Philadelphia, PA -- Over the past five years, so-called molecularly targeted therapies for cancer have held out great promise. These therapies are based on blocking a cancer-causing genetic pathway that has been turned on in a tumor, thereby allowing it to proliferate and grow in an uncontrolled manner. For a small number of cancers, chronic treatment with molecularly targeted therapies has been shown to be effective in the clinic – at least in the short-term. Recently, based on animal models, several investigators have proposed that chronic treatment – possibly even brief treatment – with molecularly targeted therapies might eliminate cancers. Curing cancers with short-term treatment, however, contrasts sharply with clinical experience with cancer patients, say Penn researchers. This suggests that tumors often become resistant to therapy by finding a way around the genetic blockade.
Using a model for breast cancer, researchers in the Abramson Family Cancer Research Institute of the University of Pennsylvania report that after blocking the gene c-MYC, which is commonly overexpressed in human breast cancers, the tumor still persists. Senior author Lewis A. Chodosh, MD, PhD, Associate Professor, Departments of Cancer Biology and Medicine, and colleagues report their findings in the December issue of Cancer Cell.
Specifically, the group found that after turning off c-MYC in a mouse model, 50 percent of c-MYC-induced mammary cancers were still able to grow. They also found that residual cancer cells persisted in all animals – even those that were seemingly cancer-free. These residual cells quickly recovered their malignant properties either spontaneously or after the researchers reactivated MYC. Additionally, by sequentially turning the MYC gene on and off in these tumors in order to simulate the treatment of patients with multiple rounds of a molecularly targeted therapy, the investigators found that nearly every tumor eventually progressed to a state that was no longer dependent upon MYC for growth.
With these experiments, Chodosh and colleagues demonstrated that small numbers of breast cancer cells that remain following targeted therapy provide a means for cancers to escape and eventually recur. When tumors shrink in response to therapy, they leave residual cells that ultimately give rise to recurrences. Furthermore, if the targeted oncogene becomes reactivated in those cells, they grow into full-blown tumors very quickly. “Any way you look at it, when physicians apply a selective pressure to a tumor by blocking an oncogenic pathway, cells escape,” says Chodosh. “They find a back door and progress to a more aggressive state that becomes independent of that pathway.”
Chodosh concludes that the type of genetically engineered mouse models used in these MYC studies yield results that are very similar to what is observed in patients and that molecular therapies will likely need to be applied chronically to prevent the regrowth of residual tumor cells that remain after therapy. He further emphasizes that molecularly targeted therapies will need to be combined with agents that target secondary pathways of tumor escape in order to achieve lasting cures.
Penn colleagues on this study are: Robert B. Boxer, Joanne W. Jang, and Louis Sintasath. This work was funded the National Cancer Institute, the US Army Breast Cancer Research Program, and the Susan G. Komen Breast Cancer Foundation.
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