Preclinical Evaluation of [18F]FACH in Healthy Mice and Piglets: An 18F-Labeled Ligand for Imaging of Monocarboxylate Transporters with PET

The expression of monocarboxylate transporters (MCTs) is linked to pathophysiological changes in diseases, including cancer, such that MCTs could potentially serve as diagnostic markers or therapeutic targets. We recently developed [18F]FACH as a radiotracer for non-invasive molecular imaging of MCTs by positron emission tomography (PET). The aim of this study was to evaluate further the specificity, metabolic stability, and pharmacokinetics of [18F]FACH in healthy mice and piglets. We measured the [18F]FACH plasma protein binding fractions in mice and piglets and the specific binding in cryosections of murine kidney and lung. The biodistribution of [18F]FACH was evaluated by tissue sampling ex vivo and by dynamic PET/MRI in vivo, with and without pre-treatment by the MCT inhibitor α-CCA-Na or the reference compound, FACH-Na. Additionally, we performed compartmental modelling of the PET signal in kidney cortex and liver. Saturation binding studies in kidney cortex cryosections indicated a KD of 118 ± 12 nM and Bmax of 6.0 pmol/mg wet weight. The specificity of [18F]FACH uptake in the kidney cortex was confirmed in vivo by reductions in AUC0–60min after pre-treatment with α-CCA-Na in mice (−47%) and in piglets (−66%). [18F]FACH was metabolically stable in mouse, but polar radio-metabolites were present in plasma and tissues of piglets. The [18F]FACH binding potential (BPND) in the kidney cortex was approximately 1.3 in mice. The MCT1 specificity of [18F]FACH uptake was confirmed by displacement studies in 4T1 cells. [18F]FACH has suitable properties for the detection of the MCTs in kidney, and thus has potential as a molecular imaging tool for MCT-related pathologies, which should next be assessed in relevant disease models.

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Proof of concept of a multimodal intravital molecular imaging system for tumour transpathology investigation

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-021-05574-y ◽

2021 ◽

Author(s):

Zhen Liu ◽

Tao Cheng ◽

Stephan Düwel ◽

Ziying Jian ◽

Geoffrey J. Topping ◽

...

Keyword(s):

Molecular Imaging ◽

Imaging System ◽

Ex Vivo ◽

Fiducial Markers ◽

Proof Of Concept ◽

Registration Accuracy ◽

Microscopic Imaging ◽

Window Chamber

Abstract Background Transpathology highlights the interpretation of the underlying physiology behind molecular imaging. However, it remains challenging due to the discrepancies between in vivo and in vitro measurements and difficulties of precise co-registration between trans-scaled images. This study aims to develop a multimodal intravital molecular imaging (MIMI) system as a tool for in vivo tumour transpathology investigation. Methods The proposed MIMI system integrates high-resolution positron imaging, magnetic resonance imaging (MRI) and microscopic imaging on a dorsal skin window chamber on an athymic nude rat. The window chamber frame was designed to be compatible with multimodal imaging and its fiducial markers were customized for precise physical alignment among modalities. The co-registration accuracy was evaluated based on phantoms with thin catheters. For proof of concept, tumour models of the human colorectal adenocarcinoma cell line HT-29 were imaged. The tissue within the window chamber was sectioned, fixed and haematoxylin–eosin (HE) stained for comparison with multimodal in vivo imaging. Results The final MIMI system had a maximum field of view (FOV) of 18 mm × 18 mm. Using the fiducial markers and the tubing phantom, the co-registration errors are 0.18 ± 0.27 mm between MRI and positron imaging, 0.19 ± 0.22 mm between positron imaging and microscopic imaging and 0.15 ± 0.27 mm between MRI and microscopic imaging. A pilot test demonstrated that the MIMI system provides an integrative visualization of the tumour anatomy, vasculatures and metabolism of the in vivo tumour microenvironment, which was consistent with ex vivo pathology. Conclusions The established multimodal intravital imaging system provided a co-registered in vivo platform for trans-scale and transparent investigation of the underlying pathology behind imaging, which has the potential to enhance the translation of molecular imaging.

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EANM recommendations based on systematic analysis of small animal radionuclide imaging in inflammatory musculoskeletal diseases

EJNMMI Research ◽

10.1186/s13550-021-00820-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Erik H. J. G. Aarntzen ◽

Edel Noriega-Álvarez ◽

Vera Artiko ◽

André H. Dias ◽

Olivier Gheysens ◽

...

Keyword(s):

Molecular Imaging ◽

Radionuclide Imaging ◽

Musculoskeletal Diseases ◽

Ex Vivo ◽

Imaging Techniques ◽

Large Body ◽

Therapeutic Interventions ◽

Histopathological Analysis ◽

Complementary Value

AbstractInflammatory musculoskeletal diseases represent a group of chronic and disabling conditions that evolve from a complex interplay between genetic and environmental factors that cause perturbations in innate and adaptive immune responses. Understanding the pathogenesis of inflammatory musculoskeletal diseases is, to a large extent, derived from preclinical and basic research experiments. In vivo molecular imaging enables us to study molecular targets and to measure biochemical processes non-invasively and longitudinally, providing information on disease processes and potential therapeutic strategies, e.g. efficacy of novel therapeutic interventions, which is of complementary value next to ex vivo (post mortem) histopathological analysis and molecular assays. Remarkably, the large body of preclinical imaging studies in inflammatory musculoskeletal disease is in contrast with the limited reports on molecular imaging in clinical practice and clinical guidelines. Therefore, in this EANM-endorsed position paper, we performed a systematic review of the preclinical studies in inflammatory musculoskeletal diseases that involve radionuclide imaging, with a detailed description of the animal models used. From these reflections, we provide recommendations on what future studies in this field should encompass to facilitate a greater impact of radionuclide imaging techniques on the translation to clinical settings.

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PROTECTIVE EFFECT OF A NEW SYNTHETIC COMPOUND: PCA-4230, ON SEVERAL In vivo THROMBOSIS MODELS.

10.1055/s-0038-1643430 ◽

1987 ◽

Author(s):

M P Ortega ◽

C Sunkel ◽

J G Priego

Keyword(s):

Protective Effect ◽

Bleeding Time ◽

Ex Vivo ◽

Platelet Activating Factor ◽

Phase I Trials ◽

Synthetic Compound ◽

Prolonged Bleeding Time ◽

Series Of Experiments ◽

Pre Treatment

PCA-4230 is a new anti-thrombotic compound which inhibits pla. telet aggregation In vltn.0 and ex. vivo in several species, including man, prolongs the bleeding time and has potent protective ac tivity in several thrombosis models. Phase I trials with different dosage schedules have recently been initiated.In the present study, the effects of PCA-4230 on bleeding time and on several In vivo thrombosis models were studied in mice. Mice were treated with one single oral dose of PCA-4230 (1-10 mg/ kg). One hour after treatment, mice were injected intravenously with four thrombotic challengers {arachidonic acid (AA), thromboxane agonist (U46619), Platelet Activating Factor (PAF) or collagen/epinephrine combination (C/E)} at a dose which induced 80-90% of mortality. The thrombotic agents were prepared in saline. The appropiate doses were dissolved in a volume of 100 μl/mouse. Bleeding time was measured in non-anesthetized mice by the tail transection technique.Effects of compound were recorded from1 to 4 hours after dosage. Acute pre-treatment with PCA-4230 showed a significant dose-depen dent protective effect.Results of each series of experiments are given in the next table.The compound inhibited thrombotic sudden death induced by U46619, PAF or C/E combination, reduced the duration of respiratory distress induced by AA and prolonged bleeding time. Thus, PCA-4230 is protective against a variety of thrombotic stimuli.These results suggest that PCA-4230 may be a promising anti-throm botic drug.

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Characterization of glomerular thromboxane receptor sites in the rat

AJP Renal Physiology ◽

10.1152/ajprenal.1989.256.6.f1111 ◽

1989 ◽

Vol 256 (6) ◽

pp. F1111-F1116 ◽

Cited By ~ 1

Author(s):

B. M. Wilkes ◽

J. Solomon ◽

M. Maita ◽

P. F. Mento

Keyword(s):

Specific Binding ◽

Binding Studies ◽

Single Class ◽

Thromboxane Receptor ◽

Renal Glomeruli ◽

Receptor Sites ◽

High Affinity Receptor ◽

Pg E2 ◽

Txa2 Receptor Antagonist

The aim of this study was to identify and characterize thromboxane (Tx) receptor sites in renal glomeruli. Binding studies were performed on freshly isolated glomeruli using the stable TxA2 receptor antagonist, [3H]SQ 29548. Specific binding was saturable, reversible, and varied with glomerular protein. Scatchard plots revealed a single class of high-affinity receptor sites (Kd = 14.3 +/- 2.4 nM, Bmax = 361 +/- 22 fmol/mg; n = 5). Specific binding was inhibited by Tx agonists (U-46619 and U-44069) and antagonist (SQ 29548) and was highly specific for Tx, since prostaglandin (PG)E2 and PGF2 alpha were 1,000-fold less potent in inhibiting binding. In vivo, U-46619 (1.75 micrograms.kg-1.min-1) was without effect on mean arterial pressure, but reduced renal blood flow by 71% (P less than 0.01) and glomerular filtration rate by 67% (P less than 0.01) and increased filtration fraction by 24% (P less than 0.05). SQ 29548 (10 micrograms.kg-1.min-1) completely blocked the renal effects of U-46619. These studies demonstrate the presence of specific receptor sites for Tx on renal glomeruli that are linked to modulation of renal hemodynamics.

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Gold Nanoparticle-Based Fluorescent Theranostics for Real-Time Image-Guided Assessment of DNA Damage and Repair

International Journal of Molecular Sciences ◽

10.3390/ijms20030471 ◽

2019 ◽

Vol 20 (3) ◽

pp. 471 ◽

Cited By ~ 2

Author(s):

Shriya S. Srinivasan ◽

Rajesh Seenivasan ◽

Allison Condie ◽

Stanton L. Gerson ◽

Yanming Wang ◽

...

Keyword(s):

Molecular Imaging ◽

Real Time ◽

Targeted Delivery ◽

Specific Binding ◽

Imaging Techniques ◽

Cancer Cell Line ◽

Molecular Probe ◽

Biodistribution Studies

Chemotherapeutic dosing, is largely based on the tolerance levels of toxicity today. Molecular imaging strategies can be leveraged to quantify DNA cytotoxicity and thereby serve as a theranostic tool to improve the efficacy of treatments. Methoxyamine-modified cyanine-7 (Cy7MX) is a molecular probe which binds to apurinic/apyrimidinic (AP)-sites, inhibiting DNA-repair mechanisms implicated by cytotoxic chemotherapies. Herein, we loaded (Cy7MX) onto polyethylene glycol-coated gold nanoparticles (AuNP) to selectively and stably deliver the molecular probe intravenously to tumors. We optimized the properties of Cy7MX-loaded AuNPs using optical spectroscopy and tested the delivery mechanism and binding affinity using the DLD1 colon cancer cell line in vitro. A 10:1 ratio of Cy7MX-AuNPs demonstrated a strong AP site-specific binding and the cumulative release profile demonstrated 97% release within 12 min from a polar to a nonpolar environment. We further demonstrated targeted delivery using imaging and biodistribution studies in vivo in an xenografted mouse model. This work lays a foundation for the development of real-time molecular imaging techniques that are poised to yield quantitative measures of the efficacy and temporal profile of cytotoxic chemotherapies.

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P0511ENHANCER AND SUPER-ENHANCER DYNAMICS IN REPAIR AFTER ISCHEMIC ACUTE KIDNEY INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa143.p0511 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Julia Wilflingseder ◽

Michaela Willi ◽

Hye Kyung Lee ◽

Hannes Olauson ◽

Jakub Jankowsky ◽

...

Keyword(s):

Acute Kidney Injury ◽

Transcription Factors ◽

Small Molecule ◽

Ischemia Reperfusion Injury ◽

Specific Binding ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Kidney Cortex ◽

Super Enhancer

Abstract Background and Aims The endogenous repair process of the mammalian kidney allows rapid recovery after acute kidney injury (AKI) through robust proliferation of tubular epithelial cells. There is currently limited understanding of which transcriptional regulators activate these repair programs and how transcriptional dysregulation leads to maladaptive repair. Here we investigate the existence of enhancer dynamics in the regenerating mouse kidney. Method RNA-seq and ChIP-seq (H3K27ac, H3K4m3, BRD4, POL2 and selected transcription factors) were performed on samples from repairing kidney cortex 2 days after ischemia/reperfusion injury (IRI) to identify activated genes, transcription factors, enhancer and super-enhancers associated with kidney repair. Further we investigated the role of super-enhancer activation in kidney repair through pharmacological BET inhibition using the small molecule JQ1 in vitro and in acute kidney injury models in vivo. Results Response to kidney injury leads to genome-wide alteration in enhancer repertoire in-vivo. We identified 16,781 enhancer sites (H3K27ac and BRD4 positive, H3K4me3 negative binding) active in SHAM and IRI samples; 6,512 lost and 9,774 gained after IRI. The lost and gained enhancer sites can be annotated to 62% and 63% of down- and up-regulated transcripts at day 2 after kidney injury, respectively. Super-enhancer analysis revealed 164 lost and 216 gained super-enhancer sites at IRI day 2. 385 super-enhancers maintain activity before and after injury. ChIP-seq profiles of selected transcription factors based on motif analysis show specific binding at corresponding enhancer sites. We observed lost enhancer binding of HNF4A and GR mainly at kidney related enhancer elements. In contrast, STAT3 showed increased binding at injury induces enhancer elements. No dynamic was observed for STAT5. Both transcription factor groups show corresponding mRNA changes after injury. Pharmacological inhibition of enhancer and super-enhancer activity by BRD4 inhibition (JQ1: 50mg/kg/day) before IRI leads to suppression of 40% of injury-induced transcripts associated with cell cycle regulation and significantly increased mortality between days 2 and 3 after AKI. Conclusion This is the first demonstration of enhancer and super-enhancer function in the repairing kidney. In addition, our data call attention to potential caveats for use of small molecule inhibitors of BET proteins that are currently being tested in clinical trials in cancer patients who are at risk for AKI. Our analyses of enhancer dynamics after kidney injury in vivo have the potential to identify new targets for therapeutic intervention.

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In vivo MRI detection of atherosclerosis in ApoE-deficient mice by using tenascin-C-targeted USPIO

Acta Radiologica ◽

10.1177/0284185118762613 ◽

2018 ◽

Vol 59 (12) ◽

pp. 1431-1437 ◽

Cited By ~ 2

Author(s):

Yan Li ◽

Jun Liu ◽

Jun-wen Huang ◽

Jia-cheng Song ◽

Zhan-long Ma ◽

...

Keyword(s):

Molecular Imaging ◽

Cerebrovascular Diseases ◽

Control Group ◽

Atherosclerotic Plaques ◽

Relative Signal Intensity ◽

Tenascin C ◽

Imaging Tool ◽

Life Threatening ◽

Magnetic Resonance Imaging Mri

Background Atherosclerosis is the main cause of cardiovascular and cerebrovascular diseases. Non-invasive molecular imaging to detect and characterize the plaques is essential for reducing life-threatening cardiovascular events. Purpose To investigate the possibility of the anti-tenascin-C-USPIO specific probe as a molecular marker of atherosclerotic plaques detected by 7.0-T magnetic resonance imaging (MRI). Material and Methods Twenty ApoE-/- mice fed with a high fat diet were used for detecting the aorta arch atherosclerotic plaques by 7.0-T MRI at 16 and 24 weeks. Ten mice in the targeted group were injected with anti-tenascin-C-USPIO and another ten in the control group were injected with pure USPIO (n = 5 each time point in each group). Histopathologic examination was used to evaluate the plaques and immunohistochemistry analysis was used to compare tenascin-C expression. Results The relative signal intensity (rSI) changes of the targeted group decreased more than those of the control group (16 weeks: −15.65 ± 0.78% vs. −3.43 ± 2.57%; 24 weeks: −26.38 ± 1.54% vs. −11.12 ± 1.60%, respectively; P < 0.05). Histopathological analyses demonstrated visible atherosclerotic plaques formation and development over time from 16 weeks to 24 weeks. Tenascin-C expression of the plaques at 24 weeks was higher than that at 16 weeks (0.22 ± 0.04 vs. 0.13 ± 0.02, P < 0.05). The MR images correlated well with the progression of atherosclerotic plaques. Conclusion Tenascin-C expression increased with the progression of atherosclerosis. Anti-tenascin-C-USPIO could provide a useful molecular imaging tool for detecting and monitoring atherosclerotic plaques by MRI.

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CRANAD-28: A Robust Fluorescent Compound for Visualization of Amyloid Beta Plaques

Molecules ◽

10.3390/molecules25040863 ◽

2020 ◽

Vol 25 (4) ◽

pp. 863 ◽

Cited By ~ 1

Author(s):

Kathleen Ran ◽

Jing Yang ◽

Anil V. Nair ◽

Biyue Zhu ◽

Chongzhao Ran

Keyword(s):

Amyloid Beta ◽

Ex Vivo ◽

Significant Negative Correlation ◽

Future Research ◽

Fluorescent Compound ◽

Number Count ◽

Interesting Insight ◽

Imaging Tool ◽

Low Toxicity

CRANAD-28, a difluoroboron curcumin analogue, has been demonstrated in earlier reports to successfully label amyloid beta (Aβ) plaques for imaging both ex vivo and in vivo. CRANAD-28’s imaging brightness, ability to penetrate the blood brain barrier, and low toxicity make the compound a potentially potent imaging tool in Alzheimer’s research. In this study, the Aβ-labeling ability of CRANAD-28 was investigated in further detail using histological staining to assess different criteria, including stained Aβ plaque brightness, Aβ plaque size, and Aβ plaque number count. The results of this study demonstrated CRANAD-28 to be superior across all criteria assessed. Furthermore, CRANAD-28 and IBA-1 antibody were used to label Aβ-plaques and microglia respectively. Statistical analysis with Spearman regression revealed a statistically significant negative correlation between the size of labeled Aβ plaques and surrounding microglia density. This finding provides interesting insight into Aβ plaque and microglia dynamism in AD pathology and corroborates the findings of previous studies. In addition, we found that CRANAD-28 provided distinct spectral signatures for Aβs in the core and periphery of the plaques. Based on the study’s results, CRANAD-28 could be considered as an alternative standard for imaging Aβ-plaques in future research studies.

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CD34+CD90+ Cord Blood Cells Which Have Undergone Multiple Cell Divisions Retain Marrow Repopulating Potential.

Blood ◽

10.1182/blood.v104.11.3228.3228 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3228-3228

Author(s):

Hiroto Araki ◽

Nadim Mahmud ◽

Mohammed Milhem ◽

Hetal S. Patel ◽

Rafael Nunez ◽

...

Keyword(s):

Cord Blood ◽

Ex Vivo ◽

Trichostatin A ◽

Cell Divisions ◽

Cd34 Cells ◽

Sequential Addition ◽

Multiple Cell ◽

Cord Blood Cells ◽

Pre Treatment

Abstract We have previously shown that the sequential addition of a hypomethylating agent, 5-aza-2′-deoxyctidine (5azaD) and a histone deacetylase inhibitor, trichostatin A (TSA) is capable of changing the fate of adult bone marrow CD34+ cells (Milhem M et al Blood 2004). We have now studied whether these drugs could alter the behavior of dividing CD34+CD90+ cord blood (CB) cells. The 5azaD/TSA treated cultures yielded 10 times greater numbers of CD34+CD90+ cells as compared to the cultures containing cytokines alone after 9 days of culture. The 5azaD/TSA treated cultures contained 2 fold greater numbers of colony forming cells (CFC) and 14 fold greater numbers of long-term (5wk) cobblestone area forming cells (CAFC) in comparison to culture containing cytokines alone. Although the CFC/CAFC plating efficiency of cells in cultures exposed to cytokines alone declined during the time of incubation, the cloning efficiency of cells exposed to 5azaD/TSA was equivalent to that of primary CD34+ cells. In order to determine the effects of cell division on the behavior of CD34+CD90+ cells in the 5azaD/TSA treated cultures, we utilized the cytoplasmic dye, CFSE. All of the CD34+CD90+ cells within the 5azaD/TSA pre-treated cultures divided at least once after 9 days of culture. 60% of the 5azaD/TSA treated CD34+CD90+ cells divided 5 times or more while 40% divided 1–4 times. The CD34+CD90+ cells lacking 5azaD/TSA pre-treatment underwent more cell divisions (90%, 5 or more divisions). The CD34+CD90+ cells pre-treated with 5azaD/TSA which had undergone 1-2 cell divisions had 11 fold greater numbers of CFU-Mix and 9 fold greater number of CAFC as compared to CD34+CD90+ cell population cultured in presence of cytokines alone. Furthermore CD34+CD90+ cells having 5 and more divisions had 4 fold more CFU-mix and 6.5 fold more CAFC in comparison to cells lacking 5azaD/TSA exposure. The CD34+CD90+ cells experiencing 1–4 divisions had 60 fold greater number of CFU-mix and 54 fold more CAFC in contrast to culture treated with cytokines alone. The in vivo SCID repopulating potential of CD34+CD90+ cells generated in presence or absence of 5azaD/TSA was then evaluated. When 5x104 CD34+CD90+ cells having undergone 1-2 cell divisions were re-isolated from 5azaD/TSA pre-treated cultures, all mice contained human hematopoietic cells. In addition, 1 of 3 mice transplanted with CD34+CD90+ cells (5x104) having undergone 3 and more cell divisions isolated from cultures pre-treated with 5azaD/TSA also displayed human hematopoietic engraftment. Furthermore 1 of 3 mice transplanted with equal numbers of the 5azaD/TSA pre-treated CD34+CD90+ cells having undergone 5 and more cell divisions also had evidence of human multilineage hematopoietic engraftment. By contrast, an equivalent number of CD34+CD90+ cells which had undergone more than 3 or more than 5 cell divisions from the cultures containing cytokines alone were incapable of engrafting NOD/SCID mice. These data suggest that the sequential addition of 5azaD and TSA ex vivo is not only capable of expanding the numbers of CD34+CD90+ cells and assayable progenitor cells but also capable of preserving their SCID repopulating potential. We conclude that 5azaD/TSA treatment of CD34+CD90+ cells results in their retention of the cellular program required to maintain their marrow repopulating potential despite their undergoing multiple cell divisions.

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A Novel Mutation In Bruton Tyrosine Kinase Confers Acquired Resistance To Ibrutinib (PCI-32765) In CLL

Blood ◽

10.1182/blood.v122.21.4914.4914 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4914-4914 ◽

Cited By ~ 2

Author(s):

Richard R. Furman ◽

Shuhua Cheng ◽

Pin Lu ◽

Menu Setty ◽

Alexandar Perez ◽

...

Keyword(s):

Tyrosine Kinase ◽

Ex Vivo ◽

Novel Mutation ◽

Expression Profiles ◽

Covalent Binding ◽

Lymphocytic Leukemia ◽

Brdu Incorporation ◽

Bruton Tyrosine Kinase ◽

Pre Treatment

Abstract The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib has produced durable remissions in chronic lymphocytic leukemia (CLL). We describe a CLL patient who progressed while receiving ibrutinib following 20 months of once daily dosing. A cysteine-to-serine amino acid replacement was identified in BTK at position 481 that disrupts the covalent, but not non-covalent, binding of ibrutinib to BTK in silico structural modeling1. The mutation was present in relapsed samples while absent in the pre-treatment and responding samples. Following the mutation, the B cell receptor (BCR) pathway was reactivated as evidenced by increased cell signaling activities and gene expression profiles. Comparing the relapsed samples with the pre-treatment and responding samples, at the cellular level, mutated CLL cells displayed higher levels of the cell proliferation marker Ki67 in vivo and higher levels of ex-vivo BrdU incorporation. Transfection of the C481S mutant construct into a sensitive lymphoma cell line rendered it much more resistant to ibrutinib treatment demonstrating the cellular impact of the mutation (see attached graph). Interestingly, the ibrutinib-resistant CLL cells remained sensitive to other BCR inhibitors such as dasatinib and SYK inhibitors. These results confirm BTK as an important pharmacologic target of ibrutinib. Further, a mechanism of resistance was revealed, and alternative therapeutic options for ibrutinib resistance were explored. (First three authors with equal contribution) Disclosures: Furman: Genentech: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Gilead: Consultancy. Chang:Pharmacyclics: Employment, Equity Ownership.

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