FGF10/FGF17 as prognostic and drug response markers in acute myeloid leukemia

2022 ◽  
Vol 70 (1) ◽  
pp. 103316
Author(s):  
Yanying Ling ◽  
Qinghua Du
Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2024-2024
Author(s):  
Michael Heuser ◽  
Luzie U. Wingen ◽  
Doris Steinemann ◽  
Gunnar Cario ◽  
Nils von Neuhoff ◽  
...  

Abstract Resistance to induction chemotherapy is of independent prognostic value in acute myeloid leukemia (AML). DNA microarrays were used to determine the gene-expression profile of AML blasts in 38 patients with good or poor response to induction chemotherapy. We selected an 11-sample training set, applying prediction analysis of microarrays (PAM) to devise a drug-response predictor which was tested on the remaining 27 samples and an independent set of samples recently published (Bullinger et al. 2004). Our drug-response predictor with 46 clones divided the 27 samples into two prognostic subgroups, the poor response group having a significantly shorter overall survival (P= .021). A subset of these 46 clones was sufficient to divide the published 62-sample test-set with intermediate risk cytogenetics into prognostically relevant subgroups (P= .028), adding prognostic information to that of known risk factors in multivariate analysis (hazard ratio, 2.8; 95 percent confidence interval, 1.4 to 5.8; P= .005). Thirteen of 39 drug resistance-enriched genes are known to be upregulated in hematopoietic stem/progenitor cells, and the expression pattern in normal CD34+ cells is highly correlated to the drug-resistance signature. This suggests that drug resistant AMLs show molecular features of hematopoietic stem/progenitor cells and can be identified by a characteristic gene-expression profile.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3624-3624
Author(s):  
Weihsu Claire Chen ◽  
Andreea C. Popescu ◽  
Yan Xing ◽  
Gitte Gerhard ◽  
Julie S. Yuan ◽  
...  

Abstract Abstract 3624 Small molecule inhibitors targeting somatic mutations of Janus kinase 2 (JAK2) have demonstrated effectiveness in clinical trials for treatment of myeloproliferative disorders. Activated JAK2 signaling has been reported in some acute myeloid leukemia (AML) samples even though the frequency of JAK2 mutations is relatively rare in AML. Whether JAK2 inhibitors are effective in AML is not clear. Since many myeloid malignancies including AML are organized as cellular hierarchies driven by leukemia stem cells (LSC) at the apex, it is also unknown whether LSCs are sensitive to JAK2 inhibition. We report that SAR302503 (SAR503, Sanofi, Cambridge, MA), an orally administered small molecule inhibitor of JAK2, shows therapeutic efficacy in a xenograft model of human AML established by intrafemoral injection of primary human AML cells into anti-NK treated irradiated NOD.SCID mice. Drug pharmacokinetic studies confirm that SAR503 exhibits good bioavailability in NOD.SCID mice. Starting 2 weeks post transplantation to permit establishment of an AML graft, mice were orally gavaged twice a day with 60 mg/kg SAR503 or vehicle alone (0.5% methylcellulose) for 14 consecutive days. In 5 of 7 AML samples, treated mice exhibited significantly lower engraftment (3 to 18 fold; p < 0.05) in the injected femur compared to control mice. For 4 samples, there was also a significantly reduced level of engraftment (2 to 19 fold; p < 0.05) in non-injected bones, indicating that JAK2 inhibition affected the migratory ability of AML cells. The observed heterogeneous drug response (5 responders and 2 non-responders) correlated well with phosphoflow analysis showing that AML samples that responded to JAK2 inhibition in vivo had high basal and marked reduction in the STAT signaling pathway after in vitro treatment, whereas non-responding samples did not. Serial transplantation studies are ongoing to evaluate the effect of JAK2 inhibition on LSCs in treated primary mice. To evaluate whether AML samples that did not respond to JAK2 inhibition alone would respond to combination therapy, we treated engrafted mice with SAR503 plus cytarabine, a standard chemotherapeutic drug used in AML. Combination therapy of one non-responding sample resulted in a significantly reduced leukemic burden (2.3%) compared to mice treated with SAR503 alone (85.8%) or cytarabine alone (16.8%; p < 0.05 versus combination therapy). Our results demonstrate the potential of SAR503 to target AML cells and AML LSCs across a cross section of primary AML samples. Our pilot studies warrant a much larger scale evaluation of AML samples to identify responders and non-responders along with associated proteomic and genomic biomarkers of drug response. The approach we have taken, which focuses on large-scale analysis of primary samples using state-of-the-art xenograft assays, offers a new paradigm for preclinical drug development to identify both novel agents that effectively target LSCs and the patient populations most likely to benefit from targeted treatment. Disclosures: Off Label Use: We describe using SAR302503 to treat AML in a mouse model.


Cancer Cell ◽  
2017 ◽  
Vol 32 (3) ◽  
pp. 324-341.e6 ◽  
Author(s):  
Diana Passaro ◽  
Alessandro Di Tullio ◽  
Ander Abarrategi ◽  
Kevin Rouault-Pierre ◽  
Katie Foster ◽  
...  

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2662-2662 ◽  
Author(s):  
Diana Passaro ◽  
Alessandro Di Tullio ◽  
Ander Abarrategi ◽  
Kevin Rouault-Pierre ◽  
Katie Foster ◽  
...  

Abstract The biological and clinical behavior of hematological malignancies are not only determined by the properties of the leukemic cells themselves, but are also highly affected by interaction with the microenvironment, pointing to the existence of an active crosstalk between the two compartments. Previous studies showed that acute myeloid leukemia (AML) cells actively modify endothelial cells ex vivovia several pathways, mainly mediated by VEGF. However, as anti-VEGF therapies haven't produced successful results in clinical trials, an extensive study of the crosstalk between AML and the vascular niche in the bone marrow (BM) is required to provide new therapeutic strategies. In the present study we combined the use of mouse models of AML, human AML patient-derived xenografts (PDX) and direct analysis on patient-derived BM biopsies to provide a global, reliable picture of the bone marrow vasculature in AML disease. We found several abnormalities in the vascular architecture and function in PDX, such as increased number of endothelial cells, increased microvascular density (MVD), decreased vascular mean diameter and increased hypoxia. Furthermore, using two-photon confocal intravital imaging we witnessed increased vascular permeability upon AML engraftment, observed homogeneously among different PDX. Interestingly, induction chemotherapy failed to normalize the vascular permeability in the BM, despite significant reduction in AML engraftment. We identified increased nitric oxide (NO) as a major mediator of the AML-induced vascular leakiness in the BM. Increased levels of NO and activated NOS3 were found in PDX and in an independent cohort of patient-derived BM biopsies. Strikingly, inhibition of NO production using genetic and pharmacological approaches reduced the vascular permeability, potentiated the normal HSC function and significantly improved treatment response in PDX. These results strongly support the notion of a primary function of the vascular permeability in AML progression, drug response and in affecting normal stem cell function, and they call for clinical trials incorporating NOS inhibitors during the remission phase to target the abnormal vascular niche and improve the treatment response. Disclosures No relevant conflicts of interest to declare.


2020 ◽  
Vol 393 (1) ◽  
pp. 112054
Author(s):  
Cheng Chen ◽  
Li Wang ◽  
Lili Li ◽  
Aoli Wang ◽  
Tao Huang ◽  
...  

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Brian S. White ◽  
Suleiman A. Khan ◽  
Mike J. Mason ◽  
Muhammad Ammad-ud-din ◽  
Swapnil Potdar ◽  
...  

AbstractThe FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vivo drug response of primary patient samples. We find that ex vivo samples often exhibit a general sensitivity to (any) drug exposure, independent of drug target. We observe that this “general response across drugs” (GRD) is associated with FLT3-ITD mutations, clinical response to standard induction chemotherapy, and overall survival. Further, incorporating GRD into expression-based regression models trained on one of the studies improved their performance in predicting ex vivo response in the second study, thus signifying its relevance to precision oncology efforts. We find that venetoclax response is independent of GRD but instead show that it is linked to expression of monocyte-associated genes by developing and applying a multi-source Bayesian regression approach. The method shares information across studies to robustly identify biomarkers of drug response and is broadly applicable in integrative analyses.


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