Receptor Axis Research Articles

Association between the HGF/c‑MET signaling pathway and tumorigenesis, progression and prognosis of hepatocellular carcinoma (Review).

Hepatocellular carcinoma (HCC) is one of the most aggressive and lethal malignancies with a rising incidence, and is characterized by rapid progression, frequent metastasis, late diagnosis, high postoperative recurrence and poor prognosis. Therefore, novel treatment strategies for HCC, particularly advanced HCC, are urgently required. The hepatocyte growth factor(HGF)/c‑mesenchymal‑epithelial transition receptor (c‑MET) axis is a key signaling pathway in HCC and is strongly associated with its highly malignant features. Available treatments based on HGF/c‑MET inhibition may prolong the lifespan of patients with HCC; however, they do not achieve the desired therapeutic effects. The aim of the present article was to review the basic knowledge regarding the role of the HGF/c‑MET signaling pathway in HCC, and examine the association between the HGF/c‑MET signaling pathway and the tumorigenesis, progression and prognosis of HCC.

The SARS-CoV-2/Receptor Axis in Heart and Blood Vessels: A Crisp Update on COVID-19 Disease with Cardiovascular Complications.

The SARS-CoV-2 virus causing COVID-19 disease has emerged expeditiously in the world and has been declared pandemic since March 2020, by World Health Organization (WHO). The destructive effects of SARS-CoV-2 infection are increased among the patients with pre-existing chronic conditions and, in particular, this review focuses on patients with underlying cardiovascular complications. The expression pattern and potential functions of SARS-CoV-2 binding receptors and the attributes of SARS-CoV-2 virus tropism in a physio-pathological state of heart and blood vessel are precisely described. Of note, the atheroprotective role of ACE2 receptors is reviewed. A detailed description of the possible detrimental role of SARS-CoV-2 infection in terms of vascular leakage, including endothelial glycocalyx dysfunction and bradykinin 1 receptor stimulation is concisely stated. Furthermore, the potential molecular mechanisms underlying SARS-CoV-2 induced clot formation in association with host defense components, including activation of FXIIa, complements and platelets, endothelial dysfunction, immune cell responses with cytokine-mediated action are well elaborated. Moreover, a brief clinical update on patient with COVID-19 disease with underlying cardiovascular complications and those who had new onset of cardiovascular complications post-COVID-19 disease was also discussed. Taken together, this review provides an overview of the mechanistic aspects of SARS-CoV-2 induced devastating effects, in vital organs such as the heart and vessels.

Oxidative phenotype induced by aerobic physical training prevents the obesity-linked insulin resistance without changes in gastrocnemius muscle ACE2-Angiotensin(1-7)-Mas axis

BackgroundWe investigate the effect of aerobic physical training (APT) on muscle morphofunctional markers and Angiotensin Converting Enzyme 2/Angiotensin 1-7/Mas receptor (ACE2/Ang 1-7/Mas) axis in an obesity-linked insulin resistance (IR) animal model induced by cafeteria diet (CAF).MethodsMale C57BL/6J mice were assigned into groups CHOW-SED (chow diet, sedentary; n = 10), CHOW-TR (chow diet, trained; n = 10), CAF-SED (n = 10) and CAF-TR (n = 10). APT consisted in running sessions of 60 min at 60% of maximal speed, 5 days per week for 8 weeks.ResultsTrained groups had lower body weight and adiposity compared with sedentary groups. CAF-TR improved the glucose and insulin tolerance tests compared with CAF-SED group (AUC = 28.896 ± 1589 vs. 35.200 ± 1076 mg dL−1 120 min−1; kITT = 4.1 ± 0.27 vs. 2.5 ± 0.28% min−1, respectively). CHOW-TR and CAF-TR groups increased exercise tolerance, running intensity at which VO2 max was reached, the expression of p-AMPK, p-ACC and PGC1-α proteins compared with CHOW-SED and CAF-SED. Mithocondrial protein expression of Mfn1, Mfn2 and Drp1 did not change. Lipid deposition reduced in CAF-TR compared with CAF-SED group (3.71 vs. 5.53%/area), but fiber typing, glycogen content, ACE2 activity, Ang 1-7 concentration and Mas receptor expression did not change.ConclusionsThe APT prevents obesity-linked IR by modifying the skeletal muscle phenotype to one more oxidative independent of changes in the muscle ACE2/Ang 1-7/Mas axis.

Indoleamine 2, 3-dioxygenase 1 aggravates acetaminophen-induced acute liver failure by triggering excess nitroxidative stress and iron accumulation

Acetaminophen (APAP) is the leading cause of acute liver failure (ALF), which is characterized by GSH depletion, oxidative stress and mitochondrial dysfunction. However, the specific mechanism of APAP-induced ALF remains to be clarified. In this study, we demonstrated that indoleamine 2,3-dioxygenase 1 (IDO1) aggravated APAP-induced ALF associated with excess lipid peroxidation, which was reversed by lipid peroxidation inhibitor (ferrostatin-1). Meanwhile, IDO1 deficiency effectively decreased the accumulation of reactive nitrogen species. Additionally, IDO1 deficiency prevented against APAP-induced liver injury through suppressing the activation of macrophages, thereby reduced their iron uptake and export, eventually reduced iron accumulation in hepatocytes through transferrin and transferrin receptor axis. In summary, our study confirmed that APAP-induced IDO1 aggravated ALF by triggering excess oxidative and nitrative stress and iron accumulation in liver. These results offer new insights for the clinical treatment of ALF or iron-dysregulated liver diseases in the future.

Abstract 1249: LP184, a novel alkylating agent, is efficacious in prostate cancer models with DNA damage repair defects

Abstract Prostate cancer (CaP) remains the most commonly diagnosed malignancy and the second leading cause of cancer related deaths in men in the US. While the 5-year survival rate for patients with localized CaP is over 99%, it is only 30% for patients with distant metastases. Despite impressive advances in the treatment of metastatic CaP with more efficacious inhibitors along the androgen/androgen receptor axis, eventual development of incurable metastatic Castration Resistant Prostate Cancer (mCRPC) is inevitable, necessitating the development of newer therapeutic strategies. Comprehensive evaluations of CaP genomes from localized and metastatic CaP have revealed that subsets harboring mutations in certain DNA Damage Repair Genes (DDRGs) account for up to 30% of patients. LP184, a novel alkylating agent belonging to the acylfulvene (AF) class is currently in preclinical development, having demonstrated appreciable anticancer activity in multiple prostate tumor models. LP184 exhibits nanomolar potency (20 - 350 nM) against widely used CaP cell lines in 2D culture while having reduced cytotoxicity in a non-tumor prostate epithelial cell line. In CaP cell lines, LP184 turned out equipotent as standard chemotherapeutic Docetaxel, 100-2000 times more potent than another alkylating agent Cisplatin, and 100-9000 times more potent than PARP inhibitor, Olaparib. LP184 is also effective in 3 CaP organoid models 3D cultured from patient-derived xenografts. We hypothesize that LP184 exhibits potent inhibitory effects on CaP cells through a compromised DNA repair milieu of mCRPC due to damaging DDRG mutations in BRCA2, FANCI, ERCC3, ERCC6, FANCG, PALB2 and ATM represented by the in vitro CaP models tested. DNA damage resulting from AF treatment is known to be processed exclusively via transcription coupled nucleotide excision repair. Consistent with this, we observed enhanced LP-184 sensitivity in a cell line model with truncated ERCC3 relative to the otherwise syngeneic parental cell line. Based on Connectivity Map (CMAP) analysis of full transcriptome profiling data on LP184 treatment in selected CaP cell lines, we identified potential drug classes including PARP inhibitors, proteasome inhibitors, topoisomerase inhibitors and MTOR inhibitors that emerged in silico as synergistic with LP184. This approach utilized matching of genes differentially expressed upon LP184 exposure compared to 5000 other small molecules within CMAP. Advancement of LP184, potentially exploiting recurrent and actionable DDRG mutations, is anticipated to be translated into future clinical trials for mCRPC, a lethal CaP that is responsible for ~33,000 deaths/year in the US alone. Given that only a subset of patients responds to any single drug in this advanced CaP stage, LP184 stands out as a unique agent that may complement or synergize with drugs currently used in treatment of mCRPC and improve the outcomes for men with lethal CaP. Citation Format: Aditya Kulkarni, Partha Banerjee, Umesh Kathad, Kishor Bhatia, Panna Sharma. LP184, a novel alkylating agent, is efficacious in prostate cancer models with DNA damage repair defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1249.

Abstract 358: A prospective study of prostate cancer metastases identifies an androgen receptor activity-low, stemness program associated with resistance to androgen receptor axis inhibitors and unveils mechanisms of clonal evolution

Abstract Background: The androgen receptor axis inhibitors (ARi) (e.g, enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown. Methods: In a prospective trial MATCH-R (NCT02517892), 55 mCRPC patients underwent whole exome sequencing (WES) (n=45) and RNA-sequencing (RNA-seq) (n=52) of metastatic biopsies before starting ARi. Also, 16 mCRPC patients underwent biopsy at time of resistance (WES=14, RNA-seq = 14). The objectives were to identify genomic alterations associated with resistance to ARi as well as to describe clonal evolution. Primary resistance was determined at 4 months of treatment using composite criteria for progression that included serum prostate specific antigen measurements, bone scan, CT imaging and symptom assessments. Acquired resistance was defined by occurrence of progressive disease after initial response or stable disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher's exact tests. Results: At 4 months, 22/55 patients in the cohort had disease progression (primary resistance). No genomic alterations from WES analysis were significantly associated with primary resistance. Analysis of sequential biopsies suggests that mCRPC follows mainly a parallel evolution model and involve DNA-repair related mutational processes. At time of acquired resistance to ARi, most tumors acquired new drivers affecting AR pathway (e.g, AR, NCOR1/2) or lineage switching (e.g, RB1, PTEN, TP53). Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis to identify pathways whose activity state correlated with resistance. AR gene alterations and AR expression were similar between responding and non-responding patients. Transcriptional analysis demonstrated that multiple specific gene sets — including those linked to low AR transcriptional activity, stemness program, RB loss and homologous repair deficiency — were activated in both primary and acquired resistance. Conclusion: Resistance to AR axis inhibitors results from multiple transcriptional programs already activated in pre-treatment samples. Clonal evolution analysis along with RNA-seq data indicate the role of genomic instability and lineage switching in driving acquired resistance Citation Format: Naoual Menssouri, Loic Poiraudeau, Carole Helissey, Ludovic Bigot, Jonathan Sabio, Tony Ibrahim, Claudio Nicotra, Maud Ngocamus, Lambros Tselikas, Thierry De Baere, Etienne Rouleau, Ludovic Lacroix, Anne Chaucherau, Luc Friboulet, Ronan Flippot, Giulia Baciarello, Laurence Albiges, Emeline Colomba, Pernelle Lavaud, Stefan Michiels, Aline Maillard, Antoine Italiano, Fabrice Barlesi, Jean-Charles Soria, Jean-Yves Scoazec, christophe Massard, Benjamin Besse, Fabrice André, Karim Fizazi, Daniel Gautheret, Yohann Loriot. A prospective study of prostate cancer metastases identifies an androgen receptor activity-low, stemness program associated with resistance to androgen receptor axis inhibitors and unveils mechanisms of clonal evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 358.

Paracrine Kynurenic Pathway Activation in the Bone of Young Uremic Rats Can Antagonize Anabolic Effects of PTH on Bone Turnover and Strength through the Disruption of PTH-Dependent Molecular Signaling.

Secondary hyperparathyroidism and abnormalities in tryptophan (TRP) metabolism are commonly observed in chronic kidney disease (CKD). The present study aimed to establish potential interactions between endogenous parathyroid hormone (PTH) and activation of the bone kynurenine (KYN) pathway in relation to bone turnover and strength in young rats after one month (CKD-1) and three months (CKD-3) of experimental CKD. TRP, KYN, KYN/TRP ratio and bone turnover markers (BTMs) were measured in trabecular and cortical bone tissue. Expression of aryl hydrocarbon receptor (AhR) and the genes involved in osteogenesis was determined in femoral bone. Biomechanical testing of femoral diaphysis and femoral neck was also performed. Activation of the KYN pathway in trabecular bone during CKD development intensified the expression of genes related to osteogenesis, which led to a decrease in cyclic adenosine monophosphate (cAMP) and BTMs levels, resulting in a stiffer and mechanically weaker femoral neck. In contrast, reduction of the KYN pathway in cortical bone allowed to unblock the PTH-dependent anabolic activating transcription factor 4/parathyroid hormone 1 receptor (PTH1R/ATF4) axis, led to cAMP accumulation, better bone turnover and strength in the course of CKD development. In summary, the paracrine KYN pathway in bone can interfere with the anabolic effects of PTH on bone through disrupting PTH-dependent molecular signaling.

Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?

Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.

New perspectives on angiotensin-converting enzyme 2 and its related diseases.

Since the worldwide outbreak of coronavirus disease 2019, angiotensin-converting enzyme 2 (ACE2) has received widespread attention as the cell receptor of the severe acute respiratory syndrome coronavirus 2 virus. At the same time, as a key enzyme in the renin-angiotensin-system, ACE2 is considered to be an endogenous negative regulator of vasoconstriction, proliferation, fibrosis, and proinflammation caused by the ACE-angiotensin II-angiotensin type 1 receptor axis. ACE2 is now implicated as being closely connected to diabetes, cardiovascular, kidney, and lung diseases, and so on. This review covers the available information on the host factors regulating ACE2 and discusses its role in a variety of pathophysiological conditions in animal models and humans.

Blocking the CCL5-CCR5 Axis Using Maraviroc Promotes M1 Polarization of Macrophages Cocultured with Irradiated Hepatoma Cells.

PurposeThe C-C chemokine ligand 5 (CCL5)–C-C chemokine receptor (CCR5) axis facilitates tumor progression via multiple mechanisms. Herein, we elucidated the effect of a CCR5 antagonist (maraviroc [MVC]; blocking the CCL5–CCR5 axis) on the phenotype of macrophages cocultured with irradiated hepatoma cells. In addition, we investigated whether modulation of macrophage polarization can alter tumor cell sensitivity to radiation.Materials and MethodsQuantitative reverse-transcription polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assays were applied to examine the levels of macrophage-associated markers. The mechanisms of macrophage polarization were explored by Western blotting in an in vitro model of coculture of human hepatoma cells with macrophages. The radiation sensitivity was examined in a clonogenic radiosensitivity assay. Tumor cell apoptosis was detected by Western blotting and flow cytometry. A mouse model of a subcutaneous tumor was also established.ResultsCCL5 skewed THP-1 M0 macrophages toward an M2-like phenotype. In coculture with hepatoma cells, macrophages manifested high levels of interleukin (IL) 10, IL-12, tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGF-β1), arginase 1 (ARG1), and IL-1β. Tumor cell irradiation further upregulated these markers in macrophages. After incubation of macrophages with MVC for 24 h, levels of M1 cytokines significantly increased, whereas those of M2 phenotype factors ARG1, TGF-β1, and IL-10 decreased, accompanied by the activation of signal transducer and activator of transcription 3 (STAT3) and downregulation of suppressor of cytokine signaling 3 (SOCS3). The macrophage phenotype reverted to M2 states after treatment with a STAT3 inhibitor. The shift of macrophages toward the M1 phenotype enhanced the radiosensitivity and apoptosis of hepatoma cells. Mice receiving a combination of X-ray irradiation and MVC experienced a better antitumor effect than those receiving either MVC or irradiation alone did.ConclusionM2 polarization of macrophages induced by CCL5–CCR5 signaling can be inhibited using MVC via the STAT3–SOCS3 pathway. The shift of macrophages toward the M1 phenotype promotes the sensitivity of human hepatoma cells to X-ray irradiation.

IL-6 contributes to metastatic switch via the differentiation of monocytic-dendritic progenitors into prometastatic immune cells

BackgroundMetastasis is the major cause of death in patients with cancer. Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, the reservoir of these cells in the...

Chronic cyclooxygenase-2 inhibition prevents the worsening of hypertension and endothelial dysfunction induced by ouabain in resistance arteries of spontaneously hypertensive rats

AimPrevious studies raise cyclooxygenase (COX) activation as a possible mechanism involved in the pathophysiology of ouabain-induced hypertension. We hypothesized that inhibition of COX-2 activity might prevent ouabain-induced vascular dysfunction and worsening of hypertension in spontaneously hypertensive rats (SHR). MethodsSHR were exposed to ouabain or vehicle and treated or not with the selective COX-2 inhibitor nimesulide for 5 weeks. Systolic blood pressure was measured by plethysmography. Vascular reactivity by wire myograph and protein expression by Western-blot were assessed in mesenteric resistance arteries (MRA) of groups. Thromboxane A2 (TXA2) production by ELISA was evaluated in MRA supernatants of groups. ResultsNoradrenaline-induced maximal contraction (Emax) was greater in MRA from SHR receiving ouabain than those of vehicle group. In situ inhibition of COX-2, TXA2 synthase, or TP receptor reduced the Emax to noradrenaline in MRA of ouabain to vehicle levels. TXA2 production was higher in ouabain than in vehicle group. Ouabain enhanced expression of cytoplasmic tyrosine kinase Src (c-Src)/ERK1/2/COX-2/TXA2 synthase/TP receptor in SHR MRA, but did not change NFkB/iKB ratio. Anticontractile effect of nitric oxide (NO) was smaller in MRA from ouabain- than vehicle-treated SHR, as well as eNOS and nNOS expression. Nimesulide co-treatment prevented the ouabain-induced worsening of hypertension and noradrenaline MRA hypercontractility in SHR. ConclusionOuabain worsen hypertension and induce MRA hypercontractility in SHR associated with upregulated c-Src/ERK1/2/COX-2/TXA2 synthase/TXA2/TP receptor axis. These effects were prevented by COX-2 inhibition.

The Apelin–Apelin Receptor Axis Triggers Cholangiocyte Proliferation and Liver Fibrosis During Mouse Models of Cholestasis

Apelin (APLN) is the endogenous ligand of its G protein-coupled receptor, apelin receptor (APJ). APLN serum levels are increased in human liver diseases. We evaluated whether the APLN-APJ axis regulates ductular reaction and liver fibrosis during cholestasis. We measured the expression of APLN and APJ and serum APLN levels in human primary sclerosing cholangitis (PSC) samples. Following bile duct ligation (BDL) or sham surgery, male wild-type (WT) mice were treated with ML221 (APJ antagonist) or saline for 1week. WT and APLN-/- mice underwent BDL or sham surgery for 1week. Multidrug resistance gene 2 knockout (Mdr2-/- ) mice were treated with ML221 for 1week. APLN levels were measured in serum and cholangiocyte supernatants, and cholangiocyte proliferation/senescence and liver inflammation, fibrosis, and angiogenesis were measured in liver tissues. The regulatory mechanisms of APLN-APJ in (1) biliary damage and liver fibrosis were examined in human intrahepatic biliary epithelial cells (HIBEpiCs) treated with APLN and (2) hepatic stellate cell (HSC) activation in APLN-treated human HSC lines (HHSteCs). APLN serum levels and biliary expression of APLN and APJ increased in PSC samples. APLN levels were higher in serum and cholangiocyte supernatants from BDL and Mdr2-/- mice. ML221 treatment or APLN-/- reduced BDL-induced and Mdr2-/- -induced cholangiocyte proliferation/senescence, liver inflammation, fibrosis, and angiogenesis. In vitro, APLN induced HIBEpiC proliferation, increased nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) expression, reactive oxygen species (ROS) generation, and extracellular signal-regulated kinase (ERK) phosphorylation. Pretreatment of HIBEpiCs with ML221, diphenyleneiodonium chloride (Nox4 inhibitor), N-acetyl-cysteine (NAC, ROS inhibitor), or PD98059 (ERK inhibitor) reduced APLN-induced cholangiocyte proliferation. Activation of HHSteCs was induced by APLN but reduced by NAC. The APLN-APJ axis induces cholangiocyte proliferation through Nox4/ROS/ERK-dependent signaling and HSC activation through intracellular ROS. Modulation of the APLN-APJ axis may be important for managing cholangiopathies.

Treatment changes in prostate cancer patients on active treatment during the COVID-19 pandemic in a community cancer center in New York City.

e18750 Background: The surge of the SARS coronavirus-2 (COVID-19) pandemic posed great challenges in the oncology community for optimal management of cancer patients. We sought to analyze the treatment changes experienced by the prostate cancer patients in March, April and May 2020 and to compare these treatment decisions to the published guidelines. Methods: We focused on patients currently receiving androgen deprivation therapy (ADT) with leuprolide acetate, and/or oral anti-androgen agents (Androgen receptor axis targeted agent, ARAT), or chemotherapy. Electronic medical records were reviewed, and the oncologists and nurse practitioners were interviewed to understand the decision-making process. Results: Seventy-five patients were included, median age 72 years old (range 47-95). All were taking ADT, and 21 were also taking ARAT, and 3 were also receiving chemotherapy. The incidence and indications for their ADT treatments and schedule changes are shown in the table below. Twenty-seven patients (36%) experienced delays in their ADT treatment, and the percentage of treatment change was similar in categories of metastatic hormone sensitive prostate cancer (mHSPC), metastatic castration resistant cancer (mCRPC), biochemical recurrence as well as stage IVA post surgery. Four patients were receiving neoadjuvant ADT planned prior to definitive radiation, and none had schedule change. One patient with mHSPC and 2 patients with mCRPC continued chemotherapy as planned. One patient declined recommended chemotherapy for mCRPC. Two patients were given q 3 months dose of ADT instead of q 1m, while all the rest were already receiving q3 months dosing. Among the 27 patients who had schedule change, 12 (44.4%) patients had a discussion with their providers first, and 15 patients (55.6%) did not keep their treatment appointment. Conclusions: About one third of patients changed ADT injection schedule with a similar percentage in patients with mHSPC, or mCRPC or Biochemical recurrence, or IVA after surgery. Every 3 months dosing of ADT recommended by NCCN significantly decreases exposure to COVID -19, delaying or skipping treatment was still encountered due to health concern or travel limitations. On the other hand, all patients receiving neoadjuvant ADT, or chemotherapy stayed on schedule. Although NCCN guideline recommended delaying myelosuppressive therapy, palliative chemotherapy for symptomatic, refractory patients may still be a priority.[Table: see text]

CYCLONE 1: A phase 2 study of abemaciclib in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a novel hormonal agent and taxane-based chemotherapy.

TPS5086 Background: In cancer cells, the cyclin-dependent kinases 4 and 6 (CDK4 & 6)/retinoblastoma protein (Rb) pathway is commonly altered, resulting in uncontrolled cell cycle entry and proliferation. CDK4 & 6 inhibitors represent a major advance in the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC or MBC, respectively). Abemaciclib is an oral selective inhibitor of CDK4 & 6 administered on a continuous dosing schedule, approved in combination with endocrine therapy for HR+, HER2- ABC or MBC. In addition, abemaciclib is also approved by the FDA as monotherapy for HR+, HER2- ABC or MBC following endocrine therapy and prior chemotherapy in the metastatic setting. Similar to the estrogen receptor signaling pathway in breast cancer cells, there is evidence that the androgen receptor axis activates CDK4 & 6 to sustain prostate cancer cell proliferation and survival. Preclinical studies in prostate cancer cell lines and xenograft models showed that abemaciclib exhibits single agent activity by inducing cell cycle arrest and tumor growth inhibition. Clinical activity of abemaciclib in combination with abiraterone and prednisone is investigated in a randomized phase 2 study in the first-line mCRPC setting (CYCLONE 2, NCT03706365). Despite recent advances, management of heavily pretreated mCRPC remains a major clinical challenge. Herein, we hypothesize that mCRPC patients whose disease progressed after novel hormonal agents (NHA) and taxane therapies may derive therapeutic benefit from single agent abemaciclib. Methods: CYCLONE 1 is a phase 2, single-arm, multicenter study to assess the safety and efficacy of abemaciclib monotherapy in 40 patients with mCRPC progressing after ≥1 NHA and 2 taxane regimens. Patients will be enrolled at time of prostate specific antigen (PSA) or radiographic progression per PCWG3 criteria and have at least 1 measurable lesion per RECIST 1.1. Metastatic tumor tissue (fresh biopsy or archival material <12 weeks) is required at baseline for biomarker analysis. Patients will receive abemaciclib 200 mg twice daily until unacceptable adverse events or disease progression. The primary objective is investigator-assessed objective response rate (ORR). Key secondary objectives include safety, radiographic progression-free survival, overall survival, PSA response rate, time to PSA progression, time to symptomatic progression, Ki-67 expression, patient-reported outcomes, and pharmacokinetics. Assuming an ORR of 15%, the study has over 73% power to observe a response rate of at least 12.5%. Accrual began in January 2021. Clinical trial information: NCT04408924.

Targeting CSF1R Alone or in Combination with PD1 in Experimental Glioma.

Simple SummaryGlioblastomas are incurable tumors of the central nervous system. Currently, treatment strategies combine neurosurgical intervention, radiation therapy, and chemotherapy. Yet, clinical experience shows that tumors acquire escape mechanisms. Furthermore, the tumor-associated microenvironment, including macrophages expressing the receptor CSF1R, promote and nourish tumor cells. The so-called PD1/PDL1 axis is a major reason why tumors can grow with a “magic hat”; i.e., unrecognized from the immune system. The aim of our study was to assess treatment strategies that target macrophages in the microenvironment by blocking CSF1R alone or in combination with PD1 blockade. Using an immune competent mouse model and an ex vivo microtumor model using freshly resected glioblastoma material, we observed prolonged survival of treated mice and an improved “attack” of the immune system. We conclude that targeting CSF1R is a promising strategy that should be explored in clinical trials, potentially in combination with PD1 blockade.Glioblastoma is an aggressive primary tumor of the central nervous system. Targeting the immunosuppressive glioblastoma-associated microenvironment is an interesting therapeutic approach. Tumor-associated macrophages represent an abundant population of tumor-infiltrating host cells with tumor-promoting features. The colony stimulating factor-1/ colony stimulating factor-1 receptor (CSF-1/CSF1R) axis plays an important role for macrophage differentiation and survival. We thus aimed at investigating the antiglioma activity of CSF1R inhibition alone or in combination with blockade of programmed death (PD) 1. We investigated combination treatments of anti-CSF1R alone or in combination with anti-PD1 antibodies in an orthotopic syngeneic glioma mouse model, evaluated post-treatment effects and assessed treatment-induced cytotoxicity in a coculture model of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TILs) ex vivo. Anti-CSF1R monotherapy increased the latency until the onset of neurological symptoms. Combinations of anti-CSF1R and anti-PD1 antibodies led to longterm survivors in vivo. Furthermore, we observed treatment-induced cytotoxicity of combined anti-CSF1R and anti-PD1 treatment in the PDM/TILs cocultures ex vivo. Our results identify CSF1R as a promising therapeutic target for glioblastoma, potentially in combination with PD1 inhibition.

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer.

Understanding the molecular mechanisms underlying prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is urgently needed to improve the therapeutic options for this almost incurable pathology. Interestingly, CRPC is known to be characterized by a peculiar hormonal landscape. It is now well established that the androgen/androgen receptor (AR) axis is still active in CRPC cells. The persistent activity of this axis in PCa progression has been shown to be related to different mechanisms, such as intratumoral androgen synthesis, AR amplification and mutations, AR mRNA alternative splicing, increased expression/activity of AR-related transcription factors and coregulators. The hypothalamic gonadotropin-releasing hormone (GnRH), by binding to its specific receptors (GnRH-Rs) at the pituitary level, plays a pivotal role in the regulation of the reproductive functions. GnRH and GnRH-R are also expressed in different types of tumors, including PCa. Specifically, it has been demonstrated that, in CRPC cells, the activation of GnRH-Rs is associated with a significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic activity. This antitumor activity is mainly mediated by the GnRH-R-associated Gαi/cAMP signaling pathway. In this review, we dissect the molecular mechanisms underlying the role of the androgen/AR and GnRH/GnRH-R axes in CRPC progression and the possible therapeutic implications.

Halting the FGF/FGFR axis leads to antitumor activity in Waldenström macroglobulinemia by silencing MYD88

The human fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström macroglobulinemia (WM). WM is still an incurable disease, and patients succumb because of disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR signaling in NSC12-treated WM cells; unveiling a significant inhibition of MYD88 was also confirmed at the protein level. Importantly, the NSC12-dependent silencing of MYD88 was functionally active, as it led to inhibition of MYD88-driven pathways, such as BTK and SYK, as well as the MYD88-downstream target HCK. Of note, both canonical and noncanonical NF-κB cascades were downregulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3, and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.

Response of themicrobiome-gut-brain axis in Drosophila to amino acid deficit.

A balanced intake of macronutrients-protein, carbohydrate and fat-is essential for the well-being of organisms. An adequate calorific intake but with insufficient protein consumption can lead to several ailments, including kwashiorkor1. Taste receptors (T1R1-T1R3)2 can detect amino acids in the environment, and cellular sensors (Gcn2 and Tor)3 monitor the levels of amino acids in the cell. When deprived of dietary protein, animals select a food source that contains a greater proportion of protein or essential amino acids (EAAs)4. This suggests that food selection is geared towards achieving the target amount of a particular macronutrient with assistance of the EAA-specific hunger-driven response, which is poorly understood. Here we show in Drosophila that a microbiome-gut-brain axis detects a deficit of EAAs and stimulates a compensatory appetite for EAAs. We found that the neuropeptide CNMamide (CNMa)5 was highly induced in enterocytes of the anterior midgut during protein deprivation. Silencing of the CNMa-CNMa receptor axis blocked the EAA-specific hunger-driven response in deprived flies. Furthermore, gnotobiotic flies bearing an EAA-producing symbiotic microbiome exhibited a reduced appetite for EAAs. By contrast, gnotobiotic flies with a mutant microbiome that did not produce leucine or other EAAs showed higher expression of CNMa and a greater compensatory appetite for EAAs. We propose that gut enterocytes sense the levels of diet- and microbiome-derived EAAs and communicate the EAA-deprived condition to the brain through CNMa.

Enhanced Vasoconstriction in Sickle Cell Disease is Mediated by ET A Receptor‐Dependent Induction of alpha 1A ‐Adrenergic Receptor Expression

Sickle cell disease (SCD) patients are at a significant risk for developing the potentially fatal vaso-occlusive crisis, which has been associated with stressful stimuli. We previously reported that SCD mice display enhanced alpha-1 adrenergic receptor mediated vasoconstriction along with increased alpha-1A receptor expression in the aorta. Also, we have demonstrated SCD mice have higher levels endothelin-1 (ET-1), a potent vasoconstrictor mediating actions via the ETA receptor as well as increased reactive oxygen species (ROS). The mechanisms underlying the enhanced vasoconstriction in SCD mice remains largely unknown. We hypothesized that the enhanced vasoconstrictor response to alpha-1 adrenergic receptor stimulation is meditated through an ET-1/ETA receptor and ROS axis. Male 16-week-old humanized SCD (HbSS) and genetic control (HbAA) mice were utilized for all experiments. Vascular reactivity of isolated thoracic aortic (100–150 μm diameter) rings to phenylephrine (PE) and potassium chloride (KCl) were examined using wire myography. Mice were pre-treated for two weeks with the specific ETA receptor antagonist, ambrisentan (AMB). Thoracic aortic rings were also pre-incubated with superoxide dismutase-polyethylene glycol (PEG-SOD) for 30 minutes ex vivo at 100 units/ml. HbSS mice treated with AMB demonstrated a significantly blunted maximum vasoconstrictive response to PE when compared to control HbSS mice (132.3 ± 3.69 vs. 113.5 ± 4.59 %KCl, p=0.003). HbSS mice treated with ex vivo PEG-SOD alone did not demonstrate a blunted maximum vasoconstrictive response to PE stimulation (132.3 ± 3.69 vs. 121.6 ± 5.36 %KCl, p>0.05). However, HbSS mice treated with a combination of AMB and ex vivo PEG-SOD demonstrated an overall significant decrease response to PE stimulation compared to HbSS control and HbSS treated with AMB alone (132.3 ± 3.69 vs. 113.5 ± 4.59 vs. 95.6 ± 11.3 %KCl, p=0.006, p=0.015, respectively). HbAA mice showed similar vasoconstrictive response across treatments (84.9 ± 5.38 vs. 78.2 ± 6.89 vs. 75.1 ± 9.92 %KCl, p>0.05). Graded concentration responses to KCl were similar between genotypes and pharmacologic treatment. To demonstrate the translational nature of this enhanced vasoconstriction response, flow mediated dilation was used in human subjects with SCD. A subset of the human subjects were treated with AMB or placebo for 3 months. SCD patients treated with AMB for 3 months did show a significant increase in baseline diameter compared to placebo (1.54 % vs -2.05 % change in diameter, p = 0.012). However, there was no increase in flow-mediated dilation supporting a role for the ET-1/ETA pathway and an enhanced vasoconstrictor response in SCD in humans. These findings suggest the enhancement of alpha-1 adrenergic mediated vasoconstriction is, in part, mediated through an ETA receptor dependent mechanism. These data suggest that reactive oxygen species contribute to this enhancement and may work synergistically with the ETA receptor pathway to produce the enhanced vasoconstrictive phenotype seen in SCD.