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Pathways to Discovery: Spring 2013

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A New Age of Radiation Therapy

Nearly half of all cancer patients receive radiation therapy, yet why some patients benefit but others do not remains poorly understood. A team of scientists at the University of Chicago Medicine Comprehensive Cancer Center (UCCCC) hope to improve the success of radiation therapy by studying how cancer cells respond to radiation.

Stephen Kron, MD, PhD, professor of molecular genetics and cell biology, has been collaborating for over a decade with Ralph Weichselbaum, MD, professor of radiation and cellular oncology, to advance new concepts in radiation therapy.

Senescent Cells

Dr. Weichselbaum and his colleagues had recently shown that patients whose cancer has begun to spread often respond well to treating the metastasis with a few, high doses of radiation therapy. At the same time, Dr. Kron was studying radiation using microscopy to follow chromosome damage and repair. Working together, they found that high radiation doses cause DNA damage that cannot be repaired. As a result, cancer cells stop dividing and instead age prematurely. Whether aging the cells in a tumor is a good idea or not continues to be controversial. Although the aged, senescent cells can no longer divide, there is concern that they may create inflammation that accelerates the recovery and growth of nearby cancer cells.

A Cancer Vaccine

Drs. Kron and Weichselbaum hypothesized that if they could selectively age cells within a tumor but manage the inflammatory signal, the radiation might bolster antitumor immunity rather than enhance cancer growth. They found that treating cancer cells concurrently with poly-ADP ribose polymerase (PARP) inhibitors and radiation not only promotes senescence, but modulates inflammation so that the cells adopt the properties of a vaccine. Injected into mice, the senescent cells activated an anti-tumor immune response. The vaccine prevented new tumors and slowed the growth of existing tumors. Most exciting, inoculating the vaccine and then treating the tumor with radiation had dramatic effects, apparently curing the mice.

Dr. Kron said, “Our studies indicate that the advantage of using PARP inhibitors to enhance the effects of radiation therapy may result from both intensifying the damage to the cancer cells, as well as stimulating the host’s immune system to recognize the tumor as a foreign invader.” These observations fit well with an emerging trend where patients receiving radiation therapy are also treated with drugs and vaccines meant to activate the patient’s immune response.

Kron and Weichselbaum envision applying their new insights by using a patient’s own cancer cells to form a senescent cell vaccine. They hope to dramatically improve the benefits of radiation therapy, particularly in patients whose cancer has recurred and spread. “Our hunt-and-kill idea combining the new immune stimulating drugs and perhaps our vaccine with image-guided radiotherapy to tackle metastasis could be quite powerful,” said Dr. Weichselbaum. “We have submitted grants in the hopes that we will be able to investigate these concepts further and progress to clinical trials in the near future.”

Ernst Lengyel

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