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Research at Mass General
Novel agents hold great promise for lung cancer patients. A key development in cancer research over the past year is understanding how to rationally target the right treatments for the right patient in order to improve outcomes for all. The Center for Thoracic Cancers has played a major role in understanding the biology of the epidermal growth factor receptor (EGFR). Our group was the first to identify mutations in EGFR and the role that they play in explaining the uniquely strong responses seen when administering EGFR tyrosine kinase inhibitors to certain lung cancer patients. This landmark finding has generated several important clinical studies that use individual patient genotyping to determine the optimal use of EGFR-based therapies in lung cancer patients. Following this algorithm, impressive response rates to therapy and survival outcomes have been achieved. Resistance is also a major concern in those treated with anti-EGFR therapy. Laboratory collaborations with Dr. Jeffrey Settleman, Dr. Daniel Haber, Dr. Sree Sharma and Dr. Jeff Engelman are actively examining strategies to overcome both intrinsic and acquired resistance to anti-EGFR therapy. The direct translation of laboratory findings to innovative clinical trials has been a major challenge but one which has defined the success of our group.
Another major focus of our research effort has been molecular epidemiology. Why do only 15% of patients with a smoking history develop lung cancer? Can we explain the variance in outcomes to treatment by looking at differences in the genome? In the laboratory of Dr. David Christiani at the Harvard School of Public Health, Dr. Rebecca Heist is investigating the relationship between germline polymorphisms and outcomes of patients with lung cancer. Similar to our studies with EGFR, the ultimate goal of this work is facilitating more rationale treatment selections for patients with lung cancer. The Christiani group has also made key observations regarding the role of vitamin-D levels and outcome from cancer therapy. Clinical trials further examining this relationship are underway.
Optimizing the delivery of systemic chemotherapy is also a major effort of our center. The integration of bevacizumab, a monoclonal antibody that targets VEGF and affects angiogenesis, into traditional chemotherapy regimens has been another recent advance in the treatment of several types of epithelial malignancies. We are actively investigating the role of bevacizumab and chemotherapy in patients with both early lung cancer and in those with more advanced disease. Despite its widespread use in a number of types of cancers, the mechanism of action of bevacizumab is not well understood. Studies in the Center for Thoracic Cancers are examining how this drug works by utilizing novel imaging modalities before and after treatment. The timing of chemotherapy is also a critical element in its success. Dr. Panos Fidias recently led a critical study suggesting that early application of second line chemotherapy may improve outcome for patients with stage IV disease.
The successful treatment of lung cancer patients requires that we care for the whole patient. Toward that end, Dr. Jennifer Temel focuses her work on the care of lung cancer patients at the end of life, as well as novel approaches to improve quality of life for all lung cancer patients. In association with Massachusetts General Hospital and Dana-Farber Cancer Institute's Palliative Care Services, Dr. Temel has published a trial of early palliative care intervention for patients with metastatic lung cancer in the Journal of Clinical Oncology. She has followed this important feasibility study with a randomized trial of early vs. standard palliative care intervention in lung cancer treatment. Depression and fatigue are also critical determinants of outcome of patients with lung cancer. Dr. William Pirl from the MGH Psychiatry Unit has done groundbreaking work on the association of major depression with outcome in lung cancer patients.
Cutting-edge treatment for early stage lung cancer is also a major focus of our group. Under the leadership of Dr. Douglas Mathisen, the Division of Thoracic Surgery has become a leading center for complex airway surgery as well as resection of thymic and esophageal cancers. Dr. Mathisen has recently recruited Dr. Christopher Morse to the Massaschusetts General Hospital, who will pioneer the application of a minimally invasive technique for resection of esophageal cancer into the multimodality treatment of this disease. From a radiation oncology perspective, Dr. Noah Choi has recently obtained R01 funding for his work on integrating dynamic biologic imaging with radiation treatment. Dr. Choi is working hard to determine the role that dynamic PET/CT scanning can play in optimizing radiation therapy effectiveness in lung cancer.
In the division of Thoracic Surgery, Dr. Michael Lanuti has developed a thoracic oncology laboratory at the Massachusetts General Hospital focusing on the design of novel therapeutics to treat lung cancer. His laboratory has modified oncolytic viruses to better target and eradicate solid tumor. Some of these strategies include development of oncolytic viruses containing therapeutic transgenes (eg. Interleukin 12, Interferon b, or Tumor Necrosis Factor) that modulate host immunity to combat tumor. The laboratory has extensively evaluated viral gene therapy strategies to undermine tumor growth by inhibiting angiogenesis (endostatin, VEGF inhibitors). This work was presented in abstract form at the American Society of Gene Therapy 2006. Efforts are underway to improve viral penetration and propagation into solid tumor with the delivery of tumor matrix proteases. The laboratory has also examined molecular risk factors for esophageal adenocarcinoma and found an elevated risk associated with mutations in the epidermal growth factor (EGF) gene.
In collaboration with thoracic radiology at Massachusetts General Hospital, Dr. Lanuti has developed a radiofrequency ablation (RFA) program for inoperable stage I lung cancer. The program is part of a multi-institutional trial being conducted by the American College of Surgeons. The Massachusetts General Hospital experience has been presented at the 2006 Chest meeting in Salt Lake City, Utah. Although the experience is based on 35 patients with a 3-year follow-up, results suggest that RFA may be curative for early stage lung cancer less than 2cm. These preliminary results appear to rival therapeutic outcomes obtained with conventional radiation therapy.
1 Rietzel E, Chen GT, Choi NC, Willet CG Four-dimensional image-based treatment planning: Target volume segmentation and dose calculation in the presence of respiratory motion. Int J Radiat Oncol Biol Phys. 04/08/2005; 61(5); 1535-50.
2 Mohiuddin MM, Choi NC The role of radiation therapy in non-small cell lung cancer. Semin Respir Crit Care Med. 07/29/2005; 26(3); 278-88.
3 Rietzel E, Liu AK, Chen GT, Choi NC Maximum-Intensity Volumes for Fast Contouring of Lung Tumors Including Respiratory Motion IN 4DCT Planning. Int J Radiat Oncol Biol Phys. 05/12/2008;
4 Sequist LV, Joshi VA, Jänne PA, Bell DW, Fidias P, Lindeman NI, Louis DN, Lee JC, Mark EJ, Longtine J, Verlander P, Kucherlapati R, Meyerson M, Haber DA, Johnson BE, Lynch TJ Epidermal growth factor receptor mutation testing in the care of lung cancer patients. Clin Cancer Res. 07/21/2006; 12(14 Pt 2); 4403s-4408s.
5 Bell DW, Lynch TJ, Haserlat SM, Harris PL, Okimoto RA, Brannigan BW, Sgroi DC, Muir B, Riemenschneider MJ, Iacona RB, Krebs AD, Johnson DH, Giaccone G, Herbst RS, Manegold C, Fukuoka M, Kris MG, Baselga J, Ochs JS, Haber DA Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 10/31/2005; 23(31); 8081-92.
6 Temel JS, Pirl WF, Lynch TJ Comprehensive symptom management in patients with advanced-stage non-small-cell lung cancer. Clin Lung Cancer. 03/03/2006; 7(4); 241-9.
7 Temel JS, Pirl WF, Recklitis CJ, Cashavelly B, Lynch TJ Feasibility and validity of a one-item fatigue screen in a thoracic oncology clinic. J Thorac Oncol. 04/05/2007; 1(5); 454-9.
8 Lynch TJ, Kim ES, Eaby B, Garey J, West DP, Lacouture ME Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 05/24/2007; 12(5); 610-21.
9 Temel JS, Jackson VA, Billings JA, Dahlin C, Block SD, Buss MK, Ostler P, Fidias P, Muzikansky A, Greer JA, Pirl WF, Lynch TJ Phase II study: integrated palliative care in newly diagnosed advanced non-small-cell lung cancer patients. J Clin Oncol. 06/11/2007; 25(17); 2377-82.
10 Asomaning K, Miller DP, Liu G, Wain JC, Lynch TJ, Su L, Christiani DC Second hand smoke, age of exposure and lung cancer risk. Lung Cancer. 01/14/2008;
11 Haber DA, Bell DW, Sordella R, Kwak EL, Godin-Heymann N, Sharma SV, Lynch TJ, Settleman J Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors. Cold Spring Harb Symp Quant Biol. 07/27/2006; 70; 419-26.
12 Sequist LV, Bell DW, Lynch TJ, Haber DAMolecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer.J Clin Oncol. 02/09/2007; 25(5); 587-95.
13 Zhou W, Heist RS, Liu G, Asomaning K, Miller DP, Neuberg DS, Wain JC, Lynch TJ, Christiani DC Second hand smoke exposure and survival in early-stage non-small-cell lung cancer patients. Clin Cancer Res. 12/05/2006; 12(23); 7187-93.
14 Heist RS, Zhai R, Liu G, Zhou W, Lin X, Su L, Asomaning K, Lynch TJ, Wain JC, Christiani DC VEGF polymorphisms and survival in early-stage non-small-cell lung cancer. J Clin Oncol. 02/18/2008; 26(6); 856-62.
15 Heist RS, Zhou W, Chirieac LR, Cogan-Drew T, Liu G, Su L, Neuberg D, Lynch TJ, Wain JC, Christiani DC MDM2 polymorphism, survival, and histology in early-stage non-small-cell lung cancer. J Clin Oncol. 05/31/2007; 25(16); 2243-7.
16 Gaissert HA, Grillo HC, Shadmehr BM, Wright CD, Gokhale M, Wain JC, Mathisen DJ Laryngotracheoplastic resection for primary tumors of the proximal airway. J Thorac Cardiovasc Surg. 05/03/2005; 129(5); 1006-9.
17 Gaissert HA, Grillo HC, Shadmehr MB, Wright CD, Gokhale M, Wain JC, Mathisen DJ Uncommon primary tracheal tumors. Ann Thorac Surg. 06/26/2006; 82(1); 268-72; discussion 272-3.
18 Lanuti M, de Delva PE, Maher A, Wright CD, Gaissert HA, Wain JC, Donahue DM, Mathisen DJ Feasibility and outcomes of an early extubation policy after esophagectomy. Ann Thorac Surg. 11/27/2006; 82(6); 2037-41.
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