mutations that arise in oncogenes and tumor suppressor genes that would normally be repaired instead persist, leading to cancer.
Under normal circumstances, Scott explained, oncogenes, tumor suppressor genes, and mutator genes function in a coordinated manner to control cell division. Altered versions of the same genes allow cancer cells to evade regulatory growth signals, obtain new blood supplies, invade other nearby tissues, and spread to distant sites in the body.
Finally Scott described how he and his CSHL colleagues including Michael Wigler, Rob Lucito, and Greg Hannon have applied powerful new techniques for 1) discovering all of the genes involved in a particular form of cancer, 2) identifying genes required for the survival of cancer cells that when switched off, lead specifically to cancer cell death, 3) exploring chemotherapy response and drug resistance in genetically well-defined mouse models of cancer, and 4) using mouse models of cancer to evaluate novel therapies and combination therapies.
The approaches to understanding and controlling cancer taken by Cold Spring Harbor Laboratory researchers have already revealed several new molecular targets for cancer therapy, some of which are now the basis of experimental cancer treatments being developed in the U.S. The arsenal of knowledge resulting from the research Scott described in his Cancer: Mission Possible lecture provides hope for physicians and their patients, and should ultimately provide much needed relief for cancer patients and their families.
--- Michelle Cilia
[Michelle is a Ph.D. candidate in the Watson School of Biological Sciences at CSHL]
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