Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine: Leading the Way in Cancer Genomics

Siteman Cancer Center

An international leader in cancer treatment, research, prevention, education, and community outreach, the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, Missouri, is the only cancer center in the state (and within a 240-mile radius of St. Louis) to be designated a Comprehensive Cancer Center by the National Cancer Institute, and to serve as a member of the National Comprehensive Cancer Network.

With more than 350 Washington University researchers and physicians providing care for over 8000 newly diagnosed patients each year, Siteman is consistently ranked among the nation’s best cancer centers by US News & World Report. It provides a full range of advanced diagnostic and therapeutic services for patients with all types of cancer, many in the state-of-the-art Center for Advanced Medicine (CAM), an outpatient facility that opened on the Barnes-Jewish Hospital campus in 2001.

Siteman patients have access to more than 250 therapeutic clinical trials, and Siteman-affiliated scientists and physicians hold more than $165 million in annual cancer research and related training grants. Two such grants, from Susan G. Komen for the Cure, were uncharacteristically awarded to scientists from the same institution, namely Washington University, in 2 consecutive years—one to research prevention of late breast cancer relapse and the other to investigate breast cancer vaccine therapy.

This research would not be possible if not for the large-scale DNA sequencing and analysis provided by geneticists Richard K. Wilson, PhD, Elaine Mardis, PhD, and Timothy Ley, MD, at The Genome Institute at Washington University. As leaders in cancer genomics, Siteman/Washington University scientists were the first to sequence and comparatively analyze a tumor and normal genome from a cancer patient, a woman with acute myeloid leukemia. They have performed similar studies in breast cancer and, in a groundbreaking study reported in Nature,¹ have sequenced 46 breast cancer tumor/normal pairs. To date, Institute scientists have sequenced the genomes of tumor cells from more than 700 cancer patients. Based on the information gleaned from this whole-genome sequencing, researchers are beginning to reclassify tumors based on their genetic makeup rather than their location, ushering in a new era in personalized medicine.

Matthew Ellis, MB, BChir, PhD

ER-Positive Disease: Preventing Late Relapse

In May 2012, oncologist and professor of Medicine at Washington University School of Medicine Matthew Ellis, MB, BChir, PhD, along with Pascal Meier, PhD, (The Institute of Cancer Research in London) and Mardis, was awarded a 5-year, $4 million Susan G. Komen for the Cure grant to investigate cell death activation to prevent late relapse in estrogen receptor (ER)—positive breast cancer.

The high prevalence of late relapse of ER-positive breast cancer can be attributed to the huge variations in efficacy of endocrine therapy. “Tumor growth may be reduced, but in many cases, cells survive and proliferate, and a woman who does fine for 5 or even 10 years can then suffer a systemic relapse,” said Ellis, noting that once this occurs, ER-positive disease produces a chronic debilitating illness that is uniformly fatal.

Working from the premise that “abnormal cell survival mechanisms in ER-positive disease that allow recurrence after 5 years can be targeted with carefully chosen experimental drugs that cause tumors to regress completely,” Ellis and colleagues are taking advantage of the new technology that has enabled identification of the differences in the DNA sequences between normal and ER-positive cancer cells. The team began by examining the pattern of these DNA changes to better understand the causes of late relapse and more accurately predict which patients are at high versus low risk, with the aim of developing precise therapeutic solutions for high-risk patients.

“Whole-genome sequencing permits a completely unbiased approach,” Ellis said. “Using the information we obtain, we plan to expand the number of cases sequenced to nearly 3000 to see if we can build better models for endocrine therapy resistance and relapse risk.”

Based on the belief that some DNA changes explain how ER-positive cells evade cell death, the second aim of the research will involve experiments (using human-to-mouse xenograft transplantation) designed to determine the best ways to utilize a number of new drugs in development with the potential to more effectively target and kill these cells, and develop evidence related to which patients are most likely to respond to such drugs.

“In ER-positive disease, endocrine therapy may slow tumor progression dramatically, but if treatment is halted or another mutation develops, the patient will relapse and most likely die,” Ellis said. “We’re hoping that combining endocrine therapy with these new agents (such as PI3 kinase inhibitors that affect a potent cell survival pathway and MDM2 inhibitors that activate the tumor suppressor TP53) will induce cell death and, in subsequent clinical trials, achieve complete pathological response.”

The research will culminate with a trial of one of these new drugs used in combination with an aromatase inhibitor prior to surgery in patients with ER- positive disease, with complete disappearance of tumor as the desired outcome—something almost never seen with aromatase inhibitor therapy alone.

Challenges Remain

“We’re entering into a new phase of cancer research that’s both exciting and challenging,” Ellis said. “We’re not going to find one solution for all breast cancers. Instead, we need to identify the many subsets of the disease, re-examine the meaning of ‘rare’ in the context of a common malignancy, and reorganize our cooperative group mechanisms to enable large-scale sequencing of hundreds of thousands of patients to foster efficient diagnosis and introduction of new drugs into these small subgroups.”

While the technology for doing so is now available, Ellis noted that much of the work to date has been done in retrospect by analyzing genomes in survivors or after a patient dies. “What we need instead is a ‘genome-forward approach,’ in which the phenotypes of mutations can be identified and modeled, and then used to match the right patient with the right treatment from the outset,” he said. “Achieving that goal will usher in the era of personalized medicine for breast cancer.”

One of the challenges Ellis sees ahead relates to how such endeavors will be funded. He also is concerned about the many companies that charge women for genome sequencing without the benefit of truly understanding what the information means. “Sequencing has become relatively easy, but interpreting the resulting information is not,” he said. Ellis also called for a paradigm shift, stressing the need to think about how best to re-engineer the approach to clinical trials to embrace the new focus on individual biology and the latest diagnostic techniques. “Rather than one-size-fits-all research,” he said, “what’s needed is an intense focus on identifying and treating the many subgroups in breast cancer. That, in essence, is what this grant is about: finding out why standard treatments fail and testing our hypotheses in small groups of patients with mutations sensitive to various drugs.”

Reida McDowell, RN, FNP

Nursing Considerations

Reida McDowell, RN, FNP, who has been helping to collect specimens for the institution’s human-to-mouse xenograft tumor bank for 8 years, notes that the tissue is obtained using a minimally invasive skin punch biopsy technique in areas of the body where the malignancy is readily accessible. While the specimens are intended for sequencing, routine pathology is also obtained.

Patients, all of whom have stage IV or locally advanced breast cancer, are recruited from Siteman clinics in the CAM and Barnes-Jewish West County Hospital, and most are women McDowell and the nursing staff have come to know well as they’re followed for recurrence or progression. Other participants come from the surrounding area or other parts of the country after hearing about the sequencing work being done. “While they certainly hope that participating might provide a way to help themselves, these women tend to do so primarily to advance research for others,” McDowell said. She added that some women undergo multiple biopsies as their cancer progresses, providing the opportunity for insight into how the disease evolves over time.

It was only recently that informed consent allowed for the sharing of information gleaned from tumor sequencing, said McDowell, who explained that Ellis discusses the information with each patient. To complement those discussions, McDowell steps into her role as educator, helping patients to sort out the complexities of the information they receive with as much sensitivity as possible, and only after assessing how each woman views her current and future situation.

William E. Gillanders, MD

Breast Cancer Vaccines:

Targeting Unique Tumor Antigens

Also reaping the benefits of the DNA sequencing effort is professor of Surgery at Washington University School of Medicine William E. Gillanders, MD, who, along with Ted Hansen, PhD, and Mardis, received a $6.5 million Susan G. Komen for the Cure grant in 2011 to study personalized breast cancer vaccines based on genome sequencing.

In the cancer vaccine field, the current paradigm of targeting self-differentiation antigens has proved disappointing, possibly because most or all of the high-affinity T-cells capable of recognizing self-differentiation antigens are eliminated when T-cells are programmed during development, the researchers wrote in their grant proposal.² Genome sequencing, they wrote, provides an opportunity to identify unique tumor antigens (antigens that result from mutations that are present in individual breast cancers).

Gillanders and his colleagues have proposed what they describe as an innovative strategy for targeting these antigens, using personalized breast cancer DNA vaccines incorporating multiple unique tumor antigens. He explained that this approach is more effective than conventional vaccines, since T-cell responses to unique tumor antigens are high in affinity, not limited by self-tolerance, and safer, because the antigens are expressed only in tumors. According to the team, another benefit of this approach is its potential application in all types of breast cancers, since all intrinsic subtypes of the disease seem to have a remarkable number of candidate-unique tumor antigens.

Now 8 months into the grant, work is moving forward in parallel on several preclinical objectives, and the team is looking ahead to a phase I clinical trial.

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine Timeline

1999

1999

2004

2005

2010

2011

Alvin J. and Ruth Siteman commit $35 million to the development of the Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine.

A landmark multi-institutional study, including Washington University researchers Perry Grigsby, MD, and David Mutch, MD, shows that women with invasive cervical cancer benefit from the addition of chemotherapy to their radiation treatment.

James W. Fleshman Jr, MD, helps to establish that laparoscopic surgery is as safe and effective as conventional surgery for removing colon tumors.

Siteman’s Program for the Elimination of Cancer Disparities (PECaD) receives a 5-year, $1.25 million award from the NCI to support its work in reducing barriers to cancer education and care for underserved groups.

The NCI renews Siteman’s Comprehensive Cancer Center designation and awards the center a second 5-year grant.

Siteman-affiliated researchers receive $7.1 million from Komen for the Cure for breast cancer research: $6.5 million to develop personalized breast cancer vaccines based on genome sequencing and $600,000 to study better ways of identifying patients likely to develop metastases or recurrences after initial therapy.

1999

2001

2005

2008

2011

2012

The National Institutes of Health awards $218 million to Siteman affiliate The Genome Institute at Washington University to sequence one-third of the human genome.

Siteman is named a National Cancer Institute—designated Cancer Center and opens a new outpatient care facility on the Washington University Medical Center campus.

Siteman is named an NCI Comprehensive Cancer Center and receives a 5-year, $21 million grant.

For the first time, scientists (Genome Institute at Washington University) decode all of the genes of a cancer patient (acute myeloid leukemia) and find a suite of mutations that might have caused the disease or aided its progression.

Scientists, led by Matthew Ellis, MB, BChir, PhD, use whole-genome sequencing to compare differences between the DNA of breast cancer tumors and healthy cells in 50 patients.

Siteman-affiliated researchers receive $5.4 million from Komen for the Cure for breast cancer research: $4.07 million to better identify which women with estrogen receptor-positive disease are at highest risk for recurrence and to determine more effective treatments; $900,000 to evaluate targeted therapies for triplenegative disease; and $450,000 to develop new strategies to prevent and treat metastasis.

• In proof-of-principle studies, investigators are generating T-cell lines specific to unique tumor antigens, and are working to determine if these cell lines can recognize and kill breast cancer cells. Gillanders’s team has already successfully generated T-cell lines in vitro, as well as cell lines from one breast cancer patient, and is now working to obtain leukapheresis patient specimens for generation of cell lines from additional patients.
• The team is working on a strategy for creating an optimized targeting vector backbone for the personalized breast cancer DNA vaccines. While the targeting vector will be the same for all patients, each woman’s specific information will be integrated.
• In addition, the team is validating the personalized vaccine strategies in mouse models—a key step in preparing for a phase I clinical trial.
• The team also is testing strategies capable of improving the memory response following DNA vaccination. “Because our data suggest that failure to induce CD8 T-cell memory is a significant weakness of current cancer vaccines, these studies will focus on improving CD8 T-cell memory,” Gillanders explained.

The goal of the phase I clinical trial, expected to begin in approximately 2 years, will be to assess the vaccine’s safety and its ability to induce an immune response.

“The identification and validation of mutations in individual breast cancers provides an unprecedented opportunity to target unique tumor antigens with personalized breast cancer vaccines,” Gillanders said. “Until now, no techniques capable of rapidly and systematically identifying unique tumor antigens have been available. DNA sequencing technologies have transformed genome sequencing, providing a unique insight into the biology of breast cancer and opening the door to new interventions, while also significantly decreasing both the cost and time required to sequence human cancer genomes.”

Even so, Gillanders cautions against the tendency to benchmark the success of vaccine therapy with the same metric used to evaluate other treatments, such as chemotherapy.

“In many settings and for many cancers, vaccine therapy can be just as effective as chemotherapy with respect to survival,” he said. “It’s important to remember, however, that these treatments work in different ways, with chemotherapy tending to produce dramatic tumor shrinkage and vaccines tending to delay tumor growth.”

References

Laura Bruck is a freelance writer and editor based in Cleveland, Ohio. She has specialized in healthcare reporting since 1987.

1. Ellis MJ, Ding L, Shen D, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature. 2012;486(7403):353-360. doi: 10.1038/nature11143.
2. Susan G. Komen for the Cure. Susan G. Komen for the Cure Research Grants — Fiscal Year 2011. Komen website. http://goo.gl/X2M4r. Accessed August 3, 2012.