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Targeted Therapy

Specific Treatments for Hereditary Cancer

by Kathy Steligo

One of the benefits of genetic research and determining an individual’s genetic makeup is the potential for individualized cancer treatment. Hereditary cancers may differ from sporadic, or nonhereditary, cancers in several ways, including which genes are activated, how the cancer develops, and how it responds to treatment. However, no treatment protocols are specific to cancers in BRCA mutation carriers.

Standard cancer therapies often involve chemotherapy to slow the growth of cancerous cells or eradicate them. Chemotherapy is often effective but indiscriminate, damaging healthy cells along with cancerous cells, causing nausea, hair loss and other undesirable side effects.

The ideal treatment eliminates cancer cells but spares unaffected cells. Developing such a “smart” drug requires a greater understanding of how cancer cells are unique from other cells and identifying their vulnerabilities. Targeted therapy, specific treatments for certain cancers based on cellular genetic traits, attacks the unique weakness of cancer cells. This is a growing area of research involving medications that are often more effective with fewer toxic side effects. Herceptin, for example, is a successful targeted therapy for women with aggressive breast cancers that overexpress the Her2neu protein. It has limited use, however, for hereditary cancers associated with BRCA mutations which usually do not overexpress Her2neu.

PARP Inhibitors

Now a breakthrough discovery in the United Kingdom may one day be just what the doctor ordered for women with BRCA1 and/or BRCA2 mutations: PARP inhibitors, targeted therapy using enzymes that appear to destroy hereditary breast cancer tumors without harming normal cells.

Healthy breast cells have two BRCA genes, one from each parent. Normally, each cell is capable of correcting DNA damage and keeping cells from growing uncontrollably. This repair function is critical throughout a person’s life, correcting accumulative cellular damage caused by aging, environmental factors, and certain hormones and viruses. Cells can function normally if one copy of the gene is damaged, as when a BRCA mutation occurs, because the second copy picks up the repair function. Irreparable damage to both copies of the gene, however, can be the first step in developing cancer, creating an environment for cells to grow uncontrollably and allowing tumors to form. For this reason, women who inherit BRCA mutations are at greater risk for developing breast and ovarian tumors.

PARP inhibitors work by selectively killing cells which have no functioning BRCA gene, preventing cells from using their backup repair mechanism. Healthy cells which retain their DNA repair capability theoretically would remain unharmed. Preliminary experiments with mice have been encouraging, killing breast cancer cells that lack BRCA function and eliminating tumors.

“If our laboratory findings are confirmed in the clinic, we could dramatically improve the treatment of patients with BRCA1 or 2 associated cancers,” says Dr. Andrew Tutt, a key researcher.

If trials involving human tumors show similar results, PARP inhibitors may turn out to be significant weapons in the arsenal against cancer, particularly for those with BRCA mutations. The new drugs would likely be used for treatment with chemotherapy, not in place of it. If they successfully treat inherited breast tumors, one day they may also prevent hereditary cancers from developing. And although PARP inhibitors are being studied first on breast cancers, they may prove effective for treating other diseases associated with BRCA mutations, such as ovarian, pancreatic, and peritoneal cancers. Nor will these drugs be limited to mutation carriers. A percentage of sporadic cancers—about 20% of breast cancers and a portion of ovarian and pancreatic cancers—may have inactivated BRCA genes and behave like cancers associated with inherited BRCA mutations. These tumors may also respond to the selective action of PARP inhibitors.

At this point, the toxicity of these drugs is unknown. Nor is it understood whether BRCA mutation carriers may be particularly sensitive to any side effects. And while the earliest test results are promising, researchers suggest tempering enthusiasm with the realities of drug development: once human testing begins, it may take 10 years to bring the new drug to market. Because they will not be available any time in the near future, PARP inhibitors are not an option for women presently making treatment decisions.

The first steps in the developmental timeline involving humans are Phase I studies; small trials of PARP inhibitors (consisting of 40 participants) are beginning in the United Kingdom to monitor the medication’s safety and establish appropriate oral patient doses. If successful, larger clinical trials with BRCA patients will follow. Under the best circumstances, funding trials of targeted therapies and finding qualified participants often requires organized, concerted efforts by patient advocacy groups. Meanwhile, we must continue to unite our community and advocate for our population.

BRCA Breast Cancer Trial

Dr. Tutt and Professor Alan Ashworth, in collaboration with the UK National Cancer Research Institute, have also set up an international study testing carboplatin, an established form of chemotherapy in BRCA-associated metastatic breast cancer. This chemotherapy drug also targets the DNA repair defect in BRCA cancers and may prove more effective and better tolerated than standard taxane-based chemotherapy. They hope US centers for women with advanced BRCA breast cancers will soon adopt this Phase II BRCA trial.

References

T Helleday. Curing hereditary breast cancer. Commentary published in Project Syndicate, May 2005.

H Farmer, N McCabe, CJ Lord, AN Tutt, DA Johnson, TB Richardson, M Santarosa, KJ Dillon, I Hickson, C Knights, NM Martin, SP Jackson, GC Smith, A Ashworth. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, April 2005; vol. 434: p. 917-921.

N Turner, A Tutt, A Ashworth. Hallmarks of ‘BRCAness’ in sporadic cancers. Nature Reviews Cancer, October 2004; vol. 4: p. 814-819.

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