Combination Therapy Strategies Research Articles

CLINICAL CASE OF REPLACEMENT OF ENDOTHELIN RECEPTOR ANTAGONIST (BOSENTAN) BY SOLUBLE GUANYLATE CYCLASE STIMULATOR (RIOCIGUAT) IN THE PATIENT WITH PULMONARY ARTERIAL HYPERTENSION

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive increase in pulmonary vascular resistance (PVR), higher pulmonary arteries mean pressure (mPAP), decrease in cardiac minute output (CMO) and other hemodynamic, functional and biochemical disorders. Existing PAH therapeutic algorithm, described in the European and Russian clinical guidelines, mainly suggest strategy of sequential combination therapy in the case of inadequate response to initial monotherapy. At this, switching from one PAH-specific drug to another is studied to a lesser extent. At the present similar approach (switching) has already been tested, for example, in switching from one endothelin receptor antagonist (ERA) to another, or from phosphodiesterase type 5 inhibitor (iPDE-5) to soluble guanylate cyclase stimulator (sGC). There are virtually no data about change of monotherapy when drugs target different molecular pathways of vascular tone regulation, in particular, in the pulmonary circulation vessels. This article describes clinical case of female patient with FC III pulmonary arterial hypertension (WHO) switched from therapy by endothelin-1 receptor antagonist (bosentan) to soluble guanylate cyclase stimulator (riociguat). Female, 37 years old, with verified by the right heart catheterization (RHC) diagnosis of idiopathic PAH (iPAH) received PAH-specific monotherapy of bosentan. Due to condition deterioration on the background of bosentan dose increase, medical conference decided to switch this patient to another class of PAH-specific therapy (sGC stimulator riociguat) with consequent follow-up. As a result of such approach positive changes in patient's condition, improvement of hemodynamic parameters, increased tolerance of physical exercise was demonstrated in comparison with previous therapy. This clinical case demonstrates safe and successful transfer from bosentan to riociguat in the patient with idiopathic PAH. Similar tactic for the change of therapy should be studied in further clinical trials.

Combination therapy: A feasibility strategy for CAR-T cell therapy in the treatment of solid tumors.

Chimeric antigen receptor (CAR) T-cell therapies have been demonstrated to have durable and potentially curative therapeutic efficacies in patients with hematological malignancies. Currently, multiple clinical trials in CAR-T cell therapy have been evaluated for the treatment of patients with solid malignancies, but have had less marked therapeutic effects when the agents are used as monotherapies. When summarizing relevant studies, the present study found that combination therapy strategies for solid tumors based on CAR-T cell therapies might be more effective. This review will focus on various aspects of treating solid tumors with CAR-T cell therapy: i) The therapeutic efficacy of CAR-T cell monotherapy, ii) the feasibility of the CAR-T cell therapy in conjunction with chemotherapy, iii) the feasibility of CAR-T cell therapy with radiotherapy, iv) the feasibility of CAR-T cell therapy with chemoradiotherapy, and v) the feasibility of the combination of CAR-T cell therapy with other strategies.

Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis

Suppressing glutaminolysis does not always induce cancer cell death in glutamine dependent tumors because cells may switch to alternative energy sources. To reveal compensatory metabolic pathways, we investigated the metabolome-wide cellular response to inhibited glutaminolysis in cancer cells. Glutaminolysis inhibition with C.968 suppressed cell proliferation but was insufficient to induce cancer cell death. We found that lipid catabolism was activated as a compensation for glutaminolysis inhibition. Accelerated lipid catabolism, together with oxidative stress induced by glutaminolysis inhibition, triggered autophagy. Simultaneously inhibiting glutaminolysis and either beta oxidation with trimetazidine or autophagy with chloroquine both induced cancer cell death. Here we identified metabolic escape mechanisms contributing to cancer cell survival under treatment and we suggest potentially translational strategy for combined cancer therapy, given that chloroquine is an FDA approved drug. Our findings are first to show efficiency of combined inhibition of glutaminolysis and beta oxidation as potential anti-cancer strategy as well as add to the evidence that combined inhibition of glutaminolysis and autophagy may be effective in glutamine-addicted cancers.

PLGA nanoparticles co-delivering MDR1 and BCL2 siRNA for overcoming resistance of paclitaxel and cisplatin in recurrent or advanced ovarian cancer

The inherent or acquired resistance to paclitaxel and cisplatin, which are commonly used chemotherapeutic agents for ovarian cancer treatment, remains an important issue in chemotherapy of multidrug resistant ovarian cancer. Currently, it is still challenging to deal with the recurrent or advanced stage ovarian cancer. When drug efflux and anti-apoptotic pathways are highly interdependent and also involved in developing the resistance of multidrug resistant ovarian cancer, simultaneous inhibition of both pathways represents the potential targets to enhance the efficacy of chemotherapy. Here, we introduce PLGA nanoparticles system as a “dual RNAi delivery system” to contain both MDR1 and BCL2 siRNA, which is designed for simultaneous inhibition of drug efflux and cell death defense pathways. In the present studies, siRNA-loaded PLGA nanoparticles efficiently elicit the simultaneous suppression of both genes, which consequently shows more enhanced drug-sensitivity than sole suppression of drug efflux or anti-apoptosis in the resistant ovarian cancer cells, owing to the interdependence of both pathways. Our siRNA-loaded PLGA nanoparticles for co-delivering MDR1 and BCL2 siRNA provide an efficient combination therapy strategy to overcome the chemoresistance of paclitaxel and cisplatin on the paclitaxel-resistant SKOV3-TR and cisplatin-resistant A2780-CP20 ovarian cancer respectively.

The p53 activator overcomes resistance to ALK inhibitors by regulating p53-target selectivity in ALK-driven neuroblastomas

Anaplastic lymphoma kinase (ALK) is an oncogenic receptor tyrosine kinase that is activated by gene amplification and mutation in neuroblastomas. ALK inhibitors can delay the progression of ALK-driven cancers, but are of limited use owing to ALK inhibitor resistance. Here, we show that resistance to ALK inhibitor in ALK-driven neuroblastomas can be attenuated by combination treatment with a p53 activator. Either ALK inhibition or p53 activator treatment induced cell cycle arrest, whereas combination treatment induced apoptosis, and prevented tumour relapse both in vitro and in vivo. This shift toward apoptosis, and away from cell-cycle arrest, in the presence of an ALK inhibitor and a p53 activator, is mediated by inhibition of the ALK–AKT–FOXO3a axis leading to a specific upregulation of SOX4. SOX4 cooperates with p53 to upregulate the pro-apoptotic protein PUMA. These data therefore suggest a novel combination therapy strategy for treating ALK-driven neuroblastomas.

PH‐Responsive, Light‐Triggered on‐Demand Antibiotic Release from Functional Metal–Organic Framework for Bacterial Infection Combination Therapy

AbstractTo satisfy the ever‐growing demand in bacterial infection therapy and other fields of science, great effort is being devoted to the development of methods to precisely control drug release and achieve targeted use of an active substance at the right time and place. Here, a new strategy for bacterial infection combination therapy based on the light‐responsive zeolitic imidazolate framework (ZIF) is reported. A pH‐jump reagent is modified into the porous structure of ZIF nanoparticles as a gatekeeper, allowing the UV‐light (365 nm) responsive in situ production of acid, which subsequently induces pH‐dependent degradation of ZIF and promotes the release of the antibiotic loaded in the mesopores. The combination of the UV‐light, the pH‐triggered precise antibiotic release, and the zinc ions enables the light‐activated nanocomposite to significantly inhibit bacteria‐induced wound infection and accelerate wound healing, indicating a switchable and synergistic antibacterial effect. The light irradiated accumulation of acid ensures the controlled release of antibiotic and controlled degradation of ZIF, suggesting the therapeutic potential of the metal–organic frameworks‐based smart platform for controlling bacterial infection.

Fe3O4@Au composite magnetic nanoparticles modified with cetuximab for targeted magneto-photothermal therapy of glioma cells.

BackgroundThermoresponsive nanoparticles have become an attractive candidate for designing combined multimodal therapy strategies because of the onset of hyperthermia and their advantages in synergistic cancer treatment. In this paper, novel cetuximab (C225)-encapsulated core-shell Fe3O4@Au magnetic nanoparticles (Fe3O4@Au-C225 composite-targeted MNPs) were created and applied as a therapeutic nanocarrier to conduct targeted magneto-photothermal therapy against glioma cells.MethodsThe core-shell Fe3O4@Au magnetic nanoparticles (MNPs) were prepared, and then C225 was further absorbed to synthesize Fe3O4@Au-C225 composite-targeted MNPs. Their morphology, mean particle size, zeta potential, optical property, magnetic property and thermal dynamic profiles were characterized. After that, the glioma-destructive effect of magnetic fluid hyperthermia (MFH) combined with near-infrared (NIR) hyperthermia mediated by Fe3O4@Au-C225 composite-targeted MNPs was evaluated through in vitro and in vivo experiments.ResultsThe inhibitory and apoptotic rates of Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group were significantly higher than other groups in vitro and the marked upregulation of caspase-3, caspase-8, and caspase-9 expression indicated excellent antitumor effect by inducing intrinsic apoptosis. Furthermore, Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group exhibited significant tumor growth suppression compared with other groups in vivo.ConclusionOur studies illustrated that Fe3O4@Au-C225 composite-targeted MNPs have great potential as a promising nanoplatform for human glioma therapy and could be of great value in medical use in the future.

Novel Indications for Bruton's Tyrosine Kinase Inhibitors, beyond Hematological Malignancies.

Bruton’s tyrosine kinase (BTK) is a critical terminal enzyme in the B-cell antigen receptor (BCR) pathway. BTK activation has been implicated in the pathogenesis of certain B-cell malignancies. Targeting this pathway has emerged as a novel target in B-cell malignancies, of which ibrutinib is the first-in-class agent. A few other BTK inhibitors (BTKi) are also under development (e.g., acalabrutinib). While the predominant action of BTKi is the blockade of B-cell receptor pathway within malignant B-cells, increasing the knowledge of off-target effects as well as a potential role for B-cells in proliferation of solid malignancies is expanding the indication of BTKi into non-hematological malignancies. In addition to the expansion of the role of BTKi monotherapy, combination therapy strategies utilizing ibrutinib with established regimens and combination with modern immunotherapy compounds are being explored.

Ultrasound-enhanced delivery of doxorubicin/all-trans retinoic acid-loaded nanodiamonds into tumors.

To build up a combined therapy strategy to address limitations of the enhanced permeability and retention (EPR) effect and improve the efficiency of tumor therapy. A pH-sensitive nanocomplex for co-delivery of doxorubicin (DOX) and all-trans retinoic acid (ATRA) was developed based on nanodiamonds (DOX/ATRA-NDs) to enhance intracellular retention of drugs. Meanwhile, ultrasound was employed to enhance tumor vascular penetration of DOX-ATRA-NDs. The distribution of DOX/ATRA-NDs in the tumor tissues increased threefold when ultrasound was applied at 1MHz and 0.6W/cm2. Comparing with unmodified chemotherapeutics, the combined therapy induced more tumor cells apoptosis and greater tumor growth inhibition in both liver and breast tumor models. DOX-ATRA-NDs demonstrate great potential in clinical applications.

595 - Functional genomics reveal mechanisms of resistance and strategies for combination therapy to CDK4/6 inhibition in bladder cancer

595 - Functional genomics reveal mechanisms of resistance and strategies for combination therapy to CDK4/6 inhibition in bladder cancer

Multifunctional mesoporous silica nanoparticles as efficient transporters of doxorubicin and chlorin e6 for chemo-photodynamic combinatorial cancer therapy.

A multimodal nanocarrier based on mesoporous silica nanoparticles (MSNs) is developed to co-delivery photosensitizer chlorin e6 (Ce6) and chemotherapeutic agent doxorubicin (Dox) for cancer combination therapy. Ce6 was covalently conjugated with mesoporous silica nanoparticles, which could increase the loading efficiency, and allowed for photodynamic therapy. Doxorubicin was loaded into the pores of mesoporous silica nanoparticles to afford the dual drug delivery system Dox@MSNs-Ce6. These hybrid nanoparticles have an average diameter of about 100 nm and slightly negative charge of about -17 mV. The Dox@MSNs-Ce6 nanoparticles could efficiently enter into cancer cells. The cellular reactive oxygen species level in treated cells increased about 17 times, upon 660 nm light irradiation (10 mW/cm2, 2 min). More importantly, Dox@MSNs-Ce6 exhibited excellent synergistic effect through combining chemotherapy and photodynamic therapy against A549 lung cancer cells. Our work provides an effective strategy for anticancer drug delivery and combination therapy.

Clinical effects of selenium yeast and levothyroxine combined therapy on patients with lymphocytic thyroiditis

Objective: This paper aims to discuss the clinical effects of selenium yeast and levothyroxine combined therapy on patients with lymphocytic thyroiditis. Methods: Eighty patients with lymphocytic thyroiditis, who were admitted in our hospital from July 2015 to June 2017, were enrolled and randomly and equally divided into control and experimental groups. The control group was treated with levothyroxine, whereas the experimental group was treated with selenium yeast and levothyroxine combined therapy. The clinical effects and relevant indexes of the two groups were statistically analysed. Results: The experimental group presented a total therapeutic effect of 90.0%, which was considerably higher than that of the control group (70.0%), and the difference was statistically significant (P<0.05). The thyroid stimulating hormone, thyroid peroxidase antibody, and thyroglobulin antibodies of the experimental group were significantly lower than those of the control group (P<0.05). The peripheral blood T-lymphocyte subpopulation indexes (i.e., CD4/CD3, CD4/CD8, and CD8/CD3) of the experimental group were significantly higher than those of the control group (P<0.05). The recovery time and total treatment time of the experimental group were substantially shorter than those of the control group (P<0.05). Conclusions: Selenium yeast and levothyroxine combined therapy demonstrated outstanding clinical effects on patients with lymphocytic thyroiditis, effectively improving the thyroid function and accelerating the recovery of the patients. Therefore, this combined therapy strategy has promising potential for clinical application.

Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors.

Molecular characterization of oncogenic mutations within genes in the MAPK and PI3K/AKT/mTOR pathways has led to the rational development of targeted therapies. Combining BRAF and MEK inhibitors to target two steps in the MAPK pathway (vertical inhibition) is now standard of care in advanced-stage melanoma harboring BRAF V600 mutation. Encouraging results have been seen in several tumor types with the same mutation, including BRAF V600-mutant non-small cell lung cancer. Yet similar results in other tumors, such as colorectal cancer, have not been observed, highlighting the unique nature of different tumors. Furthermore, considerable cross talk occurs between signaling pathways, and cancer cells usually harbor multiple aberrations and/or develop compensatory mechanisms that drive resistance. Therefore, it is logical to target multiple pathways simultaneously (horizontal inhibition) by combining selective inhibitors or engineering multitargeted agents. Yet horizontal inhibition has proven to be a significant challenge, primarily due to dose-limiting toxicities. This review focuses on ongoing or completed clinical trials with combination targeted therapies for solid tumors and highlights the successes and ongoing challenges. Novel strategies to overcome these obstacles include new delivery technologies, combinations with emerging agents, and treatment schedule optimization. Mol Cancer Ther; 17(1); 3-16. ©2017 AACR.

Circ-SHKBP1 Regulates the Angiogenesis of U87 Glioma-Exposed Endothelial Cells through miR-544a/FOXP1 and miR-379/FOXP2 Pathways.

Circular RNAs (circRNAs) are a type of endogenous non-coding RNAs, which have been considered to mediate diverse tumorigenesis including angiogenesis. The present study aims to elucidate the potential role and molecular mechanism of circ-SHKBP1 in regulating the angiogenesis of U87 glioma-exposed endothelial cells (GECs). The expression of circ-SHKBP1, but not linear SHKBP1, was significantly upregulated in GECs compared with astrocyte-exposed endothelial cells (AECs). circ-SHKBP1 knockdown inhibited the viability, migration, and tube formation of GECs dramatically. The expressions of miR-379/miR-544a were downregulated in GECs, and circ-SHKBP1 functionally targeted miR-544a/miR-379 in an RNA-induced silencing complex (RISC) manner. Dual-luciferase reporter assay demonstrated that forkhead box P1/P2 (FOXP1/FOXP2) were targets of miR-544a/miR-379. The expressions of FOXP1/FOXP2 were upregulated in GECs, and silencing of FOXP1/FOXP2 inhibited the viability, migration, and tube formation of GECs. Meanwhile, FOXP1/FOXP2 promoted angiogenic factor with G patch and FHA domains 1 (AGGF1) expression at the transcriptional level. Furthermore, knockdown of AGGF1 suppressed the viability, migration, and tube formation of GECs via phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK)1/2 pathways. Taken together, the present study demonstrated that circ-SHKBP1 regulated the angiogenesis of GECs through miR-544a/FOXP1 and miR-379/FOXP2 pathways, and these findings might provide a potential target and effective strategy for combined therapy of gliomas.

Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment.

Breast cancer is the most frequently diagnosed cancer in women, with estrogen receptor positive (ER+) breast cancer making up approximately 75% of all breast cancers diagnosed. Given the dependence on active ER signaling in these tumors, the predominant treatment strategy has been to inhibit various aspects of this pathway including directly antagonizing ER with the use of selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). Interestingly, the dependence on ER for breast cancer growth is often retained even after progression through several lines of antiestrogen therapy, making ER a bonafide biomarker for this cancer subtype and driving the continued research and development of novel ER-targeted therapeutics to treat this patient population. This, combined with the continuous discovery of mechanisms underlying endocrine resistance, is resulting in a continually evolving treatment landscape for ER+ breast cancer. This review discusses various ER antagonists investigated for the treatment of breast cancer, outlining their pharmacological and tissue-specific mechanisms of action as well as their specified use within the ER+ breast cancer setting. In addition, mechanisms of resistance to SERMs and SERDs, the use of ER antagonists in combination therapy strategies, and the ongoing development of novel drugs are also reviewed in the context of the changing clinical landscape of ER+ breast cancer. Lastly, the role of SERMs and SERDs in non-breast cancer indications is also discussed.

Development of Dual-Pore Coexisting Branched Silica Nanoparticles for Efficient Gene-Chemo Cancer Therapy.

Various strategies for combination therapy to overcome current limitations in cancer therapy have been actively investigated. Among them, simultaneous delivery of multiple drugs is a subject of high interest due to anticipated synergistic effect, but there have been difficulties in designing and developing effective nanomaterials for this purpose. In this work, dual-pore coexisting hybrid porous silica nanoparticles are developed through Volmer-Weber growth pathway for efficient co-delivery of gene and anticancer drug. Based on the different pore sizes (2-3 and 40-45 nm) and surface modifications of the core and branch domains, loading and controlled release of gene and drug are achieved by appropriate strategies for each environment. With excellent loading capacity and low cytotoxicity of the present platform, the combinational cancer therapy is successfully demonstrated against human cervical cancer cell line. Through a series of quantitative analyses, the excellent gene-chemo combinational therapeutic efficiency is successfully demonstrated. It is expected that the present nanoparticle will be applicable to various biomedical fields that require co-delivery of small molecule and nucleic acid.

Combination therapy of anabolic and nonbisphosphonates antiresorptive agents for the treatment of osteoporosis: A meta-analysis.

According to the mechanisms of action, combination therapy of anabolic and antiresorptive agents may produce more effect for the treatment of osteoporosis. However, the combination therapy of anabolic agents and bisphosphonates reports no benefit and even reduced the anabolic effects of anabolic agents. This study aims to assess the effect of combination therapy of anabolic and nonbisphosphonates antiresorptive agents in adults with osteoporosis. Medline, EMBASE, and Cochrane Library were searched from January 1, 1980 to November 1, 2017 for randomized controlled trials (RCTs) of adults with osteoporosis treated in combination therapy of anabolic and nonbisphosphonates antiresorptive agents compared with monotherapy of either agent alone. The primary outcome was the incidence of fractures. The secondary outcomes were the bone mineral density (BMD) changes at lumbar spine and total hip. Continuous outcomes were expressed as standardized mean difference (SMD) and 95% confidence interval (CI), while dichotomous outcomes were expressed as risk ratio (RR) and 95% CI. The meta-analysis was performed using a random-effects model. I statistic (I > 50% as a threshold indicates significant heterogeneity) was used to assess the heterogeneity. A total of 10 trials with a total of 1042 patients were included. The pooled results showed that the combination therapy demonstrated a significant advantage over a monotherapy in the BMD improvement at the lumbar spine (SMD 1.18; 95% CI, 0.63 to 1.72; I = 93%) and the total hip (SMD 0.89; 95% CI, 0.48 to 1.29; I = 88%) and further reduce the fracture risk (RR, 0.45; 95%CI, 0.21 to 0.94; I = 0%). Low-to-moderate-quality evidence shows that the combination therapy of anabolic and nonbisphosphonates antiresorptive agents is superior to monotherapy in improving the BMD and reducing the fracture risk. However, further high methodological quality studies are needed to determine the antifracture efficacy, cost-effectiveness and safety of this strategy of combination therapy.

Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy.

Programmed death 1 (PD-1) is an immune checkpoint molecule that negatively regulates T-cell immune function through the interaction with its ligand PD-L1. Blockage of this interaction unleashes the immune system to fight cancer. Immunotherapy using PD-1 blockade has led to a paradigm shift in the field of cancer drug discovery, owing to its durable effect against a wide variety of cancers with limited adverse effects. A brief history and development of PD-1 blockade, from the initial discovery of PD-1 to the recent clinical output of this therapy, have been summarized here. Despite its tremendous clinical success rate over other cancer treatments, PD-1 blockade has its own pitfall; a significant fraction of patients remains unresponsive to this therapy. The key to improve the PD-1 blockade therapy is the development of combination therapies. As this approach has garnered worldwide interest, here, we have summarized the recent trends in the development of PD-1 blockade-based combination therapies and the ongoing clinical trials. These include combinations with checkpoint inhibitors, radiation therapy, chemotherapy and several other existing cancer treatments. Importantly, FDA has approved PD-1 blockade agent to be used in combination with either CTLA-4 blockade or chemotherapy. Responsiveness to the PD-1 blockade therapy is affected by tumour and immune system-related factors. The role of the immune system, especially T cells, in determining the responsiveness has been poorly studied compared with those factors related to the tumour side. Energy metabolism has emerged as one of the important regulatory mechanisms for the function and differentiation of T cells. We have documented here the recent results regarding the augmentation of PD-1 blockade efficacy by augmenting mitochondrial energy metabolism of T cell.

Epidermal Growth Factor Receptor Family Inhibition Identifies P38 Mitogen-activated Protein Kinase as a Potential Therapeutic Target in Bladder Cancer

To investigate perturbations in downstream signaling pathway activation and potential resistance mechanisms to epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) inhibition in cell line models of bladder cancer. We undertook a structured screening approach by phosphokinase array, followed by validation steps, to detect activated downstream signaling pathway nodes after therapeutic inhibition of EGFR or HER2 in bladder cancer cell lines. Erlotinib treatment of RT112 cells induced phosphorylation of 9 activated phosphoprotein targets (p38 mitogen-activated protein kinase [MAPK] [Thr180/Tyr182], GSK-3α/β [Ser21/9], MEK1/2 [Ser218/222, Ser222/226], Akt (protein kinase B) [Ser473], TOR [target of rapamycin] [Ser2448], Src [Tyr419], p27 [Thr198], p27 [Thr157], and PLCγ-1 [Tyr783]), whereas STAT4 (signal transducer and activator of transcription 4) (Tyr693) phosphorylation was reduced. Of these, p38 MAPK phosphorylation was confirmed to occur in response to inhibition of either EGFR or HER2 signaling through multiple validation steps, including differing bladder cancer cell lines (RT112, UM-UC-3, and T24) and methods of receptor pathway inhibition (erlotinib, lapatinib, and siRNA depletion of EGFR or HER2). Chemical inhibition of p38 MAPK with SB203580 led to inhibition of proliferation in RT112, UM-UC-3, and T24 cell lines (IC50 20.85, 76.78, and 79.12 µM, respectively). Fractional effect analyses indicated a synergistic interaction for inhibition of cell proliferation when combining SB203580 with lapatinib. p38 MAPK is a potential therapeutic target in bladder cancer and this strategy warrants further development in this disease. It may also allow combination therapy strategies to be developed in conjunction with EGFR or HER2 inhibition.

Insights into the Impact of CD8+ Immune Modulation on Human Immunodeficiency Virus Evolutionary Dynamics in Distinct Anatomical Compartments by Using Simian Immunodeficiency Virus-Infected Macaque Models of AIDS Progression.

A thorough understanding of the role of human immunodeficiency virus (HIV) intrahost evolution in AIDS pathogenesis has been limited by the need for longitudinally sampled viral sequences from the vast target space within the host, which are often difficult to obtain from human subjects. CD8+ lymphocyte-depleted macaques infected with simian immunodeficiency virus (SIV) provide an increasingly utilized model of pathogenesis due to clinical manifestations similar to those for HIV-1 infection and AIDS progression, as well as a characteristic rapid disease onset. Comparison of this model with SIV-infected non-CD8+ lymphocyte-depleted macaques also provides a unique opportunity to investigate the role of CD8+ cells in viral evolution and population dynamics throughout the duration of infection. Using several different phylogenetic methods, we analyzed viral gp120 sequences obtained from extensive longitudinal sampling of multiple tissues and enriched leukocyte populations from SIVmac251-infected macaques with or without CD8+ lymphocyte depletion. SIV evolutionary and selection patterns in non-CD8+ lymphocyte-depleted animals were characterized by sequential population turnover and continual viral adaptation, a scenario readily comparable to intrahost evolutionary patterns during human HIV infection in the absence of antiretroviral therapy. Alternatively, animals that were depleted of CD8+ lymphocytes exhibited greater variation in population dynamics among tissues and cell populations over the course of infection. Our findings highlight the major role for CD8+ lymphocytes in prolonging disease progression through continual control of SIV subpopulations from various anatomical compartments and the potential for greater independent viral evolutionary behavior among these compartments in response to immune modulation.IMPORTANCE Although developments in combined antiretroviral therapy (cART) strategies have successfully prolonged the time to AIDS onset in HIV-1-infected individuals, a functional cure has yet to be found. Improvement of drug interventions for a virus that is able to infect a wide range of tissues and cell types requires a thorough understanding of viral adaptation and infection dynamics within this target milieu. Although it is difficult to accomplish in the human host, longitudinal sampling of multiple anatomical locations is readily accessible in the SIV-infected macaque models of neuro-AIDS. The significance of our research is in identifying the impact of immune modulation, through differing immune selective pressures, on viral evolutionary behavior in a multitude of anatomical compartments. The results provide evidence encouraging the development of a more sophisticated model that considers a network of individual viral subpopulations within the host, with differing infection and transmission dynamics, which is necessary for more effective treatment strategies.