New $4.5 million VCU grant focused on making cancer cells more sensitive to radiation

By Lorraine Cichowski and Rupert Schmidt-Ullrich

RICHMOND, Va. – A team of Virginia Commonwealth University researchers led by radiation oncologist Dr. Rupert K. Schmidt-Ullrich has been awarded a five-year, $4.5 million National Cancer Institute program project grant to continue its groundbreaking research into more effective ways to kill cancer cells with radiation.

During the past five years – the first phase of the NCI award to VCU – VCU researchers have made major contributions to the understanding of how cancer cells respond to radiation and how to exploit those responses with new therapies, including experimental gene therapy.

Specifically, the team – which includes radiation oncologists, radiation biologists, pharmacologists and hematologists affiliated with VCU's School of Medicine and the Massey Cancer Center – has identified a gene in a cancer cell's plasma membrane responsible for causing a cellular defense mechanism that prevents radiation from killing the cancer cell. The team found that blocking the gene's function makes the cancer cell significantly more susceptible to radiation.  In addition, the team has demonstrated that the herpes simplex virus gene, when injected into certain brain cancer cells, dramatically increased the effectiveness of radiation at killing brain cancer

During the next five-year grant period beginning Aug. 1, the team will study the detailed roles of genes in multiple signaling pathways involved in a wide variety of cancers, including cancers of the breast, prostate, head and neck, colon/rectum, cervix/uterus and brain. Researchers will focus on understanding the molecular mechanisms that cause cancer cells to either resist or respond to radiation by studying the cell's three major compartments: the plasma membrane, the cytoplasma and the nucleus, where, depending on the overall balance of signals passing from one part of the cell to another, ultimate responses are generated that determine a cell's survival or death.

VCU researchers hope the studies will lead to new cancer therapies, including so-called gene therapy, which is a novel technique for correcting defective genes responsible for cancer and other diseases by several methods, such as inserting new genes or swapping an abnormal gene for a normal one.

"During the past five years, we have unraveled molecular details of cancer cell responses to radiation, and this improved understanding of cellular radiation responses at the molecular level has dramatically changed our view of radiation's effects on cells," says Dr. Schmidt-Ullrich, professor and chair of the VCU School of Medicine Department of Radiation Oncology, which is located in VCU's Massey Cancer Center, one of the nation's top research and clinical cancer centers.

"We also have identified signaling molecules that are now being developed as early steps toward new gene therapy strategies for sensitizing tumors to the toxic effects of radiation," he says. "However, there are many details about these cellular response systems that we still must learn. Improved understanding of the regulation of cellular radiation signals will point to new therapeutic strategies, the ultimate goal of which is the potential of target-specific genetic radiotherapy."

Late last year, the Massey Cancer Center became one of the first institutions in the nation to begin a gene therapy clinical trial to test the effects of the gene therapy agent TNFerade with standard chemotherapy and radiation therapy to treat patients with pancreatic cancer. Pancreatic cancer was chosen for the study because of the limited success of conventional therapies. The trial is sponsored by GenVec, Inc. and directed locally by Theodore Chung, M.D., Ph.D., associate professor of radiation oncology.