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Brigham and Women's Hospital: Signature strengths advance cancer research

Nanoparticles on cell

Targeted nanoparticles (green) taken up by a prostate cancer cell.

Brigham and Women’s Hospital, renowned for excellence in patient care, research, and teaching, traces its roots in medicine back to 1832. Throughout its long history, the institution has achieved milestones in clinical, population, and basic research within the formal structure of individual departments. That research model is beginning to change.

“The center of gravity is shifting to the Biomedical Research Institute,” says Jon Aster, MD, PhD, associate professor of Pathology at BWH and co-leader of the BRI cancer group. Under the BRI, the new umbrella organization for research efforts at the Brigham, research will be clustered into centers, technology platforms, or programs to foster collaboration across disciplines and speed the translation of discoveries into better therapies. “Concentrating the research energy and power of the Brigham in the BRI is an opportunity to realign and reinvest in cancer research here.”

Aster, who is director of the DF/HCC Specialized Histopathology Core, envisions that over the next five years, the BRI will play a critical role in bringing personalized cancer diagnostics and treatments to patients. “We’re well suited to this task because of two signature research strengths: outstanding physician-scientists and pathology resources.”

Gene ratios as prognostic markers in mesothelioma

One of the most active physician-scientists at BWH is David Sugarbaker, MD, chief of the Division of Thoracic Surgery, Richard E. Wilson Professor of Surgical Oncology at HMS, and founder of the International Mesothelioma Program. The IMP is a collaboration of scientists who study the causes of mesothelioma (a tumor of the lining of the chest or abdomen) and search for therapies to extend patients’ lives.

Malignant pleural mesothelioma (MPM) is an especially lethal type of cancer. But while the median survival of patients is between four and 12 months, some patients live for 10 years. Prognostic markers could help oncologists identify which patients would likely respond to the most aggressive therapies, says Sugarbaker. He and colleagues Gavin Gordon, PhD, and Raphael Bueno, MD, also of the BWH Division of Thoracic Surgery, took a genomics approach to find such predictive markers.

Tapping the rich repository of tumors at the BWH tissue bank, investigators retrospectively compared the gene expression levels of MPM tumors from patients who did well on treatment to those who did not. Using oligonucleotide microarrays, they identified seven genes that were up- or downregulated in the samples and calculated the difference in expression levels as a ratio (the average expression level in good-outcome samples/average expression level in poor-outcome samples). This research resulted in two sets of ratios: one associated with good outcomes and the other with poor outcomes. Investigators later validated the gene-ratio strategy in prospective studies.

They also demonstrated that gene ratios derived from fine-needle biopsies are consistent with those from open biopsies. Moreover, when they compared gene ratios to post-operative staging, the genomics approach proved just as accurate a prediction of survival. “The tremendous power of this technique is that we can biopsy a tumor, look at the gene ratios, and tell the patient whether aggressive therapy is going to work,” says Sugarbaker, who is now seeking FDA approval for the prognostic test. “We’re on the verge of launching a gene-ratio treatment strategy for MPM patients.”

Parsing the proteome in gliomas

Surgeon-scientist Mark Johnson, MD, PhD, assistant professor of neurosurgery at BWH, also uses genomic approaches. Multiple research projects in his lab are aimed at understanding the biology of gliomas – the most common brain tumor, characterized by an ability to invade surrounding tissue – and finding new targets for treatment.

As a 2007 recipient of an NIH New Innovator Award, Johnson is investigating the role of microRNAs (short, noncoding strands of RNA that regulate protein expression) in determining brain cancer aggressiveness. To elucidate these elusive strands, he is exploiting genomics at every level: DNA, RNA, microRNA, and protein expression.

“Many changes in RNA expression are not reflected in amplifications or deletions of DNA; some result from epigenetic changes, and others from the activity of microRNAs,” explains Johnson. Likewise, RNA expression does not always correlate with protein translation, a process in which microRNAs might also play a role. “To really understand this complex system, you need to view all these levels of regulation,” he adds. “Any study of microRNAs must look at the final product: protein expression.”

Johnson is doing just that, using high-throughput proteomics and comparing the results to analyses of microRNA, RNA, and DNA expression. “What’s novel about this grant is that it integrates genome-wide analyses of the cancer proteome” to predict important interactions of microRNAs. He has found that many of the microRNA pathways are disrupted in cancer, resulting in abnormal growth and abnormal differentiation. Investigators will now validate their findings in cellular systems.

Johnson’s research, like that of most physician-scientists, reflects the questions he encounters every day in the clinic. Why, for example, are some tumors more aggressive? “We’re trying to answer these questions in the lab. Our hope is to develop some new treatments that will benefit glioma patients.”

Targeting tumors with nanotechnologies

Some of the most extraordinary research at BWH is emerging from the Laboratory of Nanomedicine and Biomaterials, run by Omid Farokhzad, MD, assistant professor of anesthesiology at BWH. (The term nanotechnology refers to the manipulation of matter on the scale of the nanometer; unlike matter on the micro scale, nanoparticles can penetrate the cell.)

The purpose of his lab is to engineer novel nanoparticles that have the potential to improve human health, says Farokhzad, who also practices anesthesiology and pain medicine. Although the majority of his research focuses on prostate cancer, his group is also developing nanomedicines for breast cancer, cardiovascular disease, and even diabetes. Brigham and Women's Hospital is one of the collaborating institutions – along with MGH, Harvard University, MIT, and the Broad Institute – that was awarded $15.6 million from the National Cancer Institute to develop nanotechnologies for cancer therapeutic and diagnostic applications. More recently, BWH and partners MIT, DFCI, and Cornell were also awarded $5 million from the Prostate Cancer Foundation.

Within two years, Farokhzad and colleagues plan to bring to clinical trials the first nanoparticles to treat hormone-refractory prostate cancer, for which there is no effective therapy today. Working with Robert Langer, PhD, of MIT, Farokhzad has engineered biodegradable nanoparticles to use as delivery vehicles for anticancer drugs. On the inside, these particles carry docetaxel, a common chemotherapy drug; on the outside, they are coated with single-stranded RNA molecules called aptamers, which are designed like homing devices to bind only to prostate-tumor antigens, thus sparing normal cells. When the nanoparticles enter the tumor cells, they spill their payload of cancer-killing drug. Investigators have already demonstrated tumor eradication in animal models. Farokhzad’s group is now working to optimize the drug properties of the nanoparticles, which will be tested for toxicity in further animal studies. If all goes well, clinical trials will begin in 2009.

Dual-duty quantum dots

Meanwhile, the next generation of nanomedicines is giving new meaning to “intelligent design.” Made of nanocrystals called quantum dots, these particles have been ingeniously engineered so that each component has multiple functions. The RNA aptamers, for example, contain double-stranded regions that are capable of carrying the drug as well as targeting the tumor antigens. The drug – doxorubicin, this time – not only kills cancer cells but helps to image the treated cells. The particle is designed so that the wave length of light emitted from the quantum dot is the same as the wave length of light absorbed by doxorubicin. Thus while the drug is riding along on the particle, no light radiates; but as soon as doxorubicin slips into the cancer cell – and is no longer absorbing light – the cell illuminates.

“Isn’t that the coolest thing you’ve ever heard!” marvels Farokhzad.

Lonnie Christiansen