• Translational Research

    Advancing Translational Research through Institutional Resources

    george-demetri.jpgGeorge Demetri, MD 

    In recent years, Dana-Farber has invested in initiatives that provide the organizational framework and resources needed to support outstanding translational research. "The overall strategy behind this considerable institutional support is to facilitate productive relationships, internally and externally, that lead to the highest-caliber clinical trials," says George Demetri, MD, of the Department of Medical Oncology and director of the Ludwig Center for Cancer Research at Dana-Farber. "Our aim is to decrease drug development time from twenty years to five by making these connections work effectively, and ultimately to ensure that the best science ideas from the lab are converted quickly to the clinic."

    The Ludwig Center for Cancer Research at Dana-Farber

    The first of only six of its kind in the United States, the Ludwig Center at Dana-Farber represents an expansion of the philanthropic vision of American business magnate Daniel K. Ludwig, who bequeathed his fortune to cancer research. Under the direction of Demetri, and supported by an endowment in perpetuity, this academic research center helps to translate scientific discoveries from the laboratory into the clinic as rapidly as possible. This is achieved by fostering collaborations among a multidisciplinary group of investigators and facilitating access to new therapies and technologies for preclinical and early clinical research.

    Among other achievements, the Ludwig Center has been instrumental in developing novel inhibitors for the treatment of gastrointestinal stromal tumor (GIST). Approximately 90 percent of patients benefit from first- and second-line treatment with tyrosine kinase inhibitors (TKIs), such as imatinib (Gleevec) or sunitinib (Sutent), which block the activated oncoproteins KIT and PDGFRA; however, resistance to TKIs evolves when tumors acquire secondary mutations in the target kinase. Demetri and the team at Dana-Farber, in collaboration with colleagues at Brigham and Women's Hospital, sought to inhibit these oncoproteins by targeting HSP90, a molecular chaperone that escorts "client" proteins and ensures their proper folding, localization, stability, and degradation. Since HSP90 appears to protect the mutant KIT oncoproteins from normal degradation, investigators reasoned that HSP90 might be a good therapeutic target in GIST and other cancers. A preclinical study validated HSP90 as a target and found that inhibition of the molecule dramatically inactivated KIT oncoproteins in imatinib-resistant GIST cell lines. Later, in collaboration with Infinity Pharmaceuticals, Demetri and Andrew Wagner, MD, PhD, also of the Department of Medical Oncology, and colleagues conducted the first Phase I clinical trial of an HSP90 inhibitor specifically targeting patients with TKI-resistant GIST and other sarcomas. The inhibitor was generally well tolerated and showed evidence of efficacy. This trial led to an international Phase III study in GIST, currently underway, a Phase II trial in lung cancer, and a Phase I study in breast cancer.

    The initial focus of the Center - developing molecularly targeted therapies for GIST and other sarcomas - has since expanded to encompass therapeutic initiatives in melanomas and lung cancers. "Our center has a uniquely dedicated focus on translational science and clinical opportunities," says Demetri. "The driving force, design, and academic control of clinical trials rests firmly in the hands of Dana-Farber. The Ludwig endowment gives us the certainty of continuity, long-term vision, and commitment to do this work."

    Imaging in Translational Research

    andrew-kung.jpgAndrew Kung, MD, PhD 

    "Imaging technology is a powerful tool in translational research," says Annick Van den Abbeele, MD, chair of the Department of Imaging and director of Dana- Farber's Center for Biomedical Imaging in Oncology, or CBIO. "Integrating our preclinical and clinical imaging research activities in CBIO will help us evaluate promising new drugs more efficiently and translate them more rapidly into clinical trials and practice." A critical component of CBIO is the Lurie Family Imaging Center, directed by Andrew Kung, MD, PhD, of Pediatric Oncology. The Center offers state-of-the-art technologies, techniques, and expertise for conducting small animal experiments. In the facility, all imaging equipment is located inside the animal housing barrier. Miniaturized versions of X-ray, CT, PET, SPECT, MRI, and ultrasound equipment are available, as well as a full range of clinically relevant radiotracers. Optical imaging provides an additional research tool for studying molecular targets in living animals. "These imaging modalities will help investigators understand not only whether a drug impacts tumor growth, but also whether a drug modulates its target in vivo," explains Kung. "Imaging is non-invasive and nonlethal, so it gives us the ability to conduct longitudinal studies using smaller numbers of mice to obtain significant results in a matter of days instead of weeks."

    Clinical Research Institute

    As part of a strategic effort to enhance the quality and impact of its clinical trials, Dana-Farber recently founded the Clinical Research Institute (CRI) under the direction of Philip Kantoff, MD, chief clinical research officer. An educational program, directed by Harold Burstein, MD, PhD, of Medical Oncology, offers an intensive two-month training program between the first and second year of fellowship, followed by several hours of coursework per week. Classes and hands-on workshops focus on how to write and conduct clinical protocols. Over time, says Kantoff, CRI will provide training and credentialing for all Dana-Farber clinical investigators.

    In addition, CRI offers consultative services to enhance the scientific design of investigator-initiated trials. "Before the protocol is written, the investigator presents the study concept before a multidisciplinary team of experts, who give their feedback and advice," explains Kantoff. CRI's research navigator then facilitates the execution of clinical trials by linking investigators with services needed for the trial.

    "The intent is to elevate the quality and efficiency of clinical research at Dana-Farber," says Kantoff. "Ultimately, we hope to create a new generation of clinical trials that will guide us toward personalized cancer medicine, an area where we expect to play a leading role." Many of the novel trials emerging from the efforts of CRI will be conducted in the Early Drug Development Center (EDDC), directed by Geoffrey Shapiro, MD, PhD. "CRI and EDDC represent two cornerstones of the larger clinical trials infrastructure we have built at Dana-Farber to improve outcomes for cancer patients," says Kantoff.

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