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Updates in Cancer for Clinicians A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM UPDATES IN CANCER FOR CLINICIANS JANUARY 2013 Updates from ASH 2012: Gene Encoding and Sequencing to Personalize Therapy effector cells to the B cell-specific CD19 Dr. Ley summarized his own work antigen. CAR proteins expressed on T and that of others, including several cells were composed of an antibody that presentations at the meeting, using could bind to a specific target (here the whole genome sequencing to study CD19 antigen found on B cell leukemias) clonal evolution in large numbers of fused to a transmembrane domain patients with AML. By sequencing followed by one or more cytoplasmic several hundred primary tumor and Edward Copelan, MD (right) signaling domains to generate relapse genomes, Ley and colleagues Chair of the Department of Hematologic Oncology proliferative and antitumor activity. A T have provided an unprecedented view and Blood Disorders cell engineered with this design could of the development and evolution of specifically recognize a leukemia cell, AML. A series of non-transforming Belinda Avalos, MD (left) kill it, disengage and kill another—then mutations appear to accumulate with Vice Chair of the Department of Hematologic age in pre-leukemic stem cells. A Oncology and Blood Disorders divide and make more engineered T cells so that one cell could kill more dominant mutation cluster consisting Two important themes of the 2012 than 1,000 leukemia cells following of genes recurrently mutated in AML ASH meeting emerged from special injection, meriting it the moniker “serial leads to leukemic transformation by a lectures given by Carl June, MD, from killer.” In addition to achieving sustained founding clone. Extensive mutational the University of Pennsylvania and complete remissions in four of nine analysis can be used to discriminate recipient of the Ernest Beutler Award, evaluable patients with refractory CLL, intermediate risk AML patients into and Tim Ley, MD, from Washington complete remission was also obtained clinically relevant groups with distinct University and E. Donnall Thomas in a child with ALL who experienced life- prognoses and to delineate patients Award recipient. Dr. June presented threatening cytokine storm associated who would and would not benefit striking results using tumor-specific with tumor lysis that was successfully from intensified chemotherapy and/ cellular immunotherapy in two lymphoid treated with TNF and IL-6 antagonists. or transplantation. Relapse of AML malignancies, CLL and ALL. June and Along with accrual of larger numbers of results either from a founding clone colleagues introduced genes encoding patients with B-Cell malignancies, new which gains mutations that confer a artificial receptors called chimeric protocols are currently being developed survival advantage or from a subclone antigen receptors (CARs) into patients’ to extend the groundbreaking work of of the founding clone, detectable at autologous T cells in vitro in order to cancer-specific T cells to pancreatic, diagnosis, which survives initial therapy, redirect the specificity of these immune prostate and breast cancer. gains new mutations and expands at CONTINUED ON PAGE 6 Stay Connected for Clinical Updates and Download The Cancer Letter, featuring Levine Cancer Institute: New Treatment Options Development of www.carolinashealthcare.org/updates-in-cancer Message from for Lung Cancer Highlights from Targeted Translational the President Patients with EGFR SABC 2012 Chemotherapy in Science Mutations Ovarian Cancer Message from the President of Levine Cancer Institute of Texas MD Anderson Comprehensive Cancer Center, Edward S. Kim, MD, will serve as chair of the Department of Solid Tumor Oncology. Edward A. Copelan, MD, FACP, from Cleveland Clinic’s Taussig Cancer Institute will serve as chair of the Department of Derek Raghavan, MD, PhD, President Hematologic Oncology and Blood Disorders. We have recruited more Carolinas HealthCare System’s than 50 faculty from the Carolinas and Levine Cancer Institute Research and Levine Cancer Institute is built on the across the USA. Administrative Headquarters. concept of cancer care without walls, Updates in Cancer for Clinicians will spanning throughout the system’s inform you on exiting news from Levine network of affiliated hospitals and Cancer Institute. providers in the Carolinas. The Institute is working to define the future of cancer We welcome your feedback at care – where innovations in research, [email protected] clinical trials, patient support and and look forward to bringing you more treatment are brought closer to home news in the future! for patients. We continue to build an elite cancer program, with the recruitment of A view of the infusion floor at internationally renowned experts to lead Levine Cancer Institute. the clinical teams. From the University Translational Science Pharmacogenic Approaches to Personalize Cancer Therapy A key event in the development of inhibiting its activity, the therapeutic AML is the disruption of the myeloid efficacy of ATRA could be potentiated. differentiation program and aberrant Specifically, the combination of ATRA self-renewal of leukemic stem cell. and topoisomerase II inhibitors, such as Differentiation therapy with the retinoic ICRF-193 or dexrazoxane (a clinically acid analog, all-trans retinoic acid active topoisomerase II inhibitor), (ATRA) has been successful in treating led to enhanced differentiation and Ram Ganapathi, PhD (left) acute promyelocytic leukemia, a preferential activation of the cell death Chair of Cancer Pharmacology cytogenetically distinct subtype of AML pathway, as compared to differentiation characterized by the PML-RARα gene coupled growth arrest induced by Marukh Ganapathi, PhD (right) translocation. However, ATRA has ATRA alone. Based on this preclinical Senior Scientist shown little promise in differentiation finding, we were able to formulate a therapy of other subtypes of AML. To clinical hypothesis that the combination Complexities in the genetic landscape develop strategies that would improve of ATRA with the clinically relevant of tumors significantly impact the differentiation therapy for other forms topoisomerase II catalytic inhibitor, design of optimal strategies for effective of AML, including relapsed/refractory dexrazoxane, leads to improved treatment of cancer. The goal of Cancer disease, we studied the role of a key response in AML patients. We are Pharmacology/Translational Research nuclear enzyme, topoisomerase II, in now poised to test this hypothesis in at Levine Cancer Institute is to support ATRA-induced differentiation of AML and develop novel paradigms for cancer cells. Using different AML cell lines and care. As such, our ongoing translational AML blast cells from relapsed/refractory CONTINUED ON PAGE 7 research has focused on the areas of patients, we were able to demonstrate acute myeloid leukemia (AML), renal cell that by targeting topoisomerase II, carcinoma and ovarian cancer. either by deleting the enzyme or 2 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM Novel Treatments for Lung Cancer Patients With EGFR Mutations of 13.6 versus 6.9 months (HR, 0.47; molecular profiling is necessary in order p<0.0001). (2) Additionally, objective to provide the best available therapy. response rate, disease control, cancer- This requires sufficient tissue sampling related symptoms and quality of life for precise pathologic diagnosis. While were also improved with afatinib. The patients with unknown driver mutations most frequent adverse events were are still treated with chemotherapy, diarrhea and rash, although no patients those with EGFR mutations or ALK Edward S. Kim, MD (left) discontinued afatinib for rash. LUX- rearrangements have expanding options Chair of the Department of Solid Tumor Lung 3 is the first randomized study to for targeted personalized treatment. Oncology and Investigational Therapeutics demonstrate benefit of an oral targeted REFERENCES therapy versus chemotherapy in a 1. http://seer.cancer.gov/statfacts/html/lungb.html Kathryn Mileham, MD (right) molecularly selected population. Based 2. Yang JC, Schuler MH, Yamamoto N, et al. LUX-Lung 3: Medical Oncology on these results, afatinib is currently A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with available through an open label advanced adenocarcinoma of the lung harboring EGFR-activating Lung cancer remains the leading expanded access program at a starting mutations. J Clin Oncol 2012;30(suppl): LBA7500. cause of cancer-related deaths in the dose of 40 mg/daily. United States, (1) and non-small cell While management of lung cancer lung cancer (NSCLC) accounts for more is in rapid evolution the standard of than 85 percent of the cases. With most “chemotherapy for all” no longer exists. patients presenting with advanced National guidelines concur that disease, there is an urgency to maximize treatment efficacy while minimizing drug toxicity. Through a deeper EXTRACELLULAR understanding of the biology driving DOMAIN NSCLC, novel treatment paradigms EGFR HER2 HER2 are based on disease biomarkers with EGFR HER2 EGFR A HER2 corresponding targeted therapy. This HER4 HER3 has been best achieved with advanced EGFR HER2 treatment options for the two-thirds HER3 HER4 of adenocarcinoma patients in whom EGFR driver mutations are identified. Somatic mutations in the tyrosine B kinase domain of the epidermal growth factor
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