Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.

Thermal Selection of Microbial Communities and Preservation of Microbial Function in Guaymas Basin Hydrothermal Sediments.

The Guaymas Basin in the Gulf of California is characterized by active seafloor spreading, hydrothermal activity, and organic matter accumulation on the seafloor due to high sedimentation rates. In the hydrothermal sediments of Guaymas Basin, microbial community compositions and coexistence patterns change across steep gradients of temperature, potential carbon sources, and electron acceptors. Nonmetric multidimensional scaling and guanine-cytosine percentage analyses reveal that the bacterial and archaeal communities adjust compositionally to their local temperature regime. Functional inference using PICRUSt shows that microbial communities consistently maintain their predicted biogeochemical functions in different sediments. Phylogenetic profiling shows that microbial communities retain distinct sulfate-reducing, methane-oxidizing, or heterotrophic lineages within specific temperature windows. The preservation of similar biogeochemical functions across microbial lineages with different temperature adaptations stabilizes the hydrothermal microbial community in a highly dynamic environment. IMPORTANCE Hydrothermal vent sites have been widely studied to investigate novel bacteria and archaea that are adapted to these extreme environments. However, community-level analyses of hydrothermal microbial ecosystems look beyond the presence and activity of particular types of microbes and examine to what extent the entire community of bacteria and archaea is adapted to hydrothermal conditions; these include elevated temperatures, hydrothermally generated carbon sources, and inorganic electron donors and acceptors that are characteristic for hydrothermal environments. In our case study of bacterial and archaeal communities in hydrothermal sediments of Guaymas Basin, we found that sequence-inferred microbial function was maintained in differently structured bacterial and archaeal communities across different samples and thermal regimes. The resulting preservation of biogeochemical functions across thermal gradients is an important factor in explaining the consistency of the microbial core community in the dynamic sedimentary environment of Guaymas Basin.

Does Cancer Masquerade as Sarcoidosis?

BACKGROUND/OBJECTIVE: Sarcoidosis is a granulomatous disorder. Rarely, malignancy is accompanied by a granulomatous reaction. This retrospective study addressed whether cancer can masquerade as sarcoidosis. METHODS: TriNetX identified 1029 newly diagnosed cases of sarcoidosis between October 2015 and September 2020, of whom 50 had a subsequent diagnosis of malignancy. RESULTS: In 36 cases, the malignancy was unrelated to sarcoidosis. In 7 cases, the diagnosis of sarcoidosis delayed the eventual cancer diagnosis by a range of 1 month to 2 years. In 7 cases, the subsequent diagnosis of cancer might have been related to the therapy for sarcoid. CONCLUSIONS: Cancer masquerading as sarcoidosis is very rare occurring in 7 (0.7%) of our 1029 cases. In no case was lung cancer masquerading as sarcoidosis. Searching for occult malignancy in patients with a known diagnosis of sarcoidosis is rarely indicated.

Are autoimmune diseases autoinflammatory: Is it time to change the paradigm?

The paradigm that autoimmune diseases are abberations in the adaptive immune system is over 50 years old, but recent data suggest a multitude of abnormalities in the innate immune system in lupus and other autoimmune diseases. This viewpoint elaborates the reasons that I think it is time to reexamine this paradigm and shift our research focus to the innate immune system in lupus and other prototypic autoimmune diseases.

Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers.

Cancer therapies targeting the vascular endothelial growth factor (VEGF) signaling pathway can lead to renal damage by disrupting the glomerular ultrafiltration apparatus. The objective of the current study was to identify sensitive biomarkers for VEGF inhibition-induced glomerular changes in rats. Male Sprague-Dawley rats were administered an experimental VEGF receptor (VEGFR) inhibitor, ABT-123, for seven days to investigate the correlation of several biomarkers with microscopic and ultrastructural changes. Glomeruli obtained by laser capture microdissection were also subjected to gene expression analysis to investigate the underlying molecular events of VEGFR inhibition in glomerulus. ABT-123 induced characteristic glomerular ultrastructural changes in rats, including fusion of podocyte foot processes, the presence of subendothelial electron-dense deposits, and swelling and loss of fenestrations in glomerular endothelium. The subtle morphological changes cannot be detected with light microscopy or by changes in standard clinical chemistry and urinalysis. However, urinary albumin increased 44-fold as early as Day three. Urinary ß2-microglobulin levels were also increased. Other urinary biomarkers that are typically associated with tubular injury were not significantly impacted. Such patterns in urinary biomarkers can provide valuable diagnostic insight to VEGF inhibition therapy-induced glomeruli injuries.

The COMS Randomized Trial of Iodine 125 Brachytherapy for Choroidal Melanoma: IV. Local Treatment Failure and Enucleation in the First 5 Years after Brachytherapy. COMS Report No. 19.

OBJECTIVE: To describe the frequency and predictors of local treatment failure and enucleation after iodine 125 (I125) brachytherapy in patients with choroidal melanoma treated and followed up in a large randomized clinical trial. DESIGN: Prospective, noncomparative, interventional case series within a randomized, multicenter clinical trial. PARTICIPANTS: Patients enrolled in the Collaborative Ocular Melanoma Study (COMS) trial of enucleation versus brachytherapy between February 1987 and July 1998; tumors measured 2.5 to 10.0 mm in apical height and no more than 16.0 mm in longest basal dimension. METHODS: I125 brachytherapy was administered via episcleral plaque according to a standard protocol. Follow-up ophthalmic evaluations, including ophthalmic ultrasound and fundus photography, were performed according to a standard protocol at baseline, every 6 months thereafter for 5 years, and subsequently at annual intervals. Survival analysis methods were used to estimate the cumulative risk of postirradiation treatment failure and enucleation. Factors associated with treatment failure and enucleation of plaqued eyes were evaluated using Cox proportional hazards analysis. MAIN OUTCOME MEASURES: Reports of enucleation and of local treatment failure, defined as tumor growth, recurrence, or extrascleral extension, derived from clinical reports based on echographic and photographic documentation. RESULTS: As of September 30, 2000, 638 of the 650 patients randomized to brachytherapy and so treated had been followed up for 1 year or longer, and 411 had been followed up for at least 5 years. Sixty-nine eyes were enucleated during the first 5 years after brachytherapy, and treatment failure was reported for 57 eyes. The Kaplan-Meier estimate of proportion of patients undergoing enucleation by 5 years was 12.5% (95% confidence interval [CI], 10.0%-15.6%); the risk of treatment failure was 10.3% (95% CI, 8.0%-13.2%). Treatment failure was the most common reason for enucleation within 3 years of treatment; beyond 3 years, ocular pain was most common. Risk factors for enucleation were greater tumor thickness, closer proximity of the posterior tumor border to the foveal avascular zone, and poorer baseline visual acuity in the affected eye. Risk factors for treatment failure were older age, greater tumor thickness, and proximity of the tumor to the foveal avascular zone. Local treatment failure was associated weakly with reduced survival after controlling for baseline tumor and personal characteristics (adjusted risk ratio, 1.5; P = 0.08). CONCLUSIONS: Local treatment failure and enucleation were relatively infrequent events after I125 brachytherapy within the COMS. Treatment failure typically occurred early and was associated weakly with poorer survival. The COMS randomized trial documented the absence of a clinically or statistically significant difference in survival for patients randomly assigned to enucleation versus brachytherapy. This analysis documents the efficacy of brachytherapy to achieve sustained local tumor control and to conserve the globe.

Inhibition of retinal neovascularization by a PEDF-derived nonapeptide in newborn mice subjected to oxygen-induced ischemic retinopathy.

Retinopathy of prematurity (ROP) is a growing cause of lifelong blindness and visual defects as improved neonatal care worldwide increases survival in very-low-birthweight preterm newborns. Advancing ROP is managed by laser surgery or a single intravitreal injection of anti-VEGF, typically at 33-36 weeks gestational age. While newer methods of scanning and telemedicine improve monitoring ROP, the above interventions are more difficult to deliver in developing countries. There is also concern as to laser-induced detachment and adverse developmental effects in newborns of anti-VEGF treatment, spurring a search for alternative means of mitigating ROP. Pigment epithelium-derived factor (PEDF), a potent angiogenesis inhibitor appears late in gestation, is undetected in 25-28 week vitreous, but present at full term. Its absence may contribute to ROP upon transition from high-to-ambient oxygen environment or with intermittent hypoxia. We recently described antiangiogenic PEDF-derived small peptides which inhibit choroidal neovascularization, and suggested that their target may be laminin receptor, 67LR. The latter has been implicated in oxygen-induced ischemic retinopathy (OIR). Here we examined the effect of a nonapeptide, PEDF 336, in a newborn mouse OIR model. Neovascularization was significantly decreased in a dose-responsive manner by single intravitreal (IVT) injections of 1.25-7.5 µg/eye (1.0-6.0 nmol/eye). By contrast, anti-mouse VEGFA164 was only effective at 25 ng/eye, with limited dose-response. Combination of anti-VEGFA164 with PEDF 336 gave only the poorer anti-VEGF response while abrogating the robust inhibition seen with peptide-alone, suggesting a need for VEGF in sensitizing the endothelium to the peptide. VEGF stimulated 67LR presentation on endothelial cells, which was decreased in the presence of PEDF 336. Mouse and rabbit eyes showed no histopathology or inflammation after IVT peptide injection. Thus, PEDF 336 is a potential ROP therapeutic, but is not expected to be beneficial in combination with anti-VEGF.

Pachydermodactyly associated with extensive computer gaming: A report of three cases.

Pachydermodactyly is an uncommon, progressive, nontender thickening of the fingers with prominent involvement of the proximal interphalangeal joints. Pachydermodactyly mimics inflammatory arthritis but plain film radiography is normal in this condition. Pachydermodactyly has been previously described in workers performing manual labor. Mechanical stimulation has been identified as a predisposing factor in the majority of cases. We present three cases in adolescent males arising in association with excessive computer gaming.

Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions of disease states of gout.

OBJECTIVE: There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout. METHODS: A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions. RESULTS: The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus). CONCLUSION: Consensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.

GNAQ Mutations in Diffuse and Solitary Choroidal Hemangiomas.

PURPOSE: GNAQ mutations have been identified in port wine stains (both syndromic and nonsyndromic) and melanocytic ocular neoplasms. This study investigates the presence of GNAQ mutations in diffuse (those associated with Sturge-Weber syndrome [SWS]) and solitary choroidal hemangiomas. PARTICIPANTS: Tissue from 11 patients with the following diagnoses: port wine stain (n = 3), diffuse choroidal hemangioma (n = 1), solitary choroidal hemangioma (n = 6), and choroidal nevus (n = 1). METHODS: Ten specimens were interrogated with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, a hybridization capture-based next-generation sequencing assay for targeted deep sequencing of all exons and selected introns of 468 key cancer genes in formalin-fixed, paraffin-embedded tumors. Digital polymerase chain reaction was used to detect GNAQ Q209 mutation in 1 specimen. MAIN OUTCOME MEASURES: Detection of GNAQ codon-specific mutation. RESULTS: Activating somatic GNAQ mutations (c.547C > T; p.Arg183Cys) were found in 100% (3 of 3) of the port wine stain and in the diffuse choroidal hemangioma. Somatic GNAQ mutations (c.626A > T; p.Gln209Leu) were found in 100% (6 of 6) of the solitary choroidal hemangiomas and (c.626A > C; p.Gln209Pro) in the choroidal nevus. CONCLUSIONS: GNAQ mutations occur in both diffuse and solitary hemangiomas, although at distinct codons. An R183 codon is mutant in diffuse choroidal hemangiomas, consistent with other Sturge-Weber vascular malformations. By contrast, solitary choroidal hemangiomas have mutations in the Q209 codon, similar to other intraocular melanocytic neoplasms.

Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization.

Abnormal migration and proliferation of endothelial cells (EC) drive neovascular retinopathies. While anti-VEGF treatment slows progression, pathology is often supported by decrease in intraocular pigment epithelium-derived factor (PEDF), an endogenous inhibitor of angiogenesis. A surface helical 34-mer peptide of PEDF, comprising this activity, is efficacious in animal models of neovascular retina disease but remains impractically large for therapeutic use. We sought smaller fragments within this sequence that mitigate choroidal neovascularization (CNV). Expecting rapid intravitreal (IVT) clearance, we also developed a method to reversibly attach peptides to nano-carriers for extended delivery. Synthetic fragments of 34-mer yielded smaller anti-angiogenic peptides, and N-terminal capping with dicarboxylic acids did not diminish activity. Charge restoration via substitution of an internal aspartate by asparagine improved potency, achieving low nM apoptotic response in VEGF-activated EC. Two optimized peptides (PEDF 335, 8-mer and PEDF 336, 9-mer) were tested in a mouse model of laser-induced CNV. IVT injection of either peptide, 2-5 days before laser treatment, gave significant CNV decrease at day +14 post laser treatment. The 8-mer also decreased CNV, when administered as eye drops. Also examined was a nanoparticle-conjugate (NPC) prodrug of the 9-mer, having positive zeta potential, expected to display longer intraocular residence. This NPC showed extended efficacy, even when injected 14 days before laser treatment. Neither inflammatory cells nor other histopathologic abnormalities were seen in rabbit eyes harvested 14 days following IVT injection of PEDF 336 (>200 µg). No rabbit or mouse eye irritation was observed over 12-17 days of PEDF 335 eye drops (10 mM). Viability was unaffected in 3 retinal and 2 choroidal cell types by PEDF 335 up to 100 µM, PEDF 336 (100 µM) gave slight growth inhibition only in choroidal EC. A small anti-angiogenic PEDF epitope (G-Y-D-L-Y-R-V) was identified, variants (adipic-Sar-Y-N-L-Y-R-V) mitigate CNV, with clinical potential in treating neovascular retinopathy. Their shared active motif, Y - - - R, is found in laminin (Ln) peptide YIGSR, which binds Ln receptor 67LR, a known high-affinity ligand of PEDF 34-mer.

Capillary Hemangioma Presenting as a Scleral Vascular Lesion in a Child.

A 7-year-old healthy girl presented for an evaluation of a left vascular scleral mass. The lesion appeared spontaneously with no history of trauma, coagulopathy, or topical medication use. It was nontender, enlarging, and did not extend intraocularly. Her OS vision was 20/20, and the remainder of her eye examination was normal. Evaluation of the ocular mass included B-scan ultrasound, ultrasound biomicroscopy, anterior segment optical coherence tomography (OCT), and orbital MRI. The anterior segment OCT demonstrated vessels within the mass with no defined capsule. The orbital MRI confirmed a lesion isolated to the scleral layers of the globe, with low blood flow. The patient had a partial response to oral propranolol. Because the lesion vessels began to extend into her corneal endothelium, there was a concern for malignancy. A biopsy confirmed a benign intrascleral capillary hemangioma. Discontinuation of the propranolol demonstrated stability of the lesion 6 months later.

Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors.

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.

Neurofibromatosis type 1: A neuro-psycho-cutaneous syndrome?

Neurofibromatosis type 1 (NF1) is an inherited disorder often associated with optic nerve gliomas, low-grade brain tumors, and readily visible signs. Though these features are frequently emphasized, the psychosocial and emotional morbidities are often overlooked. We present a patient with depressive disorder resulting in suicide in a patient with NF1.

Methylpyrrole inhibitors of BET bromodomains.

An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.

Bilateral Primary Mucinous Carcinoma of the Eyelid.

The aim of this study is to report a case of bilateral primary mucinous carcinoma of the eyelids. This is a case report and literature review. A 71-year-old female presented with primary mucinous carcinoma of the left upper eyelid, which was excised with Mohs surgery. One year later, she developed primary mucinous carcinoma of the right upper eyelid, which was also treated Mohs surgery. Extensive workup was negative for evidence of an unknown primary carcinoma or metastasis. Primary mucinous carcinoma of the eyelids may occur as multifocal tumors, and bilateral disease is not necessarily indicative of metastatic disease.

Correlation of Insurance, Race, and Ethnicity with Pathologic Risk in a Controlled Retinoblastoma Cohort: A Children's Oncology Group Study.

PURPOSE: To determine whether insurance status, race, and ethnicity correlate with increased retinoblastoma invasiveness as a marker of both risk and time to diagnosis. DESIGN: Retrospective case-control study. PARTICIPANTS: All 203 patients from the United States enrolled in the Children's Oncology Group (COG) trial ARET0332, a study of patients with unilateral retinoblastoma requiring enucleation. MAIN OUTCOME MEASURES: All surgical specimens underwent pathologic review to determine the presence of well-defined histopathologic features correlating with a higher risk of disease progression. Insurance status, race, and ethnicity were compiled from the study record for each patient. RESULTS: On institutional pathologic review, nonprivate insurance, nonwhite race, and Hispanic ethnicity all correlated significantly with a greater rate of high-risk pathologic findings. Hispanic ethnicity remained a significant predictor on multivariate analysis. On central pathologic review, these correlations remained but did not reach statistical significance. The differences in results from institutional versus central pathologic reviews appeared to be due to a higher likelihood of patients in minority groups of being misclassified as high risk by institutional pathologists. CONCLUSIONS: In this controlled study population of patients with retinoblastoma who had central pathologic review, our findings suggest a higher rate of more advanced disease associated with nonprivate insurance, nonwhite race, and Hispanic ethnicity; these findings may be due to delays in diagnosis for these groups. Future work should use direct methods to study the impact of other variables, including English-language proficiency and socioeconomic status. Further effort also should focus on where in the diagnostic process potential delays exist, so that interventions can be designed to overcome barriers to care for these groups. In addition, potential systematic differences in pathologic reads based on demographic variables deserve further study.

Fibrous Hamartoma of Infancy in the Eyelid: A Rare Presentation.

A 6-year-old girl presented with a left nodular mass around the punctum. Previous debulking in a similar location at 10 weeks and 8 months of age confirmed fibrous hamartoma of infancy. Pathology at the initial surgery revealed benign-appearing fibroadipose tissue, vasculature, and smooth muscle. Pathologic examination from the third debulking illustrated less fibrous trabeculae extending into increased amounts of mature-appearing adipocytes with collections of immature-appearing fibrocytes. The lesion had slight differences in pathology compared with prior surgical specimens; however, was still consistent with fibrous hamartoma of infancy. No recurrence has been reported since the last surgery.

The Significance of the Discordant Occurrence of Lens Tumors in Humans versus Other Species.

PURPOSE: The purpose of this study was to determine in which species and under what conditions lens tumors occur. DESIGN: A review of databases of available human and veterinary ocular pathologic material and the previously reported literature. PARTICIPANTS: Approximately 18 000 patients who had ocular surgical specimens submitted and studied at the University of Wisconsin School of Medicine and Public Health between 1920 and 2014 and 45 000 ocular veterinary cases from the Comparative Ocular Pathology Laboratory of Wisconsin between 1983 and 2014. METHODS: Material in 2 major archived collections at the University of Wisconsin medical and veterinary schools were studied for occurrence of lens tumors. Tumor was defined as a new growth of tissue characterized by progressive, uncontrolled proliferation of cells. In addition, cases presented at 3 major eye pathologic societies (Verhoeff-Zimmerman Ophthalmic Pathology Society, Eastern Ophthalmic Pathology Society, and The Armed Forces Institute of Pathology Ophthalmic Alumni Society) from 1975 through 2014 were reviewed. Finally, a careful search of the literature was carried out. Approval from the institutional review board to carry out this study was obtained. MAIN OUTCOME MEASURES: The presence of tumors of the lens. RESULTS: The database search and literature review failed to find an example of a lens tumor in humans. In contrast, examples of naturally occurring lens tumors were found in cats, dogs, rabbits, and birds. In the veterinary school database, 4.5% of feline intraocular and adnexal neoplasms (234/5153) were designated as feline ocular posttraumatic sarcoma, a tumor previously demonstrated to be of lens epithelial origin. Similar tumors were seen in rabbit eyes, a bird, and in a dog. All 4 species with lens tumors had a history of either ocular trauma or protracted uveitis. The literature search also revealed cases where lens tumors were induced in zebrafish, rainbow trout, hamsters, and mice by carcinogenic agents (methylcholanthrene, thioacetamide), oncogenic viruses (SV40, HPV-16), and genetic manipulation. CONCLUSIONS: Our results suggest that lens tumors do not occur in humans. In contrast, after lens capsule rupture, a lens tumor can occur in other species. We hypothesize that a genetic mechanism exists that prevents lens tumors in humans.

Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies.

BACKGROUND: Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with azacitidine in advanced hematologic malignancies. PATIENTS AND METHODS: Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n = 38), myelodysplastic syndrome (n = 12), or chronic myelomonocytic leukaemia (n = 2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus azacitidine), or D (once-weekly intravenous) treatment. RESULTS: Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. CONCLUSIONS: Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML.