ASH News Daily 2012 - Monday, December 10, 2012 - (Page A-4)

Page A–4 ® LEUKEMIA Don’t Forget to Check the ‘Back Doors’ of Cancer Cells BY MATTHEW HSIEH, MD or some time now, isolating the molecular defect in malignant cells meant not only understanding the process of cancer development, but also providing the molecular target to treat the disease. Mutations like BCR-ABL in chronic myeloid leukemia and JAK2 in myeloproliferative disorders are a couple of excellent examples of this concept. But for a growing number of cancers, the identifying molecular defect, or the “front door” only explains the phenotype or how the cancer cells got there in the first place. Checking the “back doors,” or studying the alternate pathways by which cancer cells survive, may prove to be equivalent targets. Robert A. Hromas, MD, University of Florida College of Medicine, Gainesville, FL, introduced this Plenary abstract #3 presentation by discussing the concept of synthetic lethality. Cancer cells accumulate a series of genetic mutations that al- F APL «« From Page A-1 that results from induction of both differentiation and apoptosis. A reluctance to omit chemotherapy persisted, however, until pilot studies of ATRA and arsenic trioxide, completed a few years ago, suggested that durable remissions could be achieved without either anthracyclines or cytarabine, and without their attendant toxicities. Yesterday, another milestone was reached at the Plenary session with the report of the results of a European multi-center trial comparing standard therapy with idarubicin plus ATRA to arsenic trioxide (ATO) plus ATRA in patients with low- or intermediate-risk APL (abstract 6). Francesco Lo-Coco, MD, of the University Tor Vergata, Rome, Italy, presented the results of Intergroup APL-0406 for a consortium of Italian and German cooperative groups. Investigators from more than 60 institutions accrued 154 evaluable APL patients over a three-year period. Patients with WBC greater than 10,000 were excluded. About two-thirds of patients were intermediate-risk (platelet counts < 40,000), while the remainder were low-risk (platelets > 40,000). The study was designed to demonstrate non-inferiority, by demonstrating that at least 80 percent patients in the experimental arm were alive and event-free at two years of follow-up, compared with those in the standard arm. low them to escape from normal cell cycle checkpoints. Some of these mutations, e.g., in BRCA 1 or 2 (whose normal function is DNA repair), force the cancer cells to rely on alternate pathway(s) for survival. In essence, he explains, “Cancer cells are addicted to the back-up DNA repair pathway.” Thus, inhibiting the alternate pathway should deliver a lethal blow to cancer cells, but spare normal cells – this is the central premise of synthetic lethality. One of these alternate pathways is PARP, which cancer cells depend on to repair double-stranded DNA breaks, and targeting PARP is on everyone’s radar screen. PARP inhibitors have been developed by all the major pharmaceutical companies, and phase 1 and 2 trials are currently underway. Other alternate pathways for DNA repair include CHK, ATM, RAD51, and RAD52, and more. Kimberly Cramer, PhD, Temple University School of Medicine, Philadelphia, PA, and her labora- The non-inferiority goals of the study were achieved and according to Dr. Lo-Coco, “The combination of ATO and ATRA represents a new standard therapy option for the first-line treatment of non-high-risk patients with acute promyelocytic leukemia.” Given the encouraging results in non-high-risk APL pa- tients, Dr. Lo-Coco suggested that the combination of ATO plus ATRA should be studied in patients with high-risk disease. The overwhelming majority of patients in both arms entered a complete molecular remission upon completion of therapy. After a median follow-up of 34 months, the twoyear event-free survival was no different. One death and two relapses were observed in the ATO arm, compared with seven deaths and five relapses in the chemotherapy arm. Differences were noted with respect to toxicities. Patients enrolled on the chemotherapy-containing arm experienced a significantly higher incidence of febrile events and severe, prolonged cytopenias. One of 79 patients in the ATO arm required cessation of therapy because of prolongation of the QTc interval. Elevations of liver enzymes and development of hyperleukocytosis during treatment were more frequent in patients receiving ATO, although in no instance did these side effects lead to treatment withdrawal. Other adverse effects, including differentiation syndrome, appeared to be no different in either arm. tory focus on RAD51 and RAD52 in the CML model. While tyrosine kinase inhibitors can induce molecular remission, the stem cell clone is not eliminated, evidenced by the need to chronically administer these drugs. She showed that CML stem and progenitor cells, with BRCA1/ RAD51 defect, have many doublestranded DNA breaks and rely heavily on RAD52 to repair. RAD52 is a critical binding domain to single-stranded DNA before the repair begins. In a series of proof-of-concept experiments, RAD52 mutants (which prevent binding to DNA) induced apoptosis and reduced the stem cell clones in a murine CML model while sparing normal cells. She next used a specific peptide aptamer, which blocks the binding of normal RAD52 to DNA, and obtained the same inhibitory results in CML cells. When the peptide aptamer is given in combination with imatinib, an enhanced anti-CML effect was demonstrated, again sparing normal hematopoiesis and prompt Dr. Lo-Coco emphasized that diagnosis, appropriate treatment, and meticulous attention to supportive care is critical in APL management. Most deaths in APL occur before or during induction, suggesting that early recognition and proper management of its many unique complications – including coagulopathy, differentiation syndrome, hyperleukocytosis, intracranial bleeding, and infec- demonstrating the synthetic lethality idea. This inhibitory effect, using the peptide aptamer, was extended in CML cells in chronic or accelerated phase, and many others: primary AML, B-ALL, and solid tumors with BRCA1/2 defects (breast, ovarian, and pancreatic cancer cells). Looking ahead, Dr. Cramer hopes “to use epigenetic profiling to analyze the potential responsiveness of patients to RAD52 inhibition by profiling genes involved in homologous recombination.” In police work (at least from what I’ve seen on television shows), securing the front door is important, but providing coverage for the back door is equally crucial, as it is a commonly used escape route. In our understanding of cancer pathogenesis and planning of cancer treatment, it looks like the parallel strategy is being used – to ultimately capture and bring cancer cells to their knees. Dr. Hsieh indicated no relevant conflicts of interest. tion – often determine successful outcomes. He pointed to the work of the International Consortium on Acute Promyelocytic Leukemia – established by ASH in 2004 to optimize the care of APL patients in Brazil, Peru, Mexico, Uruguay, and Chile – as a model of effective intervention. Dr. Bufill indicated no relevant conflicts of interest. ASH NEWS DAILY Monday, December 10, 2012 Dr. Paula Bockenstedt, left, of Ann Arbor, MI, talks to Dr. Alvin Schmaier, of Cleveland, OH, during the Hematology Course Directors Workshop on Sunday morning.

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ASH News Daily 2012 - Monday, December 10, 2012

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