Spinal Solitary Plasmacytoma With Minimal Marrow Involvement Presenting With Epidural Spinal Cord Compression.

Solitary plasmacytoma (SPC) is a rare type of plasma cell dyscrasia characterized by the proliferation of neoplastic monoclonal plasma cells. It can involve bone or soft tissue without signs of systemic disease. The solitary bone plasmacytoma typically involves the axial skeleton, most commonly the vertebrae. This article presents a 58-year-old male with a history of Parkinson's disease, hypertension, and cervical spine degenerative joint disease. He arrived at the emergency department with severe thoracic and lumbar back pain, accompanied by numbness and weakness in both legs, which worsened with movement and deep breathing. Magnetic resonance imaging (MRI) findings revealed a sizable mass in the T11 vertebra, leading to thoracic spinal cord compression. Treatment included high-dose dexamethasone, and surgical intervention was undertaken. Subsequent pathology confirmed plasma cell dyscrasia. Radiotherapy and chemotherapy (lenalidomide and dexamethasone) were administered, resulting in no recurrence or new masses after two years. Solitary plasmacytoma is a rare disease with limited clinical trials due to the inability to accrue larger cohorts. Prompt diagnosis and staging of plasmacytomas, involving robust histopathological and radiographic methods, are needed to prevent further complications and possible progression to multiple myeloma. Radiation therapy is the primary treatment, with some studies showing the benefits of lenalidomide and dexamethasone. Further studies are needed to improve treatment options for these patients. This case report adds to the current literature the importance of a multidisciplinary approach to the treatment of SPC.

Photo-Uncaging by C(sp3)-C(sp3) Bond Cleavage Restores ß-Lapachone Activity.

ß-Lapachone is an ortho-naphthoquinone natural product with significant antiproliferative activity but suffers from adverse systemic toxicity. The use of photoremovable protecting groups to covalently inactivate a substrate and then enable controllable release with light in a spatiotemporal manner is an attractive prodrug strategy to limit toxicity. However, visible light-activatable photocages are nearly exclusively enabled by linkages to nucleophilic functional sites such as alcohols, amines, thiols, phosphates, and sulfonates. Herein, we report covalent inactivation of the electrophilic quinone moiety of ß-lapachone via a C(sp3)-C(sp3) bond to a coumarin photocage. In contrast to ß-lapachone, the designed prodrug remained intact in human whole blood and did not induce methemoglobinemia in the dark. Under light activation, the C-C bond cleaves to release the active quinone, recovering its biological activity when evaluated against the enzyme NQO1 and human cancer cells. Investigations into this report of a C(sp3)-C(sp3) photoinduced bond cleavage suggest a nontraditional, radical-based mechanism of release beginning with an initial charge-transfer excited state. Additionally, caging and release of the isomeric para-quinone, α-lapachone, are demonstrated. As such, we describe a photocaging strategy for the pair of quinones and report a unique light-induced cleavage of a C-C bond. We envision that this photocage strategy can be extended to quinones beyond ß- and α-lapachone, thus expanding the chemical toolbox of photocaged compounds.

Comprehensive pharmacogenomic profiling of human papillomavirus-positive and -negative squamous cell carcinoma identifies sensitivity to aurora kinase inhibition in KMT2D mutants.

To address the unmet need for effective biomarker-driven targeted therapy for human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) and cervical cancer, we conducted a high-throughput drug screen using 1122 compounds in 13 HPV-positive and 11 matched HPV-negative cell lines. The most effective drug classes were inhibitors of polo-like kinase, proteasomes, histone deacetylase, and Aurora kinases. Treatment with a pan-Aurora inhibitor, danusertib, led to G2M arrest and apoptosis in vitro. Furthermore, danusertib decreased tumor size compared with controls in patient derived xenograft models of HNSCC. To identify biomarkers predicting response, we determined associations between mutations and drug sensitivity. Our data and the Genomics of Drug Sensitivity in Cancer database showed that cancer cells with KMT2D mutations were more sensitive to Aurora kinase inhibitors than were cells without mutations. Knockdown of KMT2D in wild-type cells led to increased Aurora kinase inhibitor-induced apoptosis. We identified Aurora kinase inhibitors as effective and understudied drugs in HNSCC and CESC. This is the first published study to demonstrate that mutations in KMT2D, which are common in many cancers, correlate with drug sensitivity in two independent datasets.

Association between intravenous acetaminophen and reduction in intraoperative opioid consumption during transsphenoidal surgery for pituitary tumors.

BACKGROUND AND AIMS: Pain during and after transsphenoidal surgeries originates from stimulation of branches of the trigeminal cranial nerve that supply the inner aspect of the nose cavity and dura mater. Thereby, patients undergoing transsphenoidal surgery may require moderate-to-large amounts of analgesics including opioids. Intravenous acetaminophen provides analgesia and reduces opioid consumption for a wide variety of surgeries. We hypothesized that the use of intravenous acetaminophen is associated with a reduction in intraoperative opioid consumption and provides significant analgesia during and after transsphenoidal surgery. MATERIAL AND METHODS: This retrospective study included 413 patients who underwent transsphenoidal surgery for pituitary adenomas. The primary outcome of this study was intraoperative opioid consumption. Secondary outcomes included pain intensity, Richmond Agitation Sedation Scale scores, and nausea and vomiting upon arrival to postoperative anesthesia care unit. Patients were divided into two groups based on the intraoperative acetaminophen use. A prospensity score matching analysis was used to balance for important variables between the two groups of treatment. Regression models were fitted after matching the covariates. A P < 0.05 was considered statistically significant. RESULTS: After matching, 126 patients were included in each group of treatment. Patients in the acetaminophen group required significantly less amount (a decrease by 14.9%) of opioids during surgery than those in the non-acetaminophen group. Postoperative pain, postoperative nausea and vomiting, and sedation scores were not significantly different between patients who received intravenous acetaminophen and those who did not. CONCLUSION: Intravenous acetaminophen is associated with a reduction in intraoperative opioids during transsphenoidal pituitary surgery.

Protein expression of TTF1 and cMYC define distinct molecular subgroups of small cell lung cancer with unique vulnerabilities to aurora kinase inhibition, DLL3 targeting, and other targeted therapies.

Small cell lung cancer (SCLC) is a recalcitrant cancer for which no new treatments have been approved in over 30 years. While molecular subtyping now guides treatment selection for patients with non-small cell lung cancer and other cancers, SCLC is still treated as a single disease entity. Using model-based clustering, we found two major proteomic subtypes of SCLC characterized by either high thyroid transcription factor-1 (TTF1)/low cMYC protein expression or high cMYC/low TTF1. Applying "drug target constellation" (DTECT) mapping, we further show that protein levels of TTF1 and cMYC predict response to targeted therapies including aurora kinase, Bcl2, and HSP90 inhibitors. Levels of TTF1 and DLL3 were also highly correlated in preclinical models and patient tumors. TTF1 (used in the diagnosis lung cancer) could therefore be used as a surrogate of DLL3 expression to identify patients who may respond to the DLL3 antibody-drug conjugate rovalpituzumab tesirine. These findings suggest that TTF1, cMYC or other protein markers identified here could be used to identify subgroups of SCLC patients who may respond preferentially to several emerging targeted therapies.

Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: Structure, function and therapeutics.

Mammalian exchange protein directly activated by cAMP isoform 1 (EPAC1), encoded by the RAPGEF3 gene, is one of the two-membered family of cAMP sensors that mediate the intracellular functions of cAMP by acting as guanine nucleotide exchange factors for the Ras-like Rap small GTPases. Extensive studies have revealed that EPAC1-mediated cAMP signaling is highly coordinated spatiotemporally through the formation of dynamic signalosomes by interacting with a diverse array of cellular partners. Recent functional analyses of genetically engineered mouse models further suggest that EPAC1 functions as an important stress response switch and is involved in pathophysiological conditions of cardiac stresses, chronic pain, cancer and infectious diseases. These findings, coupled with the development of EPAC specific small molecule modulators, validate EPAC1 as a promising target for therapeutic interventions.

Design, synthesis, and evaluation of hybrid vitamin D3 side chain analogues as hedgehog pathway inhibitors.

Vitamin D3 (VD3) is a moderately potent and non-selective inhibitor of the Hedgehog (Hh) signaling cascade. Previous studies have established that the CD-ring region of VD3 serves as the Hh inhibitory pharmacophore. Subsequently, compound 3, an ester linked aromatic A-ring and CD-ring derivative was identified as an improved and selective Hh inhibitor. Herein, we report modifications of the CD-ring side chain that afford enhancement of selectivity for Hh modulation thereby diminishing the detrimental effects of concomitant vitamin D receptor activation. In general, linear or moderately branched alkyl chains of five or six carbons were optimal for potent and selective inhibition of Hh signaling. Moreover, hybrid VD3 side chain derivative 20 demonstrated 4-fold improvement in Hh antagonistic activity over VD3(IC50=1.1-1.6 µM) while gaining greater than a 1000-fold selectivity for Hh signaling over canonical activation of the vitamin D receptor pathway.

Chronic nickel bioaccumulation and sub-cellular fractionation in two freshwater teleosts, the round goby and the rainbow trout, exposed simultaneously to waterborne and dietborne nickel.

Rainbow trout and round goby were exposed for 30 days to waterborne and dietary Ni in combination at two waterborne concentration ranges (6.2-12 µmol/L, 68-86 µmol/L), the lower of which is typical of contaminated environments. The prey (black worms; Lumbriculus variegatus) were exposed for 48 h in the effluent of the fish exposure tanks before being fed to the fish (ration=2% body weight/day). Ni in gills, gut, and prey was fractionated into biologically inactive metal [BIM=metal-rich granules (MRG) and metallothionein-like proteins (MT)] and biologically active metal [BAM=organelles (ORG) and heat-denaturable proteins (HDP)]. Gobies were more sensitive than trout to chronic Ni exposure. Possibly, this greater sensitivity may have been due to the goby's pre-exposure to pollutants at their collection site, as evidenced by ∼2-fold greater initial Ni concentrations in both gills and gut relative to trout. However, this was followed by ∼2-16× larger bioaccumulation in both the gills and the gut during the experimental exposure. On a subcellular level, ∼3-40× more Ni was associated with the BAM fraction of goby in comparison to trout. Comparison of the fractional distribution of Ni in the prey versus the gut tissue of the predators suggested that round goby were more efficient than rainbow trout in detoxifying Ni taken up from the diet. Assessing sub-cellular distribution of Ni in the gills and gut of two fish of different habitat and lifestyles revealed two different strategies of Ni bioaccumulation and sub-cellular distribution. On the one hand, trout exhibited an ability to regulate gill Ni bioaccumulation and maintain the majority of the Ni in the MT fraction of the BIM. In contrast goby exhibited large Ni spillovers to both the HDP and ORG fractions of the BAM in the gill. However, the same trend was not observed in the gut, where the potential acclimation of goby to pollutants from their collection site may have aided their ability to regulate Ni spillover to the BAM more so than in trout. Overall, chronic mortality observed in goby may be associated more with Ni bioaccumulation in gills than in gut; the former at either 4-d or 30-d was predictive of chronic Ni toxicity. BIM and BAM fractions of the goby gills were equally predictive of chronic (30-d) mortality. However, critical body residue (CBR50) values of the BIM fraction were ∼2-4× greater than CBR50 values of the BAM fraction, suggesting that goby are more sensitive to Ni bioaccumulation in the BAM fraction. There was insufficient mortality in trout to assess whether Ni bioaccumulation was predictive of chronic mortality.

Recent advances in the design of Hedgehog pathway inhibitors for the treatment of malignancies.

INTRODUCTION: The Hedgehog (Hh) signaling pathway is known to be dysregulated in several forms of cancer. Hence, specifically targeting this signaling cascade is a valid and promising strategy for successful therapeutic intervention. Several components within the Hh pathway have been proven to be druggable; however, challenges in the discovery and development process for small molecules targeting this pathway have been identified. AREAS COVERED: This review details both the current state and future potential of Hh pathway inhibitors as anticancer chemotherapeutics that target a variety of human malignancies. EXPERT OPINION: The initial development of Hh pathway inhibitors focused on small-molecule antagonists of Smoothened, a transmembrane protein that is a key regulator of pathway signaling. More recently, efforts to identify and develop inhibitors of pathway signaling that function through alternate mechanisms have been increasing. However, none of these have advanced into clinical trials. Further, early evidence suggesting the broad application of Hh pathway inhibitors as a monotherapy in a wide range of human cancers has not been validated. The potential for Hh pathway inhibitors as combination therapy has demonstrated promising preclinical results. However, more research to identify rational drug combinations to fully explore the potential of this anticancer drug class is warranted.

Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors.

A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 µM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.

Identification of vitamin d3-based hedgehog pathway inhibitors that incorporate an aromatic a-ring isostere.

Previous structure-activity relationship studies for vitamin D3 (VD3) inhibition of Hedgehog (Hh) signaling directed the design, synthesis, and evaluation of a series of VD3-based analogues that contain an aromatic A-ring mimic. Characterization of these compounds in a series of cellular assays demonstrated their ability to potently and selectively down-regulate Hh pathway signaling. The most active of these, 17, inhibited pathway signaling in Hh-dependent mouse fibroblasts (IC50 = 0.74 ± 0.1 µM) and cultured cancer cells (IC50 values 3.8 ± 0.1 to 5.2 ± 0.2 µM). In addition, 17 demonstrated reduced activation of the vitamin D receptor (VDR) compared to VD3 in these cellular models. These results suggest that VD3-based analogues with an aromatic A-ring are a valid scaffold for the development of more selective and potent Hh pathway inhibitors and identify 17 as an intriguing lead from this class of compounds for further development. In addition, our analysis of Hh pathway inhibitors in cancer cells suggests that the murine basal cell carcinoma cell line ASZ001 and the human medulloblastoma cell line DAOY are appropriate in vitro cancer models for early stage evaluation of pathway inhibition.

Probing the structural requirements for vitamin D3 inhibition of the hedgehog signaling pathway.

A structure-activity relationship study to elucidate the structural basis for hedgehog (Hh) signaling inhibition by vitamin D3 (VD3) was performed. Functional and non-functional regions of VD3 and VD2 were obtained through straightforward synthetic means and their biological activity was determined in a variety of cell-based assays. Several of these compounds inhibited Hh signaling at levels comparable to the parent VD3 with no effects on canonical vitamin D signaling. Most notably, compounds 5 and 9, demonstrated potent inhibition of the Hh pathway, exhibited no binding affinity for the vitamin D receptor (VDR), and did not activate VDR in cell culture. In addition, several compounds exhibited anti-proliferative activity against two human cancer cell lines through a mechanism distinct from the Hh or VDR pathways, suggesting a new cellular mechanism of action for this class of compounds.

Evaluation of vitamin D3 A-ring analogues as Hedgehog pathway inhibitors.

A structure-activity relationship study focusing on the A-ring of vitamin D3 (VD3) was undertaken to elucidate its role in inhibiting the Hedgehog pathway and in mediating anti-cancer effects. Analogues resulting from simple functional group substitution at 3' position of VD3 were evaluated in a variety of biological assays to determine their ability to selectively inhibit Hh signaling. Moderately active Hh inhibitors that have insignificant binding affinity for VDR were identified; however, these compounds also activate the traditional VDR pathway, presumably due to metabolites produced in the cultured cells. Thus, further structural modifications to the VD3 scaffold are required to yield potent, selective Hh inhibitors.