57 research outputs found

    A case of AML characterized by a novel t(4;15)(q31;q22) translocation that confers a growth-stimulatory response to retinoid-based therapy

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    Here we report the case of a 30-year-old woman with relapsed acute myeloid leukemia (AML) who was treated with all-transretinoic acid (ATRA) as part of investigational therapy (NCT02273102). The patient died from rapid disease progression following eight days of continuous treatment with ATRA. Karyotype analysis and RNA-Seq revealed the presence of a novel t(4;15)(q31;q22) reciprocal translocation involving theTMEM154andRASGRF1genes. Analysis of primary cells from the patient revealed the expression ofTMEM154-RASGRF1mRNA and the resulting fusion protein, but no expression of the reciprocalRASGRF1-TMEM154fusion. Consistent with the response of the patient to ATRA therapy, we observed a rapid proliferation of t(4;15) primary cells following ATRA treatment ex vivo. Preliminary characterization of the retinoid response of t(4;15) AML revealed that in stark contrast to non-t(4;15) AML, these cells proliferate in response to specific agonists of RARα and RARγ. Furthermore, we observed an increase in the levels of nuclear RARγ upon ATRA treatment. In summary, the identification of the novel t(4;15)(q31;q22) reciprocal translocation opens new avenues in the study of retinoid resistance and provides potential for a new biomarker for therapy of AML

    A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival

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    The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson\u27s r = 0.315; P \u3c 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 1

    Abstract 1363: Inhibition of the PI3K/AKT/mTOR Pathway Leads to Down-Regulation of c-Myc and Overcomes Resistance to ATRA in Acute Myeloid Leukemia.

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    Acute Promyelocytic Leukemia (APL) accounts for 5% of all cases of acute myeloid leukemia (AML). This disease is highly curable with all-trans-retinoic acid (ATRA) based therapy. In non-APL AML, ATRA has limited activity, and little is known about mechanisms of ATRA resistance. The apparent selective efficacy of ATRA in PML/RARα-associated APL poses an important question as to whether the presence of this fusion protein renders APL uniquely susceptible. Two compelling arguments can be made to counter this view. First, experiments in vitro show that ATRA effectively differentiates HL-60 cell lines, which lack the PML/RARα fusion protein. Second, clinical studies with ATRA in previously untreated older AML patients (excluding APL) have reported clinical activity. These observations confirm the therapeutic potential of ATRA beyond APL. In this context, our group has previously identified the lysine demethylase LSD-1, as a therapeutic target to re-sensitize leukemic blasts to ATRA. A clinical investigation of ATRA combined with LSD-1 inhibition is currently underway (NCT02273102). It is likely that other defects leading to ATRA resistance will be similarly amenable to pharmacologic manipulation. Defects in the proto-oncogene c-Myc have been widely implicated in the initiation and maintenance of AML. Over-expression of c-Myc in leukemic blasts enhances clonogenic survival and blocks ATRA induced differentiation. We hypothesized that down-regulation of c-Myc might increase the anti-leukemic effects of ATRA in AML. To date, c-Myc has been an evasive target for direct pharmacologic inhibition however, inhibitors of the PI3K/AKT/mTOR pathway have been shown to indirectly lower levels of c-Myc in leukemic blasts. In the current study, we show that the pro-differentiation effects of ATRA are markedly potentiated when combined with agents that target PI3K/AKT/mTOR signalling. In AML cell lines and primary patient samples, we observed additive pro-differentiation effects when ATRA was combined with inhibitors of PI3K (ZSTK474) and mTOR complex proteins (Torin-1, WYE-125132). However, when combined with the bromodomain inhibitor NVP-BEZ235, a dual inhibitor of PI3K and mTOR, we observed synergistic induction of CD11b by FACS analysis. Combination studies revealed loss of cell viability, cell cycle arrest in G1 phase, and impaired clonogenic survival, which was more prominent for ATRA combination treatments than with any agent used alone (Figure 1). To assess the role of c-Myc in mediating these effects, we measured c-Myc protein levels and PI3K/AKt/mTOR pathway markers at different time-points following treatment with ATRA alone and in combination with the inhibitors described above (Figure 2). Our findings suggest that ATRA alone quickly down-regulates c-Myc (within 6 hours) through transcriptional repression. Disruption of the PI3K/AKT/mTOR pathway further down-regulates c-Myc (within 3 hours) through destabilization and enhanced degradation. ATRA combined with NVP-BEZ235 produced maximal c-Myc suppression, and led to more cell kill than any other combination tested. Detailed analysis of changes in the transcriptome in MV-411 cells following treatment with ATRA and NVP-BEZ235 revealed that both agents act jointly on the regulation of the same biological pathways and processes, but regulate different sets of genes within these pathways. Updated mechanism based studies will be presented. In conclusion, suppression of c-Myc levels through disruption of PI3K/AKT/mTOR signalling augments the anti-leukemic effects of ATRA. These data support the clinical investigation of ATRA combined with rapalogs or bromodomain inhibitors

    The PIM kinases in hematological cancers

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    The PIM genes represent a family of proto-oncogenes that encode three different serine/threonine protein kinases (PIM1, PIM2 and PIM3) with essential roles in the regulation of signal transduction cascades, which promote cell survival, proliferation and drug resistance. PIM kinases are overexpressed in several hematopoietic tumors and support in vitro and in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis. PIM kinases do not have an identified regulatory domain, which means that these proteins are constitutively active once transcribed. They appear to be critical downstream effectors of important oncoproteins and, when overexpressed, can mediate drug resistance to available agents, such as rapamycin. Recent crystallography studies reveal that, unlike other kinases, they possess a hinge region, which creates a unique binding pocket for ATP, offering a target for an increasing number of potent small-molecule PIM kinase inhibitors. Preclinical studies in models of various hematologic cancers indicate that these novel agents show promising activity and some of them are currently being evaluated in a clinical setting. In this review, we profile the PIM kinases as targets for therapeutics in hematologic malignancies

    Current status of agents active against the T315I chronic myeloid leukemia phenotype

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    Introduction: T315I is a genetic mutation of the Bcr-Abl tyrosine kinase, the pathogenetic abnormality in chronic myeloid leukemia (CML). It accounts for 10 - 15% of clinically relevant CML mutations. Licensed tyrosine kinase inhibitors are ineffective against this mutation and its development reduces life expectancy of CML in chronic phase from 10 years to just 22 months. Extensive work is ongoing to establish the most effective therapy to overcome this mutation, including the development of novel specific agents and also re-examination of established therapies. Areas covered: This review examines the agents in development, dividing them into Bcr-Abl-dependant and -independent groups. It looks at the progress of this research, updating the reader on the status of agents previously reported and introducing emerging therapeutic possibilities only recently announced. Expert opinion: Development of the T315I mutation is a devastating event for some patients with CML. There are potential therapeutic agents at all stages of the drug development cycle to target this patient subpopulation. Clinical activity has been demonstrated and a number of agents are on the cusp of being licensed and available for use
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