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162


Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia

Glytsou, Christina; Chen, Xufeng; Zacharioudakis, Emmanouil; Al-Santli, Wafa; Zhou, Hua; Nadorp, Bettina; Lee, Soobeom; Lasry, Audrey; Sun, Zhengxi; Papaioannou, Dimitrios; Cammer, Michael; Wang, Kun; Zal, Tomasz; Zal, Malgorzata Anna; Carter, Bing Z; Ishizawa, Jo; Tibes, Raoul; Tsirigos, Aristotelis; Andreeff, Michael; Gavathiotis, Evripidis; Aifantis, Iannis
BH3-mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL-1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetics therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3-mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 overexpression is sufficient to drive resistance to BH3-mimetics in AML. Insensitivity to BH3-mimetics is accompanied by enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux which acts as a pro-survival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3-mimetics by impairing mitochondrial clearance and enhancing apoptosis in AML.
PMID: 37088914
ISSN: 2159-8290
CID: 5464912

68Ga-Pentixafor-PET/CT imaging represents a novel approach to detect chemokine receptor CXCR4 expression in myeloproliferative neoplasms

Kraus, Sabrina; Dierks, Alexander; Rasche, Leo; Kertels, Olivia; Kircher, Malte; Schirbel, Andreas; Zovko, Josip; Steinbrunn, Torsten; Tibes, Raoul; Wester, Hans-Jürgen; Buck, Andreas K; Einsele, Hermann; Kortüm, K Martin; Rosenwald, Andreas; Lapa, Constantin
C-X-C motif chemokine receptor 4 (CXCR4) is an attractive target for cancer diagnosis and treatment, as it is overexpressed in many solid and hematological malignancies. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using 68Ga-Pentixafor to visualize and quantify disease involvement in myeloproliferative neoplasms (MPNs). Methods: 12 patients with MPNs (n = 4 primary myelofibrosis, n = 6 essential thrombocythemia, n = 2 polycythemia vera) and 5 controls underwent 68Ga-Pentixafor-PET/CT. Imaging findings were compared with immunohistochemical stainings, laboratory data and splenic volume. Results:68Ga-Pentixafor-PET/CT was visually positive in 12/12 patients and CXCR4 target specificity could be confirmed by immunohistochemical staining. A significantly higher tracer uptake could be detected in the bone marrow of MPN patients (SUVmean 6.45±2.34 vs. 4.44±1.24). Dynamic changes of CXCR4 expression determined by 68Ga-Pentixafor-PET/CT corresponded with treatment response. Conclusion:68Ga-Pentixafor-PET/CT represents a novel diagnostic tool to non-invasively detect and quantify the extent of disease involvement in MPNs.
PMID: 34049979
ISSN: 1535-5667
CID: 4890562

Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia

Garitano-Trojaola, Andoni; Sancho, Ana; Götz, Ralph; Eiring, Patrick; Walz, Susanne; Jetani, Hardikkumar; Gil-Pulido, Jesus; Da Via, Matteo Claudio; Teufel, Eva; Rhodes, Nadine; Haertle, Larissa; Arellano-Viera, Estibaliz; Tibes, Raoul; Rosenwald, Andreas; Rasche, Leo; Hudecek, Michael; Sauer, Markus; Groll, Jürgen; Einsele, Hermann; Kraus, Sabrina; Kortüm, Martin K
The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD + AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.
PMID: 34172833
ISSN: 2399-3642
CID: 4925922

Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin

Lorza, Andres M Arias; Ravi, Harshan; Philip, Rohit C; Galons, Jean-Philippe; Trouard, Theodore P; Parra, Nestor A; Von Hoff, Daniel D; Read, William L; Tibes, Raoul; Korn, Ronald L; Raghunand, Natarajan
The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2-3 days post-crolibulin (13-24 mg/m2). ADC maps were computed from DW-MRI. Pre-contrast T1 maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC90s) and the Extended Tofts Model parameters ktrans, ve, and vp were calculated. There was a strong correlation between higher plasma drug [Formula: see text] and a linear combination of (1) reduction in tumor fraction with [Formula: see text] mM s, and, (2) increase in tumor fraction with [Formula: see text]. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with [Formula: see text], and, (2) increase in tumor fraction with [Formula: see text]. These findings are suggestive of cell swelling and decreased tumor perfusion 2-3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.
PMCID:7468301
PMID: 32879326
ISSN: 2045-2322
CID: 4583392

Safety and efficacy of the maximum tolerated dose of givinostat in polycythemia vera: a two-part Phase Ib/II study

Rambaldi, Alessandro; Iurlo, Alessandra; Vannucchi, Alessandro M; Noble, Richard; von Bubnoff, Nikolas; Guarini, Attilio; Martino, Bruno; Pezzutto, Antonio; Carli, Giuseppe; De Muro, Marianna; Luciani, Stefania; McMullin, Mary Frances; Cambier, Nathalie; Marolleau, Jean-Pierre; Mesa, Ruben A; Tibes, Raoul; Pancrazzi, Alessandro; Gesullo, Francesca; Bettica, Paolo; Manzoni, Sara; Di Tollo, Silvia
PMID: 32047238
ISSN: 1476-5551
CID: 4304342

Targeting Apoptosis in Acute Myeloid Leukemia: Current Status and Future Directions of BCL-2 Inhibition with Venetoclax and Beyond

Choi, Jun H; Bogenberger, James M; Tibes, Raoul
Acute myeloid leukemia (AML) is a disease of the hematopoietic system that remains a therapeutic challenge despite advances in our understanding of the underlying cancer biology over the past decade. Recent developments in molecular targeting have shown promising results in treating leukemia, paving the way for novel treatment strategies. The discovery of drugs that promote apoptosis in leukemic cells has translated to encouraging activity in clinical trials. B-cell lymphoma (BCL)-2 inhibition has been at the center of drug development efforts to target apoptosis in AML. Remarkable clinical success with venetoclax has revolutionized the ways we treat hematological malignancies. Several landmark trials have demonstrated the potent antitumor activity of venetoclax, and it is now frequently combined with traditional cytotoxic agents to treat AML. However, resistance to BCL-2 inhibition is emerging, and alternative strategies to address resistance mechanisms have become an important focus of research. A number of clinical trials are now underway to investigate a plurality of novel agents that were shown to overcome resistance to BCL-2 inhibition in preclinical models. Some of the most promising data come from studies on drugs that downregulate myeloid cell leukemia (MCL)-1, such as cyclin-dependent kinases (CDK) inhibitors. Furthermore, innovative approaches to target apoptosis via extrinsic pathways and p53 regulation have added new cytotoxic agents to the arsenal, including drugs that inhibit inhibitor of apoptosis protein (IAP) family proteins and murine double minute 2 (MDM2). This review provides a perspective on past and current treatment strategies harnessing various mechanisms of apoptosis to target AML and highlights some important promising treatment combinations in development.
PMID: 32319019
ISSN: 1776-260x
CID: 4397122

A final report of the phase I/Ib study of the smoothened/ hedgehog pathway inhibitor sonidegib combined with azacitidine in relapsed or refractory aml and mds patients [Meeting Abstract]

Tibes, R; Kosiorek, H; Dueck, A; Palmer, J; Slack, J; Bogenberger, J; Zblewski, D; Hogan, W; Litzow, M; Mesa, R; Foran, J; Al-Kali, A
Background: Despite the remarkable improved response rates and new standard combining the BCL-2 inhibitor Venetoclax with hypomethylating agents (HMAs) or Low-dose AraC (LDAC) in newly diagnosed elderly AML patients, the outcome of HMA and Venetoclax relapsed or refractory (R/R) AML and MDS patients remains dismal. We identified inhibition of Hedgehog pathway (HP) genes as a potential rational combination to overcome a priori and acquired HMA resistance. The smoothened (SMO)/ hedeghog pathway inhibitor glasdegib has recently been approved with LDAC in newly diagnosed AML and glasdegib with HMA in upfront treatment has shown activity. To date there is no study combining a SMO inhibitor in R/R AML and MDS. Here we report the final results of the first study combining the SMO inhibitor Sonidegib (SON, LDE225) in combination with Azacitidine (AZA) in 35 patients with R/R AML or MDS.
Result(s): In a Ph1 (3+3) dose escalation and Ph1B (expansion cohort) study 10 and 25 pts respectively were treated both arms. DLTs occurred at 400mg SON consisting of COP elevation and the MTD of the SONAZA combination was determined at 200mg SON daily and AZA 75mg/m2 for 7 days each cycle every 28 days at which level 1 pt had grade 3 vomiting (possibly related) and a 2nd pt had grade 3 fatigue (probably related). Of 28 pts evaluated at the MTD dose level of 200 mg 2 pts had a CR and MLFS, however 20 pts had no progression, only 2 pts progressed and 4 pts could not be assessed. At a median follow up of 8.7 ms, the overall survival (OS) in the AML cohort was 7.6 ms with most of the pts having failed prior HMA based treatment and/ or cytotoxic chemotherapy. The 6 ms OS was 50%. More remarkable, 1/3 of patients had a long response ranging from 7-24 ms, despite having failed prior HMA. Biomarker analysis of long-vs short responders is ongoing to identify pts at chance of durable responses and will be presented at the meeting.
Conclusion(s): Combined SMO and HMA treatment in R/R AML and MDS shows encouraging responses and biomarker stratification will help to identify pts for a personalized medicine approach in hematology
EMBASE:631302276
ISSN: 2296-5262
CID: 4367652

Corrigendum to "Triazolo[4,5-d]pyrimidines as validated general control nonderepressible 2 (GCN2) protein kinase inhibitors reduce growth of leukemia cells" [Comput. Struct. Biotechnol. J. 16 (2018) 350-360]

Lough, Lea; Sherman, Dan; Becerra-Flores, Manuel; Vasudevan, Deepika; Lavinda, Olga; Ni, Eric; Wang, Hong; Ryoo, Hyung Don; Tibes, Raoul; Cardozo, Timothy
[This corrects the article DOI: 10.1016/j.csbj.2018.09.003.].
PMID: 32435428
ISSN: 2001-0370
CID: 4444472

DNA Damage Repair Interference By WEE1 Inhibition with AZD1775 Overcomes Combined Azacitidine and Venetoclax Resistance in Acute Myeloid Leukmeia (AML) [Meeting Abstract]

Tibes, R; Ferreira, Coutinho D; Tuen, M T; Chen, X; Glytsou, C; Aifantis, I; Shmelkov, S
Acute myeloid leukemia (AML) has remained one of the most treatment resistant and deadliest cancers. The survival of AML blast cells is controlled by the balance of anti- and pro-apoptotic proteins. Recently approved Bcl-2 targeted therapy of AML with the Bcl-2 specific inhibitor Venetoclax in combinations has improved patients outcomes. However, a priori and developing resistance to venetoclax combinations with hypomethylating agents (HMA) azacitidine and decitabine challenge this treatment. As such, novel therapies to overcome venetoclax-HMA resistance are urgently needed. We have identified a combination of DNA damage repair interference by WEE1 inhibition with AZD1775, combined with low dose cytarabine (AraC) as an effective strategy to overcome combined venetoclax-azacitidine resistance (VAR). AZD1775 with low dose AraC induced massive apoptosis (by Annexin V and cleaved caspase-3) and almost completely reduced viability and clonogenic growth of primary AML cells. To delineate the molecular mechanism of the synergistic effect of AZD1775/AraC we performed RNAseq analysis of single agent or the combination of AZD1775+AraC in AML cell lines and primary CD34+ selected AML patient cells with the goal to identify deferentially regulated genes indicating a mechanistic underpinning of the potent activity. Only 2 genes were deferentially regulated across cell lines and CD34+ selected cells under AZD1775+AraC treatment: one of these is NR4A1, an orphan nuclear receptor, which we went on to validate as a potential downstream target of Wee1 inhibition. The inactivation of NR4A1 in mice was previously shown to induce AML and to maintain leukemia stem cells. Using qPCR we confirmed that the expression of NR4A1 is upregulated after AZD1775/AraC combo treatment in human leukemic cells. We then demonstrated that activators of NR4A1 (cytosporone B and pPhOCH3) reduce viability of leukemic cells, while NR4A1 inhibitor pPhOH was able to abolish the effect of AZD1775/AraC combo treatment increasing leukemic cell viability]. To investigate the involvement of mitochondria in the effect of AZD1775/AraC treatment we performed the expression of mitochondrial genes and pathway analyses in RNAseq data and found that mitochondrial gene expression, including many genes involved in apoptosis, has most dramatic changes in the combo treatment if compared to the single agents. Subsequently, we have examined the expression of the main BCL-2 family apoptotic genes by qPCR and western blot analysis. We found that AZD1775/AraC induces the expression of Bim isoforms, whereas Bcl-2, Mcl-1 and Bcl-Xl were largely unaffected. NR4A1 was previously shown to translocate to mitochondria, release Bim from Bcl-2 protein binding, as well as convert Bcl-2 to an extreme potent pro-apoptotic form. Finally, we generated several additional VAR cell lines and cells with subclones and demonstrated that AZD1775/AraC combination treatment is able to overcome VAR in almost every clone. Our results show that DNA damage repair interference with Wee1 inhibition has the potential to overcome VAR through a novel mechanisms of AZD1775 increasing NR4A1, freeing pro-apoptotic Bim irrespective of anti-apoptotic Bcl-2 proteins leading to massive apoptotic cell death in AML cells. The precise molecular mechanisms and the involvement of NR4A1 in this phenomenon will be presented at the meeting. Our findings will help to develop new therapeutic strategies in AML treatment and a trial of AZD1775 + AraC in AML is currently ongoing. Disclosures: No relevant conflicts of interest to declare.XXCopyright
EMBASE:2013253632
ISSN: 0006-4971
CID: 4928192

RAC1 Inhibitor EHT1864 and Venetoclax Overcome Midostaurin Resistance in Acute Myeloid Leukemia [Meeting Abstract]

Garitano-Trojaola, A; Sancho, A; Goetz, R; Walz, S; Jetani, H; Teufel, E; Rodhes, N; DaVia, M; Haertle, L; Nerreter, S; Vogt, C; Duell, J; Tibes, R; Kraus, S; Rosenwald, A; Rasche, L; Hudecek, M; Sauer, M; Einsele, H; Groll, J; Kortum, M
Introduction Acute Myeloid Leukemia (AML) is a genetically heterogeneous disease characterized by clonal expansion of immature myeloid progenitor cells in the bone marrow (BM). Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of AML cases, with Internal Tandem Duplications (ITD) being the most common type of mutation. Several FLT3 specific inhibitors (TKI) have been developed such as quizartinib, crenolanib and midostaurin (recently approved for clinical use). Nevertheless FLT3-ITD is associated with unfavorable prognosis and patients develop drug resistance with the underlying mechanisms remaining largely unexplained. Recently, changes within the actin cytoskeleton were associated with drug resistance development in various cancers. FLT3-ITD mutations are associated with RAC1 activation. RAC1 belongs to the family of RHO GTPases and enhances the actin polymerization by inducing the expression of N-WASP or WAVE2 and ARP2/3 complex. Therefore, we investigated actin cytoskeleton rearrangements through RAC1 activation as a potential mechanism contributing to Midostaurin resistance in AML. Material and methods First, we developed two Midostaurin resistant AML cell lines (MID-RES, MV4-11 and MOLM-13). Single cell measurements of Cell Stiffnes, cell adhesion forces between tumor and HS5 stroma cells and Actin filaments were performed by Atomic Force Microscopy (FluidFM) and SIM microscopy, respectively. RAC1 activation was measured by RAC1 activation kit provided by Cytoskeleton. FLT3 surface and intracellular expression was measured by Flow cytometry and western blot, respectively. Cell death was analyzed by Annexin/PI staining in flow cytometry. Results The MID-RES cell lines MV4-11/MOLM-13 showed higher FLT3 surface and intracellular expression compared to their MID sensitive parental cells. In line with our expectations, we observed RAC1 activation, as well as an up-regulation of actin polymerization positive regulators such as N-WASP, WAVE2, PFN1 and ARP2/3 complex and the inhibition of actin polymerization negative regulator P-ser3 CFL1 in MID-RES cells. FLT3 receptor knock down by siRNAs reversed the MID resistance and reduced RAC1 activation and actin polymerization inducers expression. Likewise, bioinformatic analysis from publicly available microarray expression data (E-MTAB-3444), confirmed positive correlation between actin polymerization inducers and FLT3 signaling expression in 178 FLT3-ITD (r=0,67) and 461 FLT3 WT(r= 0,57) de novoAML patients. RAC1 induced Actin polymerization positively correlates with actin filaments growth and cell stiffness, which was observed in our MID-RES cells, higher load of actin filaments and increased cell stiffness. The combination between RAC1 specific inhibitor, EHT1864 and Midostaurin synergistically induces cell death in MID-RES cells by arresting cell cycle in G0/G1 phase and activating apoptosis. Beside, this combination reduced the adhesion forces to stroma cells, decreased the expression of PFN1/N-WASP/ARP2 and consequently reduced drastically the number of actin filaments and cell stiffness in MID-RES cells. EHT1864 and Midostaurin (alone and in combination) were not toxic in PBMCs obtained from healthy donors. Interestingly, this combination increase >45 % cell death in cells obtained from refractory FLT3-mutated AML patient (this patient was relapsed (>= 50% residual blasts in the bone marrow)under Chemotherapy+Midostaurin combination).The specific knock down of PFN1/N-WASP/ARP2 with siRNAs equally reversed the resistance to Midostaurin. Of note, RAC1 regulates the anti-apoptotic BCL2. Indeed, EHT1864 in combination with Midostaurin reduced anti-apoptotic family BCL2/MCL1 expression and increases the pro-apoptotic proteins BAX/PUMA. As expected, our MID-RES cells showed higher sensitivity to BCL2 inhibitor Venetoclax, than their parental cells. The combinations EHT1864+venetoclax, venetoclax+midostaurin and venetoclax+Midostaurin+EHT1864 synergistically induced cell death in MID-RES cells. Conclusion Actin polymerization inducers N-WASP, ARP2/3 complex and PFN1 may provide a valuable approach to overcome Midostaurin resistance in AML. Our data further suggest that the addition of BCL2 inhibition through EHT1864 and venetoclax could represent an interesting strategy to potentiate the activity of Midostaurin in FLT3 mutated AML. [Formula presented] Disclosures: Duell: Regeneron Pharmaceuticals, Inc.: Research Funding. Rosenwald: MorphoSys: Consultancy.
Copyright
EMBASE:2013252526
ISSN: 1528-0020
CID: 4979132