The Department of Medical Oncology seeks to gain insights that lead to the prevention of cancer and to improve diagnosis and treatment of adult patients with cancer. The Department engages in a broad range of basic and clinical research, patient care, and teaching.
The Department of Medical Oncology is committed to offering compassionate care, cutting-edge clinical and basic research, and outstanding training opportunities for basic and clinical investigators. More than 200 faculty are organized into seven divisions: General Oncology (Lawrence Shulman, MD); Hematologic Malignancies (Robert Soiffer, MD); Hematologic Neoplasia (Margaret Shipp, MD); Molecular and Cellular Oncology (Myles Brown, MD); Population Sciences (Deborah Schrag, MD, MPH); Solid Tumor Oncology; and Women's Cancers (Eric Winer, MD). Division chiefs play key roles in departmental operations, planning, promotions, recruitment, and administration. Robert Mayer, MD, vice chair for academic affairs, and Edwin Alyea, MD, chief of inpatient operations, perform key administrative functions.
Clinical trials and patient care are conducted in 14 interdisciplinary disease centers, each directed by a nationally recognized leader who is responsible for the clinical and research activities of their center. These include: Bone and Sarcoma Oncology (George Demetri, MD), Breast Oncology (Eric Winer, MD), Cancer Genetics (Judy Garber, MD ), the Carole M. and Philip L. Lowe Center for Thoracic Oncology (Pasi Jänne, MD, PhD), Cutaneous Oncology (Thomas Kupper, MD), Early Drug Development Center (Geoffrey Shapiro, MD, PhD), Melanoma (F. Stephen Hodi, MD), Gastrointestinal Oncology (Charles Fuchs, MD, MPH), Gynecological Malignancies (Ursula Matulonis, MD), Head and Neck Oncology (Robert Haddad, MD), Hematologic Oncology (Robert Soiffer, MD), Hematology (Nancy Berliner, MD), the Lank Center for Genitourinary Oncology, and Neuro-Oncology (Patrick Wen, MBBS). These centers are also the focus of teaching and mentoring for the 14 first-year clinical medical oncology fellows at Dana-Farber/Partners CancerCare as well as many senior fellows. Clinical care and research involving other departments - including Radiation Oncology, the Cantor Center for Research in Nursing and Patient Care Services, and Surgical Oncology at the Brigham and Women's Hospital – also take place within the centers.
A major departmental research theme is linking knowledge of the genes that cause cancer to the discovery and testing of new therapeutics, involving both small-molecule drugs and immune approaches. Other key themes relate to developing personalized medicine strategies by using genetic, epidemiologic, and population-based studies to determine risk and ideal treatment for individual patients.
Dana-Farber currently has nearly 400 open adult therapeutic clinical trials. It accrues several thousand patients to therapeutic and non-therapeutic clinical protocols each year. Disease center members play a major role in Dana-Farber/Harvard Cancer Center's research programs and in national cooperative group trials, such as the Cancer and Leukemia Group B (CALGB).
Through the efforts of Philip Kantoff, MD, Dana-Farber has formed a Clinical Research Institute to provide training and oversight of investigators involved in clinical trial research. Clinical researchers have access to a sophisticated infrastructure of cores and other facilities to help them conduct clinical trials at the cutting edge, including an outpatient research chemotherapy unit in which the most complex of clinical trials can be conducted.
Department investigators focus on testing new drugs in Phase I and II trials, particularly first-in-human studies that have the potential to move the boundaries of oncology care. A particularly novel approach to clinical investigation is the Institute's development of a new faculty model in which selected physician/scientists, dedicated to translational research, are recruited specifically to undertake laboratory research that leads to new clinical trials. Part of the Center for Clinical and Translational Research, this Next Generation Program was initiated by Lee Nadler, MD, and is now led by Bruce Johnson, MD.
The Department currently houses 40 independent research laboratories. Recent laboratory recruits include Jennifer Allen, DSc, MPH, RN, Rameen Beroukhim, MD, PhD, James Bradner, MD, Ronny Drapkin, MD, PhD, Keith Ligon, MD, PhD, and David Weinstock, MD. Highlights of faculty research activities and accomplishments are presented below.
As part of the Specialized Programs of Research Excellence (SPORE) in breast cancer, a team of investigators led by Garber, Daniel Silver, MD, PhD, and Andrea Richardson, MD, PhD, conducted the first preoperative trial of cisplatin in patients with triple-negative breast cancer. The study demonstrated that the single agent cisplatin, administered for only four cycles, resulted in a pathologic complete response rate of approximately 22 percent. The study led to the development of other trials evaluating the platinum salts in patients with triple-negative breast cancers, including those with BRCA1 mutations. As part of the trial, tumor specimens were collected to look for predictors of response to therapy. Of interest, two patients were found to have a BRCA mutation and both had pathologic complete responses. A Phase I trial combining cisplatin with a PARP (poly (ADP-ribose) polymerase) inhibitor is now being conducted.
With the goal of tailoring therapy to the specific genetic changes present in a patient's tumor, several labs have made significant contributions to studies identifying genetic mutations associated with different forms of cancer. Among these were studies led by Matthew Meyerson, MD, PhD, in which a number of novel mutations in glioblastoma, the most common type of adult brain cancer, and lung adenocarcinoma, the most common form of lung cancer, were found. The glioblastoma study was part of The Cancer Genome Atlas (TCGA) project, a federally-funded effort to probe genomic changes involved in human cancer. Meyerson is principal investigator of a TCGA center at Dana-Farber and the Broad Institute.
Richard Stone, MD, and James Griffin, MD, are developing leukemia therapies that are pathophysiologically linked to mutations in the FLT3 tyrosine kinase oncogene. Martha Wadleigh, MD, is studying whether JAK2 mutations are important pathophysiologically in polycythemia vera and other myeloproliferative disorders. Daniel DeAngelo, MD, PhD, has shown that the histone deacetylase inhibitor panabinostat is potent in treating myelofi brosis and Hodgkin's disease.
Arnold Freedman, MD, is testing novel protein inhibitors that drive lymphoma growth and survival, using lymphoma biology data from the laboratories of Margaret Shipp, MD, and Anthony Letai, MD, PhD, from Hematologic Neoplasia. Ann LaCasce, MD, of Hematologic Malignancies, and Shipp have shown that the SYK inhibitor R788 can cause regression of a variety of lymphomas and CLL. Jennifer Brown, MD, PhD, is studying ABT263, which inhibits the effects of BCL-2 in both lymphoma and CLL. In diffuse large B-cell lymphoma (DLBCL), Shipp has identified an overproduction of the enzyme, PKC-B. She has also shown that the drug enzastaurin, which targets this enzyme, has significant activity against DLBCL. Freedman is studying antibody-mediated inhibition of the CD40/CD40 ligand growth/survival signal. The CD40 molecule has been shown to be an important regulator of malignant B cell growth.
Studies in the Jerome Lipper Center for Multiple Myeloma and Lebow Institute for Myeloma Therapeutics have shown that the proteasome inhibitor bortezomib, as well as the immunomodulatory drugs lenalidomide and thalidomide, target the multiple myeloma cell in the bone marrow microenvironment to overcome drug resistance in laboratory and animal models. Clinical trials, led by Kenneth Anderson, MD, and Paul Richardson, MD, have now moved this discovery into the initial management of patients newly diagnosed with advanced myeloma. Median survival of patients with myeloma has extended from three to seven years. The next-generation proteasome inhibitor, NPI-0052, and immunomodulatory drug, pomalidomide, are more potent and can overcome drug resistance in preclinical studies, suggesting even further progress can be expected.
Using a similarly robust translational model, clinical studies in Waldenstrom's macroglobulinemia have also been prominent. A number of new therapies have been developed by Steven Treon, MD, PhD, some in partnership with Irene Ghobrial, MD.
Studies in the Stem Cell Transplantation Program have opened new lines of inquiry into the pathogenesis and therapy of graftversus-host disease (GVHD), as well as into novel approaches to enhance graft-versus-leukemia (GVL) reactions. Joseph Antin, MD, and Corey Cutler, MD, are leading a trial to determine whether sirolimus-based GVHD prophylaxis will become the new standard of care to prevent GVHD. Jerome Ritz, MD, has revealed the cooperative role of B cells and T cells in generating tissue injury in chronic GVHD. In collaboration with Glenn Dranoff, MD, Vincent Ho, MD, and Robert Soiffer, MD, have developed a promising technique to use a genetically engineered autologous leukemia vaccine to stimulate the donor's immune response after transplantation. Edwin Alyea, MD, has developed a program in reduced-intensity transplantation and demonstrated that this potentially life-saving procedure can now be successfully offered to older patients.
As part of the lung cancer SPORE, Pasi Jänne, MD, PhD, has identified MET amplification as a cause of resistance to EGFR inhibitors gefitinib and erlotinib, both in vitro and in non-small cell lung cancer (NSCLC) patients. The preclinical studies also demonstrated that for these resistant cancers, a combination of EGFR and MET inhibition is necessary to inhibit cell viability. These findings have now been translated into clinical trials that are evaluating the combination of an EGFR inhibitor (erlotinib) and MET inhibitor (XL184) in NSCLC patients who have developed resistance to erlotinib.
Recent studies have also identified a subgroup of NSCLCs that harbor a translocation in the anaplastic lymphoma kinase (ALK) gene. Preclinical studies have demonstrated that such cancers are particularly sensitive to specific ALK kinase inhibitors. The first clinically available ALK kinase inhibitor, PF2341066, is being studied and has thus far demonstrated dramatic clinical activity in NSCLC patients with ALK translocations. Additional clinical trials are ongoing.
A pilot study of PET/CT scan screening for patients with Li Fraumeni syndrome (LFS) was conducted by Serena Masciari, MD, and Garber. LFS is an inherited cancer syndrome originally described by Frederick Li, MD, in which children and young adults have markedly increased risks of diverse cancers, including brain tumors, breast cancer, sarcomas, and other neoplasms. Mutations in the p53 gene can be detected in 70 percent of LFS families; the lifetime cancer risk is nearly 90 percent. With Lisa Diller, MD, of Pediatric Oncology, and Annick Van den Abbeele, MD, chair of Imaging, 15 individuals with LFS were evaluated. The goal was to look for early signs of cancer in these very-high risk individuals. All patients underwent a health interview, physical examination, and basic laboratory tests. Among the asymptomatic participants, three cancers were identified. Two were thyroid cancers, both of which could be removed in their entirety and the patients should be cured. The third was a gastroesophageal junction tumor, which was treated with chemotherapy and complete surgical resection. This trial is one of the first to demonstrate that a screening modality may have a role in the management of individuals with an inherited cancer syndrome. The results of this study were reported in JAMA, March 2008. These investigators are now leading a consortium of investigators in applying for a grant to expand the trial to a comprehensive evaluation of children and adults with LFS.
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