Skip Navigation LinksHome > March 2014 - Volume 21 - Issue 2 > New strategies for relapsed acute myeloid leukemia: fertile...
Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000018
MYELOID DISEASE: Edited by Martin S. Tallman

New strategies for relapsed acute myeloid leukemia: fertile ground for translational research

Dinner, Shira N.; Giles, Francis J.; Altman, Jessica K.

Free Access
Article Outline
Collapse Box

Author Information

Division of Hematology/Oncology and Northwestern Medicine Developmental Therapeutics Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University-Feinberg School of Medicine, Chicago, Illinois, USA

Correspondence to Shira Dinner, MD, 676 N. St. Clair St., Suite 850, Chicago, Illinois 60611, USA. Tel: +1 312 695 2120; e-mail: sdinner@nmff.org

Collapse Box

Abstract

Purpose of review

Although frontline treatment of acute myeloid leukemia (AML) achieves high remission rates, approximately 75–80% of patients will either not respond to or relapse after initial therapy. Some patients, generally those who are younger, can be successfully salvaged with second-line chemotherapy followed by allogeneic stem cell transplantation. There is a great need for novel therapies in AML.

Recent findings

Advances in molecular technology recently identified recurrent mutations including mutations of DNMT3A, IDH1/2, and TET2. These mutations represent a major advance in the understanding of leukemogenesis and prognosis, and have enabled the development of targeted therapies.

Summary

Improved knowledge of the molecular pathogenesis of AML has allowed development of therapies targeting epigenetic modulation, intracellular signaling pathways, prosurvival proteins, and the tumor microenvironment.

Back to Top | Article Outline

INTRODUCTION

With improvements in supportive care and optimization of induction chemotherapy regimens, approximately 60% of adult patients with untreated acute myeloid leukemia (AML) will achieve a complete remission [1,2▪]. However, only 20% of all patients will have long-term disease-free survival. Although remission rates are often higher than 60% in younger patients, still only 40% of young patients that achieve a complete remission will have long-term disease-free survival, suggesting that the majority of patients will require salvage therapy for relapsed disease [1,2▪]. Screening for cytogenetic abnormalities and molecular abnormalities in nucleophosmin (NPM1), FMS-like tyrosine kinase 3 (FLT3), and CEBPA genes is now considered standard of care for prognostic evaluation at the time of diagnosis [3,4], and more recently high throughput sequencing technology identified validated mutations in DNA methyltransferase 3A (DNMT3A), TET2, and isocitrate dehydrogenases (IDH)1/2, which are known to impact prognosis [5–8,9▪▪]. Recently, whole-genome and exome sequencing of AML patient samples demonstrated, on average, only 13 gene mutations, lower than expected compared with other malignancies. The majority of samples had at least one mutation in one of nine categories of genes, including signaling genes, DNA-methylation-related genes, chromatin-modifying genes, the gene encoding nucleophosmin, myeloid transcription-factor genes, transcription-factor fusions, tumor-suppressor genes, cohesin-complex genes, and spliceosome-complex genes [10▪▪]. Many of these categories are of clinical translational relevance. The recognition of these mutations has not only impacted the ability to refine prognosis but also expanded the understanding of leukemogenesis, and is now leading to the development of targeted therapies for AML, which will be the focus of this review. We will highlight novel agents targeting epigenetic modulation, intracellular pathways, and the tumor microenvironment.

Box 1
Box 1
Image Tools
Back to Top | Article Outline

EPIGENETIC MODULATION

Epigenetic gene regulation is the control of transcription or gene expression through DNA methylation or histone modifications, without any changes to the underlying DNA sequence (Table 1) [11▪▪,12,13,14▪,15–17,18▪,19▪▪,20–24,25▪,26–29,30▪,31,32]. Epigenetic changes are thought to, at least partially, drive chemotherapy resistance in malignancies [33]. Histone deacytlases (HDACs) are known to silence tumor suppressor genes and are a key therapeutic target of the HDAC inhibitors under investigation in AML, which include vorinostat, etinostat, and MGCD0103 [34▪,35▪,36]. Recent preclinical evidence highlights the importance of the IDHs, DOT1L, and DNMT3 in epigenetic modulation of AML and as potential therapeutic targets.

Table 1
Table 1
Image Tools
Table 1
Table 1
Image Tools
Back to Top | Article Outline
Isocitrate dehydrogenases

Mutations in the IDHs, IDH1 and IDH2, were recently identified in AML and impede oxidative decarboxylation of isocitrate to alpha-ketoglutarate [5]. These mutations lead to novel enzymatic activity that results in production of R-2-hydroxyglutarate, an oncometabolite responsible for changes to DNA methylation, inhibition of histone lysine demethylases, block in cellular differentiation, and ultimately, tumorigenesis [11▪▪]. Prognostic significance of IDH mutations likely depends on the specific mutational locus and the presence of concurrent mutations of other genes, such as NPM1 and FLT3[37]. The German–Austrian AML HD98A trial found that IDH mutations diminish the otherwise favorable prognosis seen in cytogenetically normal AML with mutated NPM1 and lack of FLT3-ITD mutation [38]. The Acute Leukemia French Association 9801 and 9802 trials reported similar findings [39]. However, Schnittger et al.[40] observed that the unfavorable effect of IDH mutation was most obvious in AML with wild-type NPM1 status and in patients younger than 60 years of age. Green et al.[41] reported no prognostic significance associated between IDH and NPM1 mutations, but when stratified by FLT3-ITD status, an IDH1 mutation was an independent adverse factor for relapse in FLT3-ITD(−) patients and a favorable factor in FLT3-ITD(+) patients.

Although further investigation is warranted in the clinical prognostic impact of IDH mutations, their role in tumorigenesis in human cancers, including glioma and AML, is clear and recent studies reported encouraging results with small molecule inhibitors of IDH [42▪,43▪▪]. AGI-6780 is a small molecule that inhibits the most commonly occurring IDH mutation in AML, IDH2-R140Q [43▪▪]. Treatment with this inhibitor lowered R-2-hydroxyglutarate to normal physiological levels in an erythroleukemia cell line and IDH2-mutated primary human AML cells. However, in the mutant primary human AML cells, a burst of proliferation occurred initially, followed by an increase in mature cell types at the expense of progenitor cells [43▪▪]. These results imply that mutant IDH2 inhibition can be used to promote differentiation of mutated AML cells. Based on preclinical results, a first in human study of the IDH2 inhibitor AG-221 is being conducted in patients with hematologic malignancies (NCT01915498).

Back to Top | Article Outline
DOT1L

MLL gene rearrangements at position 11q23 occur in approximately 10% of AML, acute lymphoid or mixed lineage leukemias and are associated with an aggressive disease course [44]. Most translocations of the MLL gene result in oncogenic fusion proteins that interact with DOT1L, which is a histone methyltransferase enzyme that targets lysine 79 in the globular domain of histone H3 (H3K79). This leads to DOT1L hypermethylation and activation of MLL target genes that drive leukemogenesis [12,13,14▪]. Recently, a potent DOT1L inhibitor, EPZ-5676, was generated with a long half-life, and in vivo demonstrated 37 000-fold greater selectivity for DOT1L histone methyltransferase than any other methyltransferase tested [45▪▪]. In addition to inhibiting H3K79 methylation, MLL-fusion target gene expression was decreased. EPZ-5676 selectively killed acute leukemia cells with MLL translocations. In-vivo use of the small molecule in a rat model of MLL leukemia by continuous infusion produced complete tumor regression, which was sustained after discontinuing the agent [45▪▪]. Based on these findings, EPZ-5676 is in an early-phase clinical trial in patients with advanced hematologic malignancies, including acute leukemias harboring translocations of the MLL gene (NCT01684150).

Back to Top | Article Outline
DNA METHYLTRANSFERASE 3

High-throughput sequencing in AML recently identified mutations in the DNMT3A gene [5]. In particular, mutations of the R882 codon impair methyltransferase activity [15]. Although the exact impact of this finding on leukemogenesis remains unclear, it is thought that these mutations may influence response to treatment with azanucleoside DNMT inhibitors (’hypomethylating agents’) such as azacitadine or decitabine. In a study of elderly patients with untreated AML, decitabine treatment produced a complete remission of 47% and provided the greatest benefit in patients with low DNMT3A activity [46]. Follow-up data from the same group reported DNMT3A-mutated patients had a higher median white blood cell count; DNMT3A mutations were significantly associated with NPM1 mutations, and a trend towards a higher prevalence of FLT3-ITD among DNMT3A-mutated patients. While the complete remission rate for the whole cohort was 41% (19/46), 75% (6/8) of DNMT3A-mutated patients achieved a complete remission [16]. These data suggest that AML with mutations in DNMT3A is associated with increased response to azanucleoside DNMT inhibitors and warrants further investigation.

Back to Top | Article Outline

INTRACELLULAR PATHWAYS

Inhibition of apoptosis by the overexpression of intracellular prosurvival proteins such as BCL-2 and RAF, as well as constitutive activation of and aberrant signaling through intracellular pathways such as the phosphoinosityl-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and the mitogen-activated protein kinase (MAPK) kinase (MEK)/extracellular-signal regulated kinase (ERK) pathway in the leukemia cells enhance survival, proliferation, and chemotherapy resistance [47] (Table 1) [11▪▪,12,13,14▪,15–17,18▪,19▪▪,20–24,25▪,26–29,30▪,31]. Thus, drugs that inhibit single or multiple proteins and pathways are actively under investigation.

Back to Top | Article Outline
BCL-2

The antiapoptotic protein BCL-2 is thought to drive leukemia stem cells and increase chemotherapy resistance in AML [17,18▪]. In a preclinical mouse model of high-risk myelodysplastic syndromes (MDS)/AML the small molecule inhibitor of BCL-2 homology domain 3 (BH3), ABT-737, down-regulated BCL-2, increased apoptosis, and extended the animal lifespan, suggesting effective targeting of the leukemia initiating cell [19▪▪]. When AML cells and xenograft AML models were exposed to both ABT-737 and a PI3-kinase inhibitor, expression of antiapoptotic proteins decreased and induced apoptosis along with tumor regression, suggesting a potential benefit for dual pathway inhibition [48▪,49▪]. Despite encouraging preclinical data for BCL-2 inhibition, prior clinical trials of the BCL-2 antisense oligonucleotide G3139 in acute leukemia were disappointing [50]. ABT-737, the BH3 inhibitor, is currently under investigation in solid tumors only.

Back to Top | Article Outline
PI3K/AKT/mTOR

The PI3K/AKT/mTOR pathway drives cell cycling, replication, and death. PI3-K, a kinase near the cell surface, is activated by a number of receptor tyrosine kinases, including FLT3 [20]. Constitutive activation of the PI3K/AKT/mTOR pathway occurs in 60–80% of cases of AML, most frequently in AML with a FLT3-ITD mutation, and is associated with shorter disease-free and overall survival [51,52]. In vitro, simultaneous blockade of PI3K with GDC-0941 and FLT3 with sorafenib in AML FLT3-ITD mutant cells inhibited prosurvival AKT signaling and promoted apoptosis [53▪]. As a single agent, another PI3K inhibitor, LY294002, induced apoptosis of AML cells in a dose-dependent manner [54,55]. Based on these data, BKM120, an oral PI3K inhibitor, is currently being evaluated in relapsed and refractory acute leukemias. (NCT01396499).

Several early-phase clinical trials investigated mTOR inhibitors in AML, such as rapamycin and deforolimus. These studies showed that the agents are effective in suppressing phosphorylation of downstream targets of mTOR but have limited clinical activity as monotherapy [21,22]. This may be because of the fact that these rapamycin analogues only target mTORC1, and do not inhibit mTORC2. OSI-027 targets both mTORC1 and mTORC2 and produced more potent antileukemic responses than selective mTORC1 targeting with rapamycin in AML cell lines [56]. Results of a clinical trial with OSI-027 in solid tumors and lymphoma are awaited (NCT00698243). Another agent, NVP-BEZ235, inhibits mTORC1 and mTORC2, as well as PI3K, leading to a decreased proliferation rate and apoptosis in AML cells in vitro[57]. BEZ235, is currently being evaluated in a clinical trial of relapsed or refractory acute leukemia (NCT01756118). Additional dual TORC and PI3K/mTOR inhibitors are currently in development.

Because of limited single-agent activity with rapalogues, preclinical studies have been conducted in combination with chemotherapy. When temsirolimus was combined with clofarabine, this led to increased apoptotic effects on AML cells [58]. Modest clinical efficacy was demonstrated with this combination in elderly patients with relapsed and refractory AML. In 53 patients, 21% achieved a complete remission with a median disease-free survival of 3.5 months, and median overall survival of 4 months (9.1 months for responders) [23]. Similarly, rapamycin added to mitoxantrone, etoposide, and cytarabine (MEC) in relapsed and refractory AML produced a 22% response rate [24]. Another study evaluated the addition of everolimus to conventional daunorubicin plus cytarabine (’3 + 7’) in relapsed AML and demonstrated a response rate of 68% [25▪]. These data suggest further study is warranted of mTOR inhibitors or dual TORC inhibitors, given their increased antitumor activity, in combination with chemotherapy or other novel agents in AML.

Back to Top | Article Outline
MEK/ERK

Aberrant signaling through cell surface growth factor and cytokine receptors, RAS mutations, and RAF overexpression lead to constitutive activation of the MEK and ERK pathways. Deregulation of these pathways occurs frequently in AML, resulting in aggressive and refractory disease [26]. AZD6244, an orally available inhibitor of the MEK kinase, decreased peripheral and marrow blasts, but failed to produce complete responses in patients with both newly diagnosed and relapsed AML in a phase II clinical trial [27]. This may be explained by in-vitro data showing that MEK inhibition leads to compensatory upstream hyperactivation of RAF and/or parallel signaling through the PI3K/AKT/mTOR pathway, both of which may function as ‘escape’ pathways [59]. In-vitro data demonstrated improved antitumor activity with dual inhibition of MEK and PI3K/AKT/mTOR pathways [60▪,61]. An upcoming trial will combine the oral MEK inhibitor, trametinib, with an oral AKT inhibitor, GSK2141795, in AML patients with RAS mutations (NCT01907815).

Back to Top | Article Outline

MICROENVIRONMENT

Stem cells within the bone marrow microenvironment are distinguished by their ability to proliferate, differentiate, and self-renew (Table 1). The cross-talk between the AML blast cells and the tumor microenvironment in the hematopoietic stem cell niche is thought to influence chemotherapy resistance and disease relapse [62]. Therefore, targeting the interaction between blast cells and the microenvironment has been a focus of novel drug development.

Back to Top | Article Outline
CXCR4

Both normal stem cells and leukemic blasts express the chemokine receptor, CXCR4, which is essential to stem cell migration and engraftment in the bone marrow. Activation of the CXCR4 transmembrane receptor by its ligand, CXCL12, leads to increased signaling in the PI3K/AKT and MAPK pathways, ultimately causing cell proliferation and survival [28]. Increased CXCR4 levels are associated with chemotherapy resistance and poor outcomes in AML [63▪▪,64]. Plerixafor is a small molecule antagonist of CXCR4 that mobilizes stem cells into the peripheral blood and sensitizes them to cytoxic chemotherapy [65]. Based on these findings, a phase 1/2 study of plerixafor in combination with MEC chemotherapy was conducted in 52 patients with relapsed or refractory AML. Forty-six percent of patients achieved a complete remission and correlative studies demonstrated a two-fold mobilization in leukemic blasts into the peripheral circulation [66]. Clinical trials investigating plerixafor in combination with decitabine and in combination with clofarabine are currently underway in older patients with AML (NCT01352650, NCT01160354).

BMS-936564/MDX-1338 is a fully human IgG(4) monoclonal antibody targeted against CXCR4. MDX-1388 demonstrated antileukemia activity in AML xenograft models and induced apoptosis in AML cell lines [67▪]. A phase I first in human study of MDX-1338 is currently underway in relapsed AML and select B cell hematologic malignancies (NCT01120457) After demonstrating safety in multiple myeloma, another high-affinity antagonist for CXCR4, BL-8040, is also currently being investigated in a phase IIa trial in relapsed and refractory AML (NCT01838395).

Back to Top | Article Outline
Provirus integration site for Moloney murine leukemia virus

Provirus integration site for Moloney murine leukemia virus (PIM) family proteins are serine/threonine kinases involved in oncogenesis. Three PIM kinases (PIM-1, 2, and 3) have been identified and regulate transcription, translation, cell cycle, survival, and drug resistance [29]. In-vitro data suggest PIM-1 activity is essential for normal CXCR4 surface expression. PIM-1-deficient bone marrow resulted in ineffective cell migration and displayed decreased surface CXCR4 expression and impaired CXCL12–CXCR4 signaling. Increased PIM-1 produced high levels of CXCR4, which could be reduced with use of a PIM-1 inhibitor in vitro[68]. These preclinical data suggest that PIM-1 inhibitors may interfere with leukemic blast cell interactions with the microenvironment leading to antitumor activity. Additional in-vitro and xenograft AML model data with the PIM-1 inhibitor SGI-1776 showed that PIM-1 inhibition induced apoptosis by blocking RNA and protein synthesis [69].

FLT3-ITD-mediated leukemogenesis has also been linked to CXCR4 through PIM serine/threonine kinases. FLT3-ITD-mutated leukemia is associated with increased expression of oncogenic PIM serine/threonine kinases [29]. Another PIM-1 inhibitor, AR00459339, caused dephosphorylation of downstream FLT3 targets, STAT5, AKT, and BAD. Combining AR00459339, the PIM-1 inhibitor, with a FLT3 inhibitor resulted in additive cytotoxic effects in FLT3-ITD mutant AML cells. AR00459339 was cytotoxic to samples from patients with resistance to FLT3 inhibitors, suggesting a possible benefit to combining these agents in FLT3-ITD mutant AML [70]. AZD1208 is an orally available, potent, and highly selective inhibitor that effectively inhibits all three PIM isoforms and has demonstrated activity in vitro and in xenograft models [71]. A phase I trial of AZD1208 is underway in relapsed and refractory AML patients with either FLT3-ITD wild-type or mutated disease (NCT01489722). In this trial, it may be of particular interest to assess whether there is differential response between those patients with ITD mutated AML and those lacking the mutation.

Back to Top | Article Outline
Axl

Axl is a member of the Tyro3, Axl, Mer tyrosine kinase receptor family expressed on AML blast cells [30▪,72]. In vivo, AML cells stimulate bone marrow stomal cells in the microenvironment to express the Axl ligand growth arrest-specific gene 6 (Gas6), which drives cancer cell proliferation and survival [73,74]. Concurrent upregulation of Axl and Gas6 induces chemoresistance in AML cells and in-vivo data suggest AML cells have the ability to instruct the bone marrow stomal cells to increase Gas6 expression [30▪]. When Axl signaling is inhibited by a small-molecule Axl kinase inhibitor, BGB324, AML cell proliferation is reduced and apoptosis increases [30▪]. Additional in-vivo data demonstrated that phosphorylation of Axl resulted in FLT3 activation and Axl blockade inhibited the growth of FLT3-positive AML cells [31]. This suggests that targeting Axl in both FLT3-ITD wild-type and mutated AML is a promising therapeutic strategy. The first in human clinical trial of BGB324 in AML will begin shortly.

Back to Top | Article Outline

CONCLUSION

Advances in AML treatment and survival outcomes have been limited in the last several decades. However, as molecular analysis of AML becomes more sophisticated and prevalent in clinical practice with further advances in next generation sequencing, treatment for AML is expected to evolve. The clinical impact of both individual and combined mutations will need to be discerned in order to direct selection of both conventional chemotherapy and novel targeted therapies. Decoding these mutations will continue to allow us to both improve prognosis and develop novel therapies for patients with AML. Extensive preclinical work has led to the identification of relevant pathways and the development of a large number of potential novel therapeutic agents. The pathways and compounds discussed in this review are of major clinical-translational interest and the results of the evolving clinical trials and continued laboratory advances are expected to lead the way to an even greater understanding of leukemogeneis and the development of more targeted therapies. The precise role of how to most effectively manipulate these mutations and pathways in combination with other novel agents or chemotherapy is still yet to be defined and expected to be the topic of future clinical trials.

Back to Top | Article Outline

Acknowledgements

None.

Back to Top | Article Outline
Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Back to Top | Article Outline

REFERENCES

1. Bennett JM, Young ML, Andersen JW, et al. Long-term survival in acute myeloid leukemia: the Eastern Cooperative Oncology Group experience. Cancer. 1997; 80:2205–2209.

2▪. Forman S, Rowe J. The myth of the second remission of acute leukemia in the adult. Blood. 2013; 121:1077–1082.

This article highlights the poor prognosis of AML in the adult patient population despite advances in care.


3. Dohner H, Estey E, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010; 115:453–474.

4. Acute Myeloid Leukemia. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2. 2013; .

5. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009; 361:1058–1066.

6. Ley TJ, Ding L, Walter M, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010; 363:2424–2433.

7. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009; 360:2289–2301.

8. Marcucci G, Maharry K, Wu Y, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2010; 28:2348–2355.

9▪▪. Patel J, Gonen M, Figueroa M, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012; 366:1079–1089.

This manuscript provides results of genetic profiling from a large clinical trial in adult AML.


10▪▪. The Cancer Genome Atlas Research Network Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013; 368:2059–2074.

This genomic analysis of AML samples identified mutations driving leukemogenesis in nearly all patients.


11▪▪. Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012; 483:474–478.

This key study outlines the role of IDH in cell differentiation.


12. Bernt KM, Zhu N, Sinha AU, et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell. 2011; 20:66–78.

13. Daigle SR, Olhava EJ, Therkelsen CA, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011; 20:53–65.

14▪. Deshpande A, Chen L, Fazio M, et al. Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l. Blood. 2013; 121:2533–2541.

This study demonstrates a potential mechanism of leukemogenesis by the MLL oncogene.


15. Yamashita Y, Yuan J, Suetake I, et al. Array-based genomic resequencing of human leukemia. Oncogene. 2010; 29:3723–3731.

16. Metzeler KH, Walker A, Geyer S, et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia. 2012; 26:1106–1152.

17. Campos L, Rouault JP, Sabido O, et al. High expression of Bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood. 1993; 81:3091–3096.

18▪. Mehta S, Shukla S, Vora H. Overexpression of Bcl2 protein predicts chemoresistance in acute myeloid leukemia: Its correlation with FLT3. Neoplasma. 2013; 60:666–675.

This study demonstrates the antiapoptotic effects and chemoresistance induced by Bcl-2 in AML.


19▪▪. Beurlet S, Omidvar N, Gorombei P, et al. BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells. Blood. 2013; 122:2864–2876.

This study identifies BCL-2 as a therapeutic target in leukemia and the potential clinical efficacy of ABT-737.


20. Witzig T, Kaufmann S. Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol. 2006; 7:285–294.

21. Rizzieri D, Feldman E, Dipersio J, et al. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2008; 14:2756–2762.

22. Callera F, Lopes C, Rosa E, Mulin C. Lack of antileukemic activity of rapamycin in elderly patients with acute myeloid leukemia evolving from a myelodysplastic syndrome. Leuk Res. 2008; 32:1633–1634.

23. Amadori S, Stasi R, Martelli AM, et al. Temsirolimus, an mTOR inhibitor, in combination with lower-dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107). Br J Haematol. 2012; 156:205–212.

24. Perl A, Kasner M, Tsai D, et al. A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia. Clin Can Res. 2009; 15:6732–6739.

25▪. Park S, Chapuis N, Saint Marcoux F, et al. A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse. Leukemia. 2013; 27:1479–1486.

This phase I study suggests that the combination of mTOR inhibitors and chemotherapy may be well tolerated and effective in AML.


26. Kornblau SM, Womble M, Qiu YH, et al. Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia. Blood. 2006; 108:2358–2365.

27. Odenike O, Curran E, Iyengar N, et al. Phase II study of the oral MEK inhibitor AZD6244 in advanced acute myeloid leukemia (AML) [abstract]. Blood. 2009; 114:

Abstr. 2081


28. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999; 283:845–848.

29. Shah N, Pang B, Yeoh KG, et al. Potential roles for the PIM1 kinase in human cancer: a molecular and therapeutic appraisal. Eur J Cancer. 2008; 44:2144–2151.

30▪. Ben-Batalla I, Schultze A, Wroblewski M, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia, mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood. 2013; 122:2443–2452.

These preclinical data suggest Axl drives leukemogenesis through AML blast cell interaction with the bone marrow microenvironment, which can be successfully targeted with the novel agent BGB324.


31. Park IK, Mishra A, Chandler J, et al. Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target. Blood. 2013; 121:2064–2073.

32. Rodriguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med. 2012; 17:1–10.

33. Baylin SB. Resistance, epigenetics and the cancer ecosystem. Nat Med. 2011; 17:288–289.

34▪. Gojo I, Tan M, Fang H, et al. Translational phase I trial of vorinostat (suberoylanilide hydroxamic acid) combined with cytarabine and etoposide in patients with relapsed, refractory, or high-risk acute myeloid leukemia. Clin Cancer Res. 2013; 19:1838–1851.

Phase I clinical trial with the HDAC inhibitor, vorinostat, added to chemotherapy.


35▪. Zhuo L, Ruvolo V, McQueen T, et al. HDAC inhibition by SNDX-275 (Entinostat) restores expression of silenced leukemia-associated transcription factors Nur77 and Nor1 and of key pro-apoptotic proteins in AML. Leukemia. 2013; 27:1358–1368.

This study demonstrates the importance of epigenetic modulation for the expression of proapoptotic proteins in AML.


36. Garcia-Manero G, Assouline S, Cortes J, et al. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood. 2008; 112:981–989.

37. Green CL, Evans CM, Zhao L, et al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood. 2011; 118:409–412.

38. Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010; 28:3636–3643.

39. Boissel N, Nibourel O, Renneville A, et al. Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group. J Clin Oncol. 2010; 28:3717–3723.

40. Schnittger S, Haferlach C, Ulke M, et al. IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood. 2010; 116:5486–5496.

41. Green C, Evans C, Hils R, et al. The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status. Blood. 2010; 116:2779–2782.

42▪. Rohle D, Popovici-Muller J, Palaskas N, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013; 340:626–630.

This study identifies IDH1 mutations as a key driver for glioma tumors.


43▪▪. Wang F, Travins J, DeLaBarre B, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 2013; 340:622–626.

This study identifies IDH2 as a therapeutic target in leukemia.


44. Muntean AG, Hess JL. The pathogenesis of mixed-lineage leukemia. Annu Rev Pathol. 2012; 7:283–301.

45▪▪. Daigle S, Olhava E, Therkelsen C, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013; 122:1017–1025.

This study identifies DOT1L as a therapeutic modality in MLL rearranged leukemia.


46. Metzeler KH, Walker A, Geyer S, et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia. 2012; 26:1106–1107.

47. Steelman L, Abrams S, Whelan J, et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia. 2008; 22:686–707.

48▪. Rahmani M, Aust MM. Attkisson E. Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism. Cancer Res. 2013; 73:1340–1351.

This study demonstrates the potential clinical benefit of inhibiting both Bcl-2 and the PI3K pathway in AML.


49▪. Jin L, Tabe Y, Kojima K, et al. PI3K inhibitor GDC-0941 enhances apoptotic effects of BH-3 mimetic ABT-737 in AML cells in the hypoxic bone marrow microenvironment. J Mol Med (Berl). 2013; 91:1383–1397.

This study demonstrates the potential clinical benefit of inhibiting both Bcl-2 and the PI3-K pathway in AML.


50. Marcucci G, Byrd JC, Dai G, et al. Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood. 2003; 101:425–432.

51. Min YH, Eom JI, Cheong JW, et al. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia. 2003; 17:995–997.

52. Evangelisti C, Evangelisti C, Bressanin D, et al. Targeting phosphatidylinositol 3-kinase signaling in acute myelogenous leukemia. Expert Opin Ther Targets. 2013; 17:921–936.

53▪. Jin L, Tabe Y, Lu H, et al. Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment. Cancer Lett. 2013; 329:45–58.

This study demonstrates the potential therapeutic benefit of dual inhibition of PI3-K and FLT3 in AML.


54. Grandage VL, Gale RE, Linch DC, Khwaja A. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, MAP kinase and p53 pathways. Leukemia. 2005; 19:586–594.

55. Xu Q, Simpson SE, Scialla TJ, et al. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood. 2003; 102:972–980.

56. Altman JK, Sassano A, Kaur S, et al. Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors. Clin Cancer Res. 2011; 17:4378–4388.

57. Chapuis N, Tamburini J, Green AS, et al. Dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia. Clin Cancer Res. 2010; 16:5424–5435.

58. Chiarini F, Lonetti A, Teti G, et al. A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia. Oncotarget. 2012; 3:1615–1628.

59. Ricciardi M, Scerpa M, Bergamo P, et al. Therapeutic potential of MEK inhibition in acute myelogenous leukemia: rationale for ‘vertical’ and ‘lateral’ combination strategies. J Mol Med. 2012; 90:1133–1144.

60▪. Xing Y, Hogge DE. Combined inhibition of the phosphoinosityl-3-kinase (PI3Kinase) P110δ subunit and mitogen-extracellular activated protein kinase (MEKinase) shows synergistic cytotoxicity against human acute myeloid leukemia progenitors. Leuk Res. 2013; 37:697–704.

This study assesses the role of the P110 gamma subunit of PI3-K in AML.


61. Liu H, Diaz-Flores E, Poire X, et al. Combination of a MEK inhibitor, AZD6244, and dual PI3K/mTOR inhibitor, NVP-BEZ235: an effective therapeutic strategy for acute myeloid leukemia [abstract]. Blood. 2010; 116:

Abstr. 3978


62. Raaijmakers MH, Scadden DT. Evolving concepts on the microenvironmental niche for hematopoietic stem cells. Curr Opin Hematol. 2008; 15:301–306.

63▪▪. Chen Y, Jacamo R, Konopleva M, et al. CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia. J Clin Invest. 2013; 123:2395–2407.

The role of CXCR4 in chemoresistance is highlighted in this study.


64. Spoo AC, Lubbert M, Wierda WG, Burger JA. CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood. 2007; 109:786–791.

65. Nervi B, Ramirez P, Rettig MP, et al. Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. Blood. 2009; 113:6206–6214.

66. Uy G, Rettig M, Motabi I, et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood. 2012; 119:3917–3924.

67▪. Kuhne MR, Belanger B, Chen S, et al. BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies. Clin Cancer Res. 2013; 19:357–366.

This study identifies a CXCR4-targeted antibody with clinical relevance.


68. Grundler R, Brault L, Gasser C, et al. Dissection of PIM serine/threonine kinases in FLT3-ITD-induced leukemogenesis reveals PIM1 as regulator of CXCL12-CXCR4-mediated homing and migration. J Exp Med. 2009; 206:1957–1970.

69. Chen LS, Redkar S, Taverna P, et al. Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia. Blood. 2011; 118:693–702.

70. Fathi AT, Arowojolu O, Swinnen I, et al. A potential therapeutic target for FLT3-ITD AML: PIM1 kinase. Leuk Res. 2012; 36:224–231.

71. Keeton E, McEachern K, Alimzhanov M, et al. Efficacy and biomarker modulation by AZD1208, a novel, potent and selective pan-Pim kinase inhibitor, in models of acute myeloid leukemia [abstract]. Cancer Res. 2012; 72:

abstr. 2796


72. Schmidt T, Ben-Batalla I, Schultze A, Loges S. Macrophage-tumor crosstalk: role of TAMR tyrosine kinase receptors and of their ligands. Cell Mol Life Sci. 2012; 69:1391–1414.

73. Loges S, Schmidt T, Tjwa M, et al. Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. Blood. 2010; 115:2264–2273.

74. Sainaghi PP, Castello L, Bergamasco L, et al. Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor. J Cell Physiol. 2005; 204:36–44.

Keywords

acute myeloid leukemia; epigenetic modulation; intracellular signaling pathways; tumor microenvironment

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.