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Recent developments in myelofibrosis

Raoul Tibes, James Bogenberger, Ruben Mesa
2012 Blood and Lymphatic Cancer : Targets and Therapy  
Dovepress Dovepress 126 Tibes et al submit your manuscript | Blood and Lymphatic Cancer: Targets and Therapy downloaded from by on  ...  Dovepress Dovepress 131 Recent MF developments submit your manuscript | Tibes et al Blood and Lymphatic Cancer: Targets and Therapy downloaded from  ... 
doi:10.2147/blctt.s24960 fatcat:mver7phqevbqnmhfxj4eokdsme

Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies

Raoul Tibes, Ruben A Mesa
2014 Journal of Hematology & Oncology  
Other combination partners, including hypomethylating agents (Tibes, unpublished observation) and Aurora-kinase inhibtors have also been proposed [52] .  ...  In addition, we are currently working on preclinical studies and the development of a clinical trial to test the combination of Hh pathway inhibitors with the hypomethylating agent 5-azacitidine (Tibes  ... 
doi:10.1186/1756-8722-7-18 pmid:24598114 pmcid:PMC3975838 fatcat:4yufz4qozvf7vfc4gfamh73odu

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

Raoul Tibes, James M. Bogenberger
2019 Frontiers in Oncology  
Copyright © 2019 Tibes and Bogenberger. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).  ... 
doi:10.3389/fonc.2019.01205 pmid:31921615 pmcid:PMC6920180 fatcat:o642mwrw5fghrgrh4kgr64kboe

18-FDG PET/CT assessment of basal cell carcinoma with vismodegib

Curtis A. Thacker, Glen J. Weiss, Raoul Tibes, Lisa Blaydorn, Molly Downhour, Erica White, Jason Baldwin, Daniel D. Von Hoff, Ronald L. Korn
2012 Cancer Medicine  
The use of 18-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET/CT) in subjects with advanced basal cell carcinoma (BCC) has not been fully explored due to the rarity of disease presentation. This study evaluated PET/CTs from subjects with advanced BCC participating in a phase I dose-escalation clinical trial of vismodegib. Fourteen subjects with BCC were imaged with 18-FDG PET/CT for lesion identification and response categorizing (European Organisation for
more » ... earch and Treatment for Cancer [EORTC] and PET response criteria in solid tumors [PERCIST] 1.0). Several parameters including metabolic activity of target lesions, site of disease presentation and spread, treatment response, and prognostic significance of metabolic activity following therapy were evaluated. All subjects exhibited at least one hypermetabolic lesion. Most subjects had only four organ systems involved at study enrollment: skin-muscle (93%), lung (57%), lymph nodes (29%), and bone (21%). SUVmax measured across all lesions decreased (median 33%, SD ± 45%) following therapy with metabolic activity normalizing or disappearing in 42% of lesions. No significant difference was observed between EORTC and PERCIST 1.0. Subjects that demonstrated at least a 33% reduction in SUVmax from baseline had a significantly longer progression-free survival (PFS) (median 17 months, 95% confidence interval [CI] ±4 months vs. 9 months, 95% CI ±5 months, P = 0.038) and overall survival (OS) (median 24 months, 95% CI ±4 months vs. 17 months, 95% CI ±13 months, P = 0.019). BCC lesions are hypermetabolic on 18-FDG PET/CT. A decrease in SUVmax was associated with improved PFS and OS. These results further support the incorporation of 18-FDG PET/CT scans in advanced BCC management. PET/CT Imaging After Vismodegib C. A. Thacker et al.
doi:10.1002/cam4.33 pmid:23342272 pmcid:PMC3544445 fatcat:pqmkyorjybcsvpeqox6twlucsy

RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma

Shilpi Arora, Irma M Gonzales, R Hagelstrom, Christian Beaudry, Ashish Choudhary, Chao Sima, Raoul Tibes, Spyro Mousses, David O Azorsa
2010 Molecular Cancer  
Ewing's sarcomas are aggressive musculoskeletal tumors occurring most frequently in the long and flat bones as a solitary lesion mostly during the teen-age years of life. With current treatments, significant number of patients relapse and survival is poor for those with metastatic disease. As part of novel target discovery in Ewing's sarcoma, we applied RNAi mediated phenotypic profiling to identify kinase targets involved in growth and survival of Ewing's sarcoma cells. Results: Four Ewing's
more » ... rcoma cell lines TC-32, TC-71, SK-ES-1 and RD-ES were tested in high throughput-RNAi screens using a siRNA library targeting 572 kinases. Knockdown of 25 siRNAs reduced the growth of all four Ewing's sarcoma cell lines in replicate screens. Of these, 16 siRNA were specific and reduced proliferation of Ewing's sarcoma cells as compared to normal fibroblasts. Secondary validation and preliminary mechanistic studies highlighted the kinases STK10 and TNK2 as having important roles in growth and survival of Ewing's sarcoma cells. Furthermore, knockdown of STK10 and TNK2 by siRNA showed increased apoptosis. Conclusion: In summary, RNAi-based phenotypic profiling proved to be a powerful gene target discovery strategy, leading to successful identification and validation of STK10 and TNK2 as two novel potential therapeutic targets for Ewing's sarcoma.
doi:10.1186/1476-4598-9-218 pmid:20718987 pmcid:PMC2933621 fatcat:6ammfuxq5baz5otnel5s7z3lni


Raoul Tibes
2013 European Medical Journal Hematology  
Tibes, personal communication).  ...  Tibes R, Bogenberger JM, Mesa RA. JAK inhibition: the key to treating  ... 
doaj:8036284608704e68a2eab9afc58dfefd fatcat:6i6noiqt25blrknqlr5aitgaeq

Central Nervous System Leukemia in Acute Myeloid Leukemia

Mohamad Altriki, Meng-Ru Cheng, Veena Fauble, Nandita Khera, Jose Leis, Ruben A. Mesa, Pierre Noel, James L. Slack, Raoul Tibes, Lisa Ostrosky Sproat
2014 Biology of Blood and Marrow Transplantation  
doi:10.1016/j.bbmt.2013.12.237 fatcat:dapwbtpjsfb6xd3gjj3eeedq2q

Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma

Rochelle L. Tiedemann, Ryan A. Hlady, Paul D. Hanavan, Douglas F. Lake, Raoul Tibes, Jeong-Heon Lee, Jeong-Hyeon Choi, Thai H. Ho, Keith D. Robertson
2015 OncoTarget  
Clear cell renal cell carcinomas (ccRCCs) harbor frequent mutations in epigenetic modifiers including SETD2, the H3K36me3 writer. We profiled DNA methylation (5mC) across the genome in cell line-based models of SETD2 inactivation and SETD2 mutant primary tumors because 5mC has been linked to H3K36me3 and is therapeutically targetable. SETD2 depleted cell line models (long-term and acute) exhibited a DNA hypermethylation phenotype coinciding with ectopic gains in H3K36me3 centered across
more » ... ic regions adjacent to low expressing genes, which became upregulated upon dysregulation of the epigenome. Poised enhancers of developmental genes were prominent hypermethylation targets. SETD2 mutant primary ccRCCs, papillary renal cell carcinomas, and lung adenocarcinomas all demonstrated a DNA hypermethylation phenotype that segregated tumors by SETD2 genotype and advanced grade. These findings collectively demonstrate that SETD2 mutations drive tumorigenesis by coordinated disruption of the epigenome and transcriptome,and they have important implications for future therapeutic strategies targeting chromatin regulator mutant tumors.
doi:10.18632/oncotarget.6481 pmid:26646321 pmcid:PMC4811507 fatcat:6kxtwe6ftbgnjopfotdk4mhu6a

Combined venetoclax and alvocidib in acute myeloid leukemia

James Bogenberger, Clifford Whatcott, Nanna Hansen, Devora Delman, Chang-Xin Shi, Wontak Kim, Hillary Haws, Katherine Soh, Ye Sol Lee, Peter Peterson, Adam Siddiqui-Jain, Steven Weitman (+5 others)
2017 OncoTarget  
More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25-50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase
more » ... inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro, ex vivo and in vivo. Alvocidib decreased MCL-1, and/or increased pro-apoptotic proteins such as BIM or NOXA, often synergistically with venetoclax. Over-expression of BCL-XL diminished synergy, while knock-down of BIM almost entirely abrogated synergy, demonstrating that the synergistic interaction between alvocidib and venetoclax is primarily dependent on intrinsic apoptosis. CDK9 inhibition predominantly mediated venetoclax sensitization, while CDK4/6 inhibition with palbociclib did not potentiate venetoclax activity. Combined, venetoclax and alvocidib modulate the balance of BCL-2 family proteins through complementary, yet variable mechanisms favoring apoptosis, highlighting this combination as a promising therapy for AML or high-risk MDS with the capacity to overcome intrinsic apoptosis mechanisms of resistance. These results support clinical testing of combined venetoclax and alvocidib for the treatment of AML and advanced MDS.
doi:10.18632/oncotarget.22284 pmid:29291023 pmcid:PMC5739808 fatcat:ovett6645jhuxatr22cdo4tmja

Targeting mitochondrial structure sensitizes acute myeloid leukemia to Venetoclax treatment

Xufeng Chen, Christina Glytsou, Hua Zhou, Sonali Narang, Denis E. Reyna, Andrea Lopez, Theodore Sakellaropoulos, Yixiao Gong, Andreas Kloetgen, Yoon Sing Yap, Eric Wang, Evripidis Gavathiotis (+3 others)
2019 Cancer Discovery  
Tibes was supported by the Leukemia and Lymphoma Society (CDA#2312-15 and TRP#6080-12) and NCI grant R01-CA17897.  ...  Tibes is a consultant/advisory board member for AbbVie. No potential conflicts of interest were disclosed by the other authors.  ...  Tibes, personal communication), either directly with novel MCL1 inhibitors, or indirectly via cyclin-dependent kinase inhibition affecting MCL1 transcript expression, as we and others have proposed (11  ... 
doi:10.1158/ pmid:31048321 pmcid:PMC6606342 fatcat:73ffk4myuvhtzksc7lxfjhjcom

PI3K/AKT pathway activation in acute myeloid leukaemias is not associated with AKT1 pleckstrin homology domain mutation

Raoul Tibes, Steven M. Kornblau, Yihua Qiu, Spyro M. Mousses, Christiane Robbins, Tracy Moses, John D. Carpten
2008 British Journal of Haematology  
Methodological details have been published and presented Tibes et al, 2006) .  ...  proteins, thus more comprehensively assessing protein expression and activation of an entire pathway (Petricoin et al, 2005; Kornblau et al, 2006; Tibes et al, 2006) .  ... 
doi:10.1111/j.1365-2141.2007.06920.x pmid:18053070 pmcid:PMC3385948 fatcat:fnvgpfytczdk5fulx3mxcproqe

Ex vivoactivity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies

James M. Bogenberger, Devora Delman, Nanna Hansen, Riccardo Valdez, Veena Fauble, Ruben A. Mesa, Raoul Tibes
2014 Leukemia and Lymphoma  
Novel targeted therapies for the treatment of acute myeloid leukemia (AML) and other advanced myeloid malignancies are urgently needed. Recently we reported results from in vitro studies comparing the BCL-2, BCL-X L and BCL-w inhibitor ABT-737 (preclinical compound with similar inhibitory profile to ABT-263/navitoclax) with the selective BCL-2 inhibitor ABT-199, as single-agent and in combination with 5-azacytidine (5-Aza) in AMLderived cell lines [1] . This study demonstrated greater in vitro
more » ... otency of ABT-737 in most AML-derived cell lines, as compared to ABT-199, including greater sensitization to 5-Aza. Additionally, we demonstrated that the combination of ABT-737 and 5-Aza exhibits strong synergy in short-term ex vivo cultures of myeloid malignancies, including de novo and secondary AML, myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs). Tsao et al. reported synergistic activity between 5-Aza and ABT-737 in AML as well [2] . Recently, Pan et al. published a comparison between single-agent ABT-737 or ABT-263 and ABT-199 in vitro and in animal models, demonstrating potent ABT-199 activity in AML, although ABT-263 was more potent in some primary samples [3] . However, none of these studies directly compared the potential of ABT-737 versus ABT-199 to sensitize the anti-leukemic activity of 5-Aza. Therefore, we directly compared the ability of ABT-737 versus ABT-199 to synergize with 5-Aza in myeloid malignancies using short-term ex vivo cultures of primary AML and MDS/chronic myelomonocytic leukemia (CMML) samples. In primary AML and MDS/CMML samples tested in ex vivo drug dose combination response assays (n = 5), all samples showed synergy, and the synergistic effect with 5-Aza was similar for ABT-199 and ABT-737 [ Figures 1(A) , 1(C) and 1(D)], making this the first published evidence, to our knowledge, that ABT-199 also synergizes with 5-Aza in a limited number of AML and MDS/CMML samples ex vivo. The level of ex vivo synergy for ABT-737 and 5-Aza was comparable to that previously published [1] . Synergy occurred at low nM doses of ABT-737 and ABT-199, mostly in the range of 40-160 nM for both
doi:10.3109/10428194.2014.910657 pmid:24707940 pmcid:PMC4331188 fatcat:24gpepfutrdmffuqsxk63abbwi

Association of Therapy for Autoimmune Disease With Myelodysplastic Syndromes and Acute Myeloid Leukemia

Natalie Ertz-Archambault, Heidi Kosiorek, Gretchen E. Taylor, Katalin Kelemen, Amylou Dueck, Janna Castro, Robert Marino, Susanne Gauthier, Laura Finn, Lisa Z. Sproat, Jeanne Palmer, Ruben A. Mesa (+3 others)
2017 JAMA Oncology  
Administrative, technical, or material support: Taylor, Castro, Gauthier, Finn, Sproat, Mesa, Foran, Tibes. Study supervision: Mesa, Al-Kali, Foran, Tibes.  ...  Study concept and design: Kosiorek, Finn, Sproat, Mesa, Al-Kali, Foran, Tibes.  ... 
doi:10.1001/jamaoncol.2016.6435 pmid:28152123 pmcid:PMC5547922 fatcat:yby4rshsnnblrbhac4nuusrktm

Long-term safety, tolerability, and efficacy of vismodegib in two patients with metastatic basal cell carcinoma and basal cell nevus syndrome

Glen J. Weiss, Raoul Tibes, Lisa Blaydorn, Gayle Jameson, Molly Downhour, Erica White, Ivor Caro, Daniel D. Von Hoff
2011 Dermatology Reports  
Tumor responses in advanced basal cell carcinoma (BCC) have been observed in clinical trials with vismodegib, a SMO antagonist. The result of SMO antagonism is inhibition Hedgehog Signaling Pathway (HHSP) downstream target genes. HHSP inhibition has been shown to affect stem cells responsible for blood, mammary, and neural development. We report on our experience of treating two patients with advanced BCC participating. These two patients have had no new BCCs develop for at least 2.25 years.
more » ... h patients have been receiving ongoing daily treatment with vismodegib for greater than 2.75 years without experiencing any significant side effects. After prolonged continuous daily dosing with a SMO antagonist, we have not observed a significant alteration in hematologic parameters or physical abnormalities of the pectoral regions of two patients with advanced BCC.
doi:10.4081/dr.2011.e55 pmid:25386306 pmcid:PMC4211514 fatcat:phmo2y7iyvakhizzs3gignhl5e

Usefulness of 3 Monthly Marrow Evaluations in Predicting Relapse of Myeloid Malignancies After HCT

Katalin Kelemen, Veena Fauble, Lisa Ostrosky Sproat, Jose Leis, Pierre Noel, Jared Klein, Raoul Tibes, James Slack, Roberta Adams, Ruben Mesa, Nandita Khera
2013 Biology of Blood and Marrow Transplantation  
Tibes 3 , James Slack 6 , Roberta Adams 7 , Ruben Mesa 3 , Nandita Khera 3 . 1 Department of Laboratory Medicine and Pathology, Mayo Clinic, Arizona; 2 BMT, Banner/MD Anderson Blood & Marrow Transplant  ...  Usefulness of 3 Monthly Marrow Evaluations inPredicting Relapse of Myeloid Malignancies After HCT Katalin Kelemen 1 , Veena Fauble 2 , Lisa Ostrosky Sproat 3 , Jose Leis 4 , Pierre Noel 3 , Jared Klein 5 , Raoul  ... 
doi:10.1016/j.bbmt.2012.11.272 fatcat:55frbvdarbgj7ptu2mi4xzaxv4
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