• Turning Point 2012

    Bridges and Partnerships

    Speeding discovery from lab to clinic

    Yawkey-Smith Bridge 

    At a time when collaborations among cancer investigators often span countries and continents, is there any benefit to having potential research partners right next door? In a word: absolutely.

    When Dana-Farber decided to build a new cancer care center alongside a scientific research building, the hope was that proximity would spur collegiality; basic scientists and their clinical investigator neighbors would find new opportunities to work together. The result would be a direct connection between the laboratories where new therapies are discovered and the clinics where they're studied in patients.

    In the year since the opening of Dana-Farber's Yawkey Center for Cancer Care – home to the Institute's adult treatment areas and clinics – this goal has been met many times over. Research that bridges the once "great divide" between laboratory experiment and clinical treatment is gathering momentum throughout the Institute.

    The Susan F. Smith Center for Women's Cancers is a prime example. From clinics on the ninth and 10th floors of the Yawkey Center, the center's specialists in breast and gynecologic cancers are involved in dozens of research projects, collaborating with lab-based scientists a short walk away.

    "We were determined that the bridges connecting the Yawkey Center to the Richard A. and Susan F. Smith Research Laboratories not be just a symbol, but a real crossroads for scientists from different disciplines and specialties," says J. Dirk Iglehart, MD, the Smith Center's director. "All evidence indicates they have become just that."

    As Dr. Iglehart is the first to note, proximity alone is not enough to encourage basic and clinical scientists to work together. But when the potential research partners next door are leaders in their fields, the opportunity is too inviting to pass up. In some cases, scientists have chosen to pursue a particular line of research precisely because it offered a chance to work with a fellow Dana-Farber investigator.

    Examples of bench-to-bedside research abound in the Susan F. Smith Center for Women's Cancers.

    Testing new compounds for HER2-positive breast cancer

    Like a character in Charles Dickens' novel Oliver Twist, cancer is an Artful Dodger, able to slip past many of the impediments that medicine puts in its way. A prime example is HER2-positive breast cancer, named for a protein that saturates its surface.

    The drug trastuzumab – better known as Herceptin – has become a staple for treating such cancers. By blocking HER2, it disrupts the signals involved in cell division, halting or reversing tumor growth. Often, however, the tumor cells improvise a comeback by activating signal transmission lines that work independently of HER2.

    Dana-Farber's Jean Zhao, PhD, has demonstrated that proteins known as PI3 kinases play a key role in these alternate circuits. Researchers have begun to explore whether drugs that target those kinases can offer a useful therapy for cancers with an activation of the PI3 kinase pathway.

    The search for such drugs narrowed when Dr. Zhao found that one variety, or "isoform," of PI3 kinase plays an outsized role in cancer cell growth and proliferation.

    "Drugs that inhibit that one isoform – known as p110α – may be the most effective at blocking PI3 kinase activity," says Dr. Zhao, whose Dana-Farber collaborators include Thomas Roberts, PhD.

    Taking a cue from Dr. Zhao's work, Eric Winer, MD, director of Dana-Farber's Breast Oncology Center, along with colleagues Ian Krop, MD, PhD, and Nancy Lin, MD, are organizing a clinical trial of compounds that specifically attack the p110α isoform. "Our goal is to find new approaches to treat resistant HER2-positive cancers," Dr. Winer states. "We recognize that one treatment will not work for all patients, but this approach may be highly effective for some women."

    Endometrial cancer genetics

    Another research duo is taking aim at the most common gynecologic malignancy in the U.S. – endometrial cancer, a growth in the lining of the uterus that affects 40,000 women in the U.S. every year.

    Little is known about the molecular mishaps that trigger and sustain endometrial cancer, but investigators at Dana-Farber are trying to solve these mysteries. Jean Zhao, PhD, is creating genetically engineered mice to model the development of endometrial tumors.

    She has already found that when the mice have mutations in certain tumor-suppressing or tumor-causing genes, a molecular pathway known as the PI3-kinase/mTOR pathway becomes overactive in endometrial tissue. These events produce highly invasive tumors that mirror the characteristics of advanced uterine cancers in humans.

    "Endometrial tumors contain many mutations, but they cluster in the PI3-kinase pathway," Dr. Zhao remarks. "Targeting that pathway is a key to treatment."

    In conjunction with Dr. Zhao's work, Andrea Myers, MD, PhD, is leading a multi-center clinical trial of a targeted therapy in women whose endometrial tumors have PI3-kinase mutations. The drug works by inhibiting a key element in the PI3-kinase pathway. Preliminary results of the study are expected to be ready later this year.

    "As part of the research, we'll be analyzing tissue from trial participants to determine the molecular characteristics of the tumors that respond best to the drug," Dr. Myers comments. "This is one step in matching treatments to patients who can derive the most benefit from them."

    Triple-negative breast tumors

    By its very name, triple-negative breast cancer suggests a particularly obstinate form of disease. Although chemotherapy is often effective in this type of tumor, the cancerous cells lack three molecules that might make them vulnerable to more advanced, targeted treatments.

    Research by Dana-Farber's Kornelia Polyak, MD, PhD, has revealed, however, that this once-inscrutable type of breast cancer in fact harbors several very promising molecular targets for drug therapy. A soon-to-be-opened trial led by her colleague Nancy Lin, MD, clinical director of the Breast Oncology Center, is examining whether a drug that hits one of those targets is effective in patients with the disease.

    Last year, Dr. Polyak and her colleagues reported that many of the cells within triple-negative breast tumors have an overactive network of genes known as the Jak2/Stat3 pathway. When the investigators tested compounds that block those genes – first in laboratory samples of triple-negative breast cancer cells, then in mice with the disease – tumor growth halted.

    The success of these experiments led Dr. Polyak to contact Dr. Lin, who leads clinical trials of novel breast cancer drugs.

    "Pharmaceutical companies have been developing drugs that inhibit the Jak2 pathway because the same set of genes is involved in blood malignancies such as leukemia," Dr. Polyak comments. "We discovered several pathways that seem to drive triple-negative cancers; we decided to focus first on Jak2 because of the existence of drugs that could be tested in clinical trials."

    The trial is the first to study whether a drug that targets the Jak2 pathway can benefit breast cancer patients, Dr. Lin says. "If it succeeds, we'll begin thinking of ways to combine it with other drugs for maximum effectiveness."

    Bridges near and far

    One of the United States' most valuable exports is the expertise of physicians and researchers who come here to work and study, then bring their knowledge and skills back to their own countries. The benefits flow not only overseas but also to the American clinics and labs where the visitors train: Sharing ideas and techniques can educate everyone involved.

    The Susan F. Smith Center for Women's Cancers has several programs that create this kind of exchange. An international fellowship program brings breast cancer physician-scientists to Dana-Farber for two years of clinical work and research. Launched in 2010, the program has hosted fellows from Australia, Brazil, and Portugal, says Eric Winer, MD, director of Dana-Farber's Breast Oncology Center.

    "Our hope is that they learn from us just as we learn from them," Dr. Winer remarks. "They have an opportunity to see how we work clinically and to engage in short-term research, and when they return to their own countries, they can continue to collaborate with us."

    Another program is geared to the individual interests and schedules of foreign breast cancer surgeons. "We can tailor the program to the time physicians have available – whether a week or a year – and address what they hope to learn," says Mehra Golshan, MD, director of Breast Surgical Services. "They may be in the middle of their medical residencies, or in practice, or changing specialties. They may be interested in surgical oncology, medical oncology, or imaging. The program is flexible enough for a variety of situations."

    Most of the participants have been young – fresh out of specialty training or junior faculty members. However, a recent participant was a general surgeon in her 60s who was switching to a specialty in breast surgery and setting up a clinic in her home city in India.

    Occasionally, Dana-Farber breast specialists have a chance to visit the program's "graduates" in their home countries, as Dr. Golshan did recently when he observed a fellow breast surgeon in Taiwan.

    Clinician Composite 

    Turning Point 2012 

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