A newly established fund to support innovative cancer research at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine has awarded its first two $900,000 grants to high-tech efforts to undermine cancer cells’ ability to resist treatment. The awards will help scientists use genetic data to find new ways to attack treatment-resistant breast cancer and precisely target treatments for various kinds of cancer cells based on their responses to radiation therapy.
The Alvin J. Siteman Cancer Research Fund was established in 2010 by Alvin J. Siteman, an emeritus Washington University trustee who has received several major awards from the institution for his support and generosity. He is chairman of Site Oil Co. of Missouri and president of Flash Oil Corp. He was president and chief executive officer of the Siteman Organization, a major real estate developer, property manager and leasing agent. He also chaired Mark Twain Bancshares Inc., the company he helped merge with Mercantile Bancorporation in 1997. In 1999, Alvin and Ruth Siteman committed $35 million to the development of the Siteman Cancer Center at Washington University School of Medicine and Barnes‐Jewish Hospital, which was named in recognition of the gift.
“The Siteman Cancer Research Fund supports short-term projects and major initiatives with great potential for advancing cancer prevention, diagnosis and treatment,” says Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine. “It was created to help innovative, paradigm-challenging projects whose unconventional natures may make them less likely to receive federal funding or support from other foundations.”
“The projects that the new Siteman awards support apply some of the latest developments in science and technology to the challenge of fighting cancer,” says Timothy J. Eberlein, MD, director of the Siteman Cancer Center. “These two projects combine some of the most outstanding investigators doing exciting and innovative work that may quickly lead to new cancer treatments.”
Helen Piwnica-Worms, PhD, the Gerty T. Cori Professor and head of Cell biology and Physiology, and Jason Weber, PhD, associate professor of medicine and of cell biology and physiology, received one of the awards for their plan to develop new tumor treatment strategies using information gained from sequencing all the DNA of individual cancer patients.
Piwnica-Worms and Weber will focus on breast cancer patients whose tumors make a receptor for the hormone estrogen. Researchers at Washington University’s Genome Institute sequenced all of the DNA of 50 of these patients, dividing them into two groups: patients whose tumors shrank in response to estrogen-deprivation therapy and patients whose tumors did not respond to this therapy.
“That called our attention to certain pathways that were altered in the DNA of both patient populations,” Piwnica-Worms says. “The challenge is to identify which of those changes made the most important contributions to the development of the breast cancers, which is the first step toward detailing those contributions and developing new approaches to block them.”
Piwnica-Worms and Weber will apply a novel and powerful technique called zinc finger nucleases to identify which of the changes in individual pathways are key to driving breast cancer. They will test FDA-approved drugs that block important proteins in these pathways to see if the drugs can kill breast tumor cells in culture and in mouse models.
“If we’re successful, what we learn in the lab may set the stage for immediate clinical trials of new drugs for treatment-resistant breast cancers,” Piwnica-Worms says.
Dennis Hallahan, MD, the Elizabeth H. and James S. McDonnell III Distinguished Professor and head of Radiation Oncology; Michael J. Welch, PhD, professor of radiology; and Thomas Ellenberger, DVM, PhD, head of biochemistry and molecular biology, received an award for their proposal to use cancer cells’ responses to radiation treatments to better target them for additional therapies.
“Since 1998, my lab has identified more than four dozen stress proteins that only appear on the surface of cancer cells when they have been exposed to ionizing radiation, which is the type of radiation used in cancer treatment,” Hallahan explains. “We screened more than 2 billion peptides, or protein fragments, multiple times to identify which were best at specifically binding to these cancer stress proteins.”
Hallahan used several criteria to analyze the protein-peptide pairs, including which bound together best and which might be useful in the widest variety of cancers. With support from the Siteman Cancer Research Fund, he is now ready to try out the combination that seems to have the most therapeutic potential: peptides that bind to a cancer stress protein known as TIP-1.
Researchers plan further tweaks in computer models, the test tube and animal models to ensure that the peptide they use can target TIP-1 with maximum selectivity and strength. They will then link the optimized peptide to microscopic doses of the cancer drugs Taxol and Doxil and test whether this combination can treat mouse models of human cancers.
“When we’re done, we’ll know which types of cancers are best suited for Phase I and Phase II trials of this approach,” Hallahan says. “If it’s successful, this could be very helpful for fighting cancers that can’t be treated surgically or keep recurring.”
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.