REVIEW Treatment by Design in Leukemia, a Meeting Report
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Leukemia (2003) 17, 2358–2382 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu REVIEW Treatment by design in leukemia, a meeting report, Philadelphia, Pennsylvania, December 2002 RA Larson1, GQ Daley2, CA Schiffer3, P Porcu4, C-H Pui5, J-P Marie6, LS Steelman7, FE Bertrand7 and JA McCubrey7,8 1Section of Hematology/Oncology, University of Chicago Pritzker School of Medicine, Chicago, IL, USA; 2Whitehead Institute for Biomedical Research and Harvard Medical School, Cambridge, MA, USA; 3Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI, USA; 4Division of Hematology Oncology, Ohio State University College of Medicine and Public Health, Columbus, OH, USA; 5St Jude Children’s Research Hospital and the University of Tennessee Health Science Center, Memphis, TN, USA; 6Onco-Hematology Department, Hoˆtel-Dieu de Paris, Paris, AP-HP, France; 7Department of Microbiology and Immunology, The Brody School of Medicine at East Carolina University, Greenville, NC, USA; and 8Leo Jenkins Cancer Center, The Brody School of Medicine at East Carolina University, Greenville, NC, USA Novel approaches have been designed to treat leukemia based disseminated cancer was ushered in approximately 50 years on our understanding of the genetic and biochemical lesions ago, when investigators recognized that inhibiting folate present in different malignancies. This meeting report sum- marizes some of the recent advances in leukemia treatment. metabolism led to the death of childhood leukemia cells. Based on the discoveries of cellular oncogenes, chromosomal Methotrexate, which inhibits dihydrofolate reductase and other translocations, monoclonal antibodies, multidrug resistance enzymes, is still a cornerstone of treatment for acute lympho- pumps, signal transduction pathways, genomics/proteonomic blastic leukemia (ALL), although it has a minimal role in acute approaches to clinical diagnosis and mutations in biochemical myeloid leukemia (AML). However, methotrexate is not pathways, clinicians and basic scientists have been able to selective. It inhibits the target enzymes in both normal and identify the particular genetic mutations and signal transduc- tion pathways involved as well as design more appropriate malignant cells. treatments for the leukemia patient. This meeting report This symposium reviewed a number of pathways that are discusses these exciting new therapies and the results known to be important in the regulation of cell proliferation, obtained from ongoing clinical trials. Furthermore, rational apoptosis, drug resistance and metabolism in acute and chronic approaches to treat complications of tumor lysis syndrome by leukemia. Promising new anticancer drugs and the current status administration of the recombinant urate oxidase protein, also of clinical trials of investigational agents that have been known as rasburicase, which corrects the biochemical defect present in humans, were discussed. Clearly, over the past 25 designed to specifically inhibit or alter these pathways and years, molecular biology and biotechnology has provided the interact with leukemia-specific targets were discussed at this hematologist/oncologist novel bullets in their arsenal that will meeting. allow treatment by design in leukemia. This meeting report covers the role and requirement of the Leukemia (2003) 17, 2358–2382. doi:10.1038/sj.leu.2403156 BCR-ABL oncoprotein in chronic myelogenous leukemia (CML), Published online 9 October 2003 the transition from the chronic to the blast crisis stage and the Keywords: leukemia therapy; signal transduction inhibitors; chromosomal translocations; multidrug resistance; monoclonal permissive role for additional chromosomal translocations antibodies; rasburicase; elitekt; tumor lysis syndrome involving transcription factor genes and the roles of FLT-3 and RAS mutations in leukemia. The treatment of CML and other leukemias with Gleevect, and FLT-3 and RAS inhibitors is also Introduction and overview of meeting: Richard A Larson, MD discussed. Certain chromosomal translocations involve the expression of novel transcription factors that can exert dominant Several decades of prospective clinical trials have allowed the negative (DN) effects on gene expression by silencing transcrip- identification of important determinants of response for patients tion through chromatin remodeling by tethering histone with leukemia that correlate with both treatment and survival. decacetylases (HDAC). Treatment of certain leukemias with These have included age, the presence of comorbid illnesses, retinoic acids and HDAC inhibitors may prove efficacious. and the number of white blood cells (WBC) at time of diagnosis, A frequent consequence observed in leukemia treatment with and precise morphological diagnoses. Recently, more sophisti- common anticancer drugs is drug resistance. Hematopoietic cated techniques have been used to examine the biological precursor cells may be intrinsically resistant to many drugs since characteristics of the leukemia itself including immunopheno- they were ‘designed’ to survive repeated exposure to hetero- typing, karyotyping and gene expression. This knowledge has geneous toxins and natural products. Drug resistance can arise led to risk-adapted treatment plans in which the use of particular by many different mechanisms; however, a common mechan- cytotoxic drugs and supportive care measures have been ism is increase in expression of a family of proteins called drug designed for individual patients. Empiricism is gradually being transporters (P-glycoprotein (P-gp), MRP-1, breast cancer replaced by individualized therapy. resistance protein (BCRP) and others). These transmembrane Targeted therapy did not start with STI571, now known as proteins contain an ATP-binding cassette (ABC) and are imatinib mesylate or Gleevect. The possibility of curing associated with energy-dependent efflux of natural products. Many antileukemia drugs are substrates for multidrug resistance Correspondence: JA McCubrey, Department of Microbiology and (MDR)-mediated efflux. P-gp, the protein product of the MDR-1 Immunology, The Brody School of Medicine at East Carolina gene, is frequently overexpressed in stem cells. P-gp over- University, Brody Building 5N98C, Greenville, NC 27858, USA; Fax: þ 1 252 744 3104 expression in AML is associated with a poorer prognosis. A Received 1 August 2003; accepted 26 August 2003; Published online means to circumvent MDR is the use of MDR inhibitors. 9 October 2003 Numerous MDR inhibitors have been developed and their Novel approaches to treat leukemia RA Larson et al 2359 effects are being evaluated in clinical trials (cyclosporine, PSC- Promising targets in leukemia: translating molecular 833, LY335979, VX710, XR9575, R101933, PK11195 and mechanisms into rational therapies: George Q Daley, MD GG120918). The commonly used immunosuppressive drug cyclosporine is known to reverse the effects of P-gp. Dr Daley (Whitehead Institute and Harvard Medical School, Chronic lymphocytic leukemia (CLL) is the most frequent Cambridge, MA, USA) discussed some of the scientific basis for leukemia observed in the Western Hemisphere. Historically, rational drug design in leukemia. The dramatic success of CLL has been treated with alkylating drugs. Now, however, Gleevec has galvanized the drug development community fludarabine is the best single agent for initial therapy. Chimeric toward the identification of further such agents. This develop- and humanized monoclonal antibodies (mAbs) represent novel ment has been facilitated by insights into the molecular therapeutic options for CLL. The humanized mAb targeting mechanisms of cancer. s s CD52 (CAMPATH ), a chimeric aCD20 Ab (Rituxan ), an mAb There is an ongoing debate as to whether Gleevec will prove targeting CD23 (IDEC 152) and a humanized mAb targeting an to be a rare example of great success or whether the principles epitope of the HLA-DR b chain (Hu1D10, Remitogent) are in responsible for Gleevec’s usefulness can be generalized to other various stages of clinical trials in CLL patients. These modified tumor types. It is likely that our understanding of the rather antibodies may exert their cytotoxic effects by inducing limited set of pathways in cancer cells that lead to transforma- apoptosis. tion can in many instances be targeted in the next decade or ALL can be cured in approximately 80% of children and 30– two. 40% of adults. While up to 75% of ALL patients show How many mutations are required to transform a normal cell identifiable genetic abnormalities associated with prognostic into a malignant cell? This fundamental issue has been studied and therapeutic relevance, there remains considerable genetic extensively in solid tumors by Vogelstein and colleagues at heterogeneity, which can complicate effective treatment. Some Johns Hopkins University (Baltimore, MD, USA). By studying high-risk ALL patients with certain chromosomal translocations the occurrence of various mutations in colon cancers, Vogel- (eg, BCR-ABL and MLL-AF4) can be effectively treated with stein has derived a cancer model referred to by some as a allogeneic hematopoietic stem cell transplantation. The ability ‘Vogelgram’, which assigns a sequence of stepwise mutations to classify ALL by genomic/proteomic approaches represents a across the spectrum of colon cancer. It is estimated that at least significant advance in our understanding of the disease and will four independent mutations must cooperate in the creation of a eventually provide