Structural effects of morpholine replacement in ZSTK474 on Class I PI3K isoform inhibition: Development of novel MEK/PI3K bifunctional inhibitors.

Established roles for PI3K and MAPK signaling pathways in tumorigenesis has prompted extensive research towards the discovery of small-molecule inhibitors as cancer therapeutics. However, significant compensatory regulation exists between these two signaling cascades, leading to redundancy among survival pathways. Consequently, initial clinical trials aimed at either PI3K or MEK inhibition alone have proven ineffective and highlight the need for development of targeted and innovative therapeutic combination strategies.

Engineered Antibody Fragment against the Urokinase Plasminogen Activator for Fast Delineation of Triple-Negative Breast Cancer by Positron Emission Tomography.

The urokinase plasminogen activator (uPA) and its cofactors are important regulators of tumor initiation and progression (including metastasis), and its overexpression is associated with unfavorable situations in cancer patients. We have previously used positron emission tomography (PET) imaging with a radiolabeled monoclonal antibody against the uPA (named ATN-291) to detect the uPA signaling activity in various cancer types; however, good tumor contrast can only be observed 24 h postinjection. To shorten the antibody circulation time and decrease interactions of ATN-291 with the mononuclear phagocyte system (MPS), our goal in this study is to develop an engineered antibody fragment (F(ab')) from the parent antibody.

Associations between bone attenuation and prevalent vertebral fractures on chest CT scans differ with vertebral fracture locations.

Unlabelled: Vertebral fracture (VF) locations are bimodally distributed in the spine. The association between VF and bone attenuation (BA) measured on chest CT scans varied according to the location of VFs, indicating that other factors than only BA play a role in the bimodal distribution of VFs.

Introduction: Vertebral fractures (VFs) are associated with low bone mineral density but are not equally distributed throughout the spine and occur most commonly at T7-T8 and T11-T12 ("cVFs") and less commonly at T4-T6 and T9-T10 ("lcVF").

Association between vertebral fractures and coronary artery calcification in current and former smokers in the ECLIPSE cohort.

Unlabelled: In smokers and former smokers from the ECLIPSE cohort, there is an association between prevalent vertebral fractures (VFs) and coronary artery calcification (CAC). Chest CT scans provide the opportunity to evaluate VFs and CAC, which are potentially important comorbidities, each of which is amenable to effective interventions.

Introduction: Prevalence of VFs among smokers and patients with chronic obstructive pulmonary disease (COPD) is high, and an association between CAC and osteoporosis has been described.

Vertebral bone attenuation in Hounsfield Units and prevalent vertebral fractures are associated with the short-term risk of vertebral fractures in current and ex-smokers with and without COPD: a 3-year chest CT follow-up study.

Unlabelled: CT scans performed to evaluate chronic obstructive pulmonary disease (COPD) also enable evaluation of bone attenuation (BA; a measure of bone density) and vertebral fractures (VFs). In 1239 current/former smokers with (n = 999) and without (n = 240) COPD, the combination of BA and prevalent VFs was associated with the incident VF risk.

Introduction: Chest CT scans are increasingly used to evaluate pulmonary diseases, including COPD.

Positron Emission Tomography/Magnetic Resonance Imaging of Glioblastoma Using a Functionalized Gadofullerene Nanoparticle.

Water-soluble gadofullerene nanomaterials have been extensively investigated as magnetic resonance imaging (MRI) contrast agents, radical scavengers, sensitizers for photodynamic therapy, and inherent antineoplastic agents. Most recently, an alanine-modified gadofullerene nanoparticle (Gd@C-Ala) with excellent anticancer activity has been reported; however, the absolute tumor uptake of Gd@C-Ala is still far from being satisfactory, and its dynamic pharmacokinetics and long-term metabolic behaviors remain to be elucidated. Herein, Gd@C-Ala was chemically modified with eight-arm polyethylene glycol amine to improve its biocompatibility and provide the active sites for the attachment of a tumor-homing ligand (cRGD) and positron emission tomography (PET) isotopes (i.

Thoracic Kyphosis on Chest CT Scans Is Associated With Incident Vertebral Fractures in Smokers.

Greater kyphosis angles lead to increased loading on vertebral bodies in computational models. However, results about the relationship between severity of kyphosis and incident vertebral fracture (VF) risk have been conflicting. Therefore, the aim of this study was to evaluate associations between 1) prevalent VFs and severity of kyphosis, and 2) severity of kyphosis and incident VF risk in smokers with or without chronic obstructive pulmonary disease (COPD).

Multimodal imaging provides insight into targeted therapy response in metastatic prostate cancer to the bone.

Metastatic prostate cancer to bone remains incurable, driving efforts to develop individualized, targeted therapies to improve clinical outcomes while limiting adverse side-effects. Due to the complexity in cellular signaling pathways and the interaction between cancer and its microenvironment, multiparametric imaging approaches for treatment response may improve understanding of the biological effects of therapy. An orthotopic model of castration resistant prostate cancer (CRPC) bone metastasis was treated with the tyrosine kinase inhibitor Cabozantinib (CABO).

Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors.

Purpose: ST-162 and ST-168 are small-molecule bifunctional inhibitors of MEK and PI3K signaling pathways that are being developed as novel antitumor agents. Previous small-molecule and biologic MEK inhibitors demonstrated ocular toxicity events that were dose limiting in clinical studies. We evaluated in vitro and in vivo ocular toxicity profiles of ST-162 and ST-168.

High Imminent Vertebral Fracture Risk in Subjects With COPD With a Prevalent or Incident Vertebral Fracture.

Subjects with chronic obstructive pulmonary disease (COPD) have an increased risk of vertebral fractures (VFs); however, VF incidence is largely unknown. Therefore, the aim of our study was to determine the incidence of new and/or worsening VF in subjects with COPD. Smokers and subjects with COPD (GOLD II-IV) from the ECLIPSE study with complete set of chest CT scans (baseline and 1- and 3-year follow-up) to evaluate vertebrae T down to L were included.

Diagnosis of vertebral deformities on chest CT and DXA compared to routine lateral thoracic spine X-ray.

Unlabelled: X-ray, CT and DXA enable diagnosis of vertebral deformities. For this study, level of agreement of vertebral deformity diagnosis was analysed. We showed that especially on subject level, these imaging techniques could be used for opportunistic screening of vertebral deformities in COPD patients.

Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168).

The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (, ), which displays improved MEK1 and PI3K isoform inhibition, is described. demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.

A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis.

Responses to targeted therapies frequently are brief, with patients relapsing with drug-resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways.

In Vivo Targeting and Positron Emission Tomography Imaging of Tumor with Intrinsically Radioactive Metal-Organic Frameworks Nanomaterials.

Nanoscale metal-organic frameworks (nMOF) materials represent an attractive tool for various biomedical applications. Due to the chemical versatility, enormous porosity, and tunable degradability of nMOFs, they have been adopted as carriers for delivery of imaging and/or therapeutic cargos. However, the relatively low stability of most nMOFs has limited practical in vivo applications.

Design and Investigation of a [F]-Labeled Benzamide Derivative as a High Affinity Dual Sigma Receptor Subtype Radioligand for Prostate Tumor Imaging.

High overexpression of sigma (σ) receptors (σ and σ subtypes) in a variety of human solid tumors has prompted the development of σ receptor-targeting radioligands, as imaging agents for tumor detection. A majority of these radioligands to date target the σ receptor, a potential marker of tumor proliferative status. The identification of approximately equal proportions of both σ receptor subtypes in prostate tumors suggests that a high affinity, dual σ receptor-targeting radioligand could potentially provide enhanced tumor targeting efficacy in prostate cancer.

Antibody-based PET of uPA/uPAR signaling with broad applicability for cancer imaging.

Mounting evidence suggests that the urokinase plasminogen activator (uPA) and its receptor (uPAR) play a central role in tumor progression. The goal of this study was to develop an 89Zr-labeled, antibody-based positron emission tomography (PET) tracer for quantitative imaging of the uPA/uPAR system. An anti-uPA monoclonal antibody (ATN-291) was conjugated with a deferoxamine (Df) derivative and subsequently labeled with 89Zr.

Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K).

The synthesis of a series of single entity, bifunctional MEK1/PI3K inhibitors achieved by covalent linking of structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive MEK inhibitor PD0325901 is described. Inhibitors displayed potent in vitro inhibition of MEK1 (0.015 < IC50 (nM) < 56.

Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor.

The MAP kinase (Ras/MEK/ERK) and PI3K/Akt/mTOR oncogenic signaling pathways are central regulators of KRAS-mediated transformation. Molecular reciprocity between the Ras/MEK/ERK and PI3K/Akt/mTOR pathways provides cancer cells with the ability to evade treatment when targeting only one pathway with monotherapy. Multi-kinase targeting was explored through the development of a single bivalent chemical entity by covalent linking of high-affinity MEK and PI3K inhibitors.

The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling.

Transforming growth factor-β (TGF-β) signaling regulates cell proliferation and differentiation, which contributes to development and disease. Upon binding TGF-β, the type I receptor (TGFBRI) binds TGFBRII, leading to the activation of the transcription factors SMAD2 and SMAD3. Using an RNA interference screen of the human kinome and a live-cell reporter for TGFBR activity, we identified the kinase BUB1 (budding uninhibited by benzimidazoles-1) as a key mediator of TGF-β signaling.

Synthesis and investigation of a radioiodinated F3 peptide analog as a SPECT tumor imaging radioligand.

A radioiodinated derivative of the tumor-homing F3 peptide, (N-(2-{3-[(125)I]Iodobenzoyl}aminoethyl)maleimide-F3Cys peptide, [(125)I]IBMF3 was developed for investigation as a SPECT tumor imaging radioligand. For this purpose, we custom synthesized a modified F3 peptide analog (F3Cys) incorporating a C-terminal cysteine residue for site-specific attachment of a radioiodinated maleimide conjugating group. Initial proof-of-concept Fluorescence studies conducted with AlexaFluor 532 C(5) maleimide-labeled F3Cys showed distinct membrane and nuclear localization of F3Cys in MDA-MB-435 cells.

Applications of molecular imaging.

Today molecular imaging technologies play a central role in clinical oncology. The use of imaging techniques in early cancer detection, treatment response, and new therapy development is steadily growing and has already significantly impacted on clinical management of cancer. In this chapter, we overview three different molecular imaging technologies used for the understanding of disease biomarkers, drug development, or monitoring therapeutic outcome.

Targeted imaging and therapy of brain cancer using theranostic nanoparticles.

The past decade has seen momentous development in brain cancer research in terms of novel imaging-assisted surgeries, molecularly targeted drug-based treatment regimens or adjuvant therapies and in our understanding of molecular footprints of initiation and progression of malignancy. However, mortality due to brain cancer has essentially remained unchanged in the last three decades. Thus, paradigm-changing diagnostic and therapeutic reagents are urgently needed.

Evaluation of treatment-associated inflammatory response on diffusion-weighted magnetic resonance imaging and 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography imaging biomarkers.

Purpose: Functional imaging biomarkers of cancer treatment response offer the potential for early determination of outcome through the assessment of biochemical, physiologic, and microenvironmental readouts. Cell death may result in an immunologic response, thus complicating the interpretation of biomarker readouts. This study evaluated the temporal effect of treatment-associated inflammatory activity on diffusion magnetic resonance imaging and 2-[(18)F]-fluoro-2-deoxy-D-glucose-positron emission tomography imaging (FDG-PET) biomarkers to delineate the effects of the inflammatory response on imaging readouts.

Inhibition of furin/proprotein convertase-catalyzed surface and intracellular processing by small molecules.

Furin is a ubiquitously expressed proprotein convertase (PC) that plays a vital role in numerous disease processes including cancer metastasis, bacterial toxin activation (e.g. anthrax and Pseudomonas), and viral propagation (e.