Personalized medicine for acute myelogenous leukemia—At the entrance gate
Authors: Ronan T. Swords, Bruce J. Dezube, Bruno C. Medeiros
Journal: American Journal of Hematology (2011)

With the advent of molecularly targeted therapies in the oncology clinic, previously fatal blood cancers have now become chronic diseases. Imatinib, a small molecule tyrosine kinase inhibitor that targets the BCR-ABL fusion protein, dramatically extends survival for patients with chronic myelogenous leukemia and has opened the flood gates for modern “personalized cancer medicine”. Rituximab, a monoclonal antibody with affinity for the CD20 antigen of B-lymphocytes, in an analogous fashion has revolutionized treatment for patients with B-cell lymphomas. Does this paradigm, a rather commonplace approach for the treatment of hematologic malignancies, apply also to acute myelogenous leukemia (AML)? This is an exciting time to be involved in AML research, and an explosion of new basic science discoveries has formed a springboard for some brand new personalized treatment concepts that this commentary will serve to outline. A target worth pursuing should be one that is essential in generating or maintaining the malignant state and at the same time, be amenable to inhibition without causing excessive toxicity to normal cells. An eclectic range of these “druggable” opportunities exist in acute myelogenous leukemia (AML). Protein neddylation involves the conjugation of NEDD8 proteins to target substrates, and this pathway regulates the post-translational modification of several proteins important in the survival of AML cells in laboratory models. Neddylation inhibitors (MLN4924) are now being evaluated in the clinic [1]. The X-linked inhibitor of apoptosis proteins (XIAP) confers chemoresistance in AML cell lines. Blockade of this target with XIAP antisense oligonucleotides reduces XIAP mRNA (AEG35156) and may improve the activity of standard AML chemotherapy [2]. Other resistance mechanisms, which have been more extensively investigated in AML, such as over-expression of drug efflux pumps, are still ripe for further clinical investigation. The Wilms' tumor 1 protein (WT1), a nearly universal tumor antigen, is an exciting new immunotherapeutic target because of its established role in leukemogenesis and superior immunogenic characteristics. Immunization of patients using WT1 antigen-loaded dendritic cells holds promise for adjuvant treatment of AML after standard therapy [3]. Other targeted approaches include reactivation of the tumor suppressor protein p53, a powerful growth suppressive and proapoptotic molecule frequently inactivated in cancer by gene mutations or defective signaling. Activation of p53 by antagonism of its negative regulator MDM2 has been proposed as a novel strategy for AML therapy and RG7112, a member of the Nutlin family of MDM2 antagonists, appears to be safe and effective in early clinical studies [4]. A vast array of constitutively activated protein kinases lead to inappropriate proliferation and prolong survival of AML cells and many of these are fair game for cancer therapeutics. Probably, the most studied of these has been FLT3, a receptor tyrosine kinase which is mutated in a third of patients with AML and which generally heralds a bad prognosis. The available inhibitors tested in the clinic have not been as exciting as anticipated however, second generation drugs like AC220 warrant further investigation [5]. The monoclonal antibody (mAb) gemtuzumab ozogamicin, targeting the universally expressed CD33 protein on the surface of AML cells, was recently withdrawn by the FDA due to higher rates of fatal toxicity in randomized studies [6]. Nonetheless, there is still some merit to using other monoclonal antibodies in the clinic. Proteins like CD123 and CD47 might be more viable targets since these are expressed on the surface of so-called leukemia-initiating cells where CD33 is not [7]. In addition, attaching alpha-emitting radioisotopes or protein toxins to rationally designed mAbs may be other ways to increase the therapeutic index of these agents. Newer insights into AML biology including cell stress mechanisms such as unfolded protein check points, redox balance and metabolic susceptibility (e.g., fatty acid biosynthesis and glucose metabolism) can now also be considered as new targets for drug discovery. The long established view that AML clones are derived from biologically distinct leukemia initiating cells (LICs) has been borne out by several lines of evidence. These unique leukemia stem cells have a distinct phenotype, different from that of normal myeloid stem cells and early progenitor cells. In some cases, more than one LIC subpopulation may be found in the leukemic environment. These cells, like most normal stem cells, will lie dormant in a quiescent pool. As a consequence, the enthusiasm for using cell cycle dependant cytotoxic drugs is diminished. Therefore, agents that eliminate these cells regardless of their cell cycle activity are attractive, or alternately, agents that commit them to cell division may help augment the efficacy of existing cytotoxics. The signaling pathways important for the survival and cellular fate of these LICs have obvious therapeutic implications. The NF-kB, PI3/Akt/mTOR, and Wnt/beta-catenin pathways appear to be intrinsically important in LIC survival and many of the agents that disrupt these pathways are already in clinical development for other indications [7]. In addition to the intrinsic features of LICs, numerous agents are now in development and exert their cytotoxic activity by disrupting the relationship the LIC has with its microenvironment, antiangiogenic drugs being the more established of these. Newer drugs like plerixafor, inhibit the LIC/stromal (CXCR4/SDF-1) interaction and eliminate extrinsic survival signals overcoming drug resistance [8]. Multiple submicroscopic genetic alterations with prognostic significance have recently been discovered in AML and account for some of the heterogeneity within this disease. Genome-wide expression signatures have now allowed us to separate out newly diagnosed patients into separate previously unrecognized biologic and/or prognostic subgroups [9]. These discoveries will certainly have management implications because many of the identified genetic alterations not only represent independent prognosticators and predictors of response to specific therapies, but also represent new targets for treatment. Next generation sequencing technologies will analyze diagnostic material in real time and based on individual changes in a patients' genome/transcriptome should allow clinicians to decide on appropriate selection of the treatments outlined above. In addition, existing therapies in AML, which have been disappointing in the clinic (e.g., epigenetic agents) may become more relevant as our ability to identify sensitive populations improves. The challenge in AML therapeutics is clear. Conventional treatments for this disease are the same in many of their particulars now as they were 3 decades ago. Only about 40% of patients considered to have an “intermediate” prognosis will be cured with these drugs. The tools of modern cancer cell biology have presented us with an exciting array of new treatment concepts, all of which merit clinical investigation. Advances in clinical trial design to confine Phase III studies to the target population will lead to the success of these new therapies. Personalized cancer medicine for AML is here and offers real hope for the cure of this disease. Authors would like to thank Francis J. Giles, MD who provided valuable feedback as the content of this Commentary was developed and for critical review of its final version. No compensation was received.