Pharmaceutical strategies in the emerging era of antibody-based biotherapeutics for the treatment of cancers overexpressing MET receptor tyrosine kinase.

Pharmaceutical innovation in the development of novel antibody-based biotherapeutics with increased therapeutic indexes makes MET-targeted cancer therapy a clinical reality.

Crosstalk between autophagy and apoptosis: Mechanisms and therapeutic implications.

The cellular recycling process of macroautophagy, which is the mechanism by which cellular material is delivered to lysosomes via double membraned vesicles called autophagosomes, is intimately connected to programmed cell death pathways, especially apoptosis. In this article, I discuss some underlying mechanisms and their implications for improving cancer therapy and propose that the approaches that have been taken to understand the autophagy-apoptosis connection to enhance cancer drug action can serve as a model for the kinds of information that should be developed to understand how autophagy controls other biological processes as well.

The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma.

Proteasome inhibitors have provided a significant advance in the treatment of multiple myeloma (MM). Consequently, there is increasing interest in developing strategies to target E3 ligases, de-ubiquitinases, and/or ubiquitin receptors within the ubiquitin proteasome pathway, with an aim to achieve more specificity and reduced side-effects. Previous studies have shown a role for the E3 ligase HUWE1 in modulating c-MYC, an oncogene frequently dysregulated in MM. Here we investigated HUWE1 in MM. We identified elevated expression of HUWE1 in MM compared with normal cells. Small molecule-mediated inhibition of HUWE1 resulted in growth arrest of MM cell lines without significantly effecting the growth of normal bone marrow cells, suggesting a favorable therapeutic index. Studies using a HUWE1 knockdown model showed similar growth inhibition. HUWE1 expression positively correlated with MYC expression in MM bone marrow cells and correspondingly, genetic knockdown and biochemical inhibition of HUWE1 reduced MYC expression in MM cell lines. Proteomic identification of HUWE1 substrates revealed a strong association of HUWE1 with metabolic processes in MM cells. Intracellular glutamine levels are decreased in the absence of HUWE1 and may contribute to MYC degradation. Finally, HUWE1 depletion in combination with lenalidomide resulted in synergistic anti-MM activity in both in vitro and in vivo models. Taken together, our data demonstrate an important role of HUWE1 in MM cell growth and provides preclinical rationale for therapeutic strategies targeting HUWE1 in MM.

Proactive Vs Reactive Therapeutic Drug Monitoring of Infliximab in Crohn's Disease: A Cost-Effectiveness Analysis in a Simulated Cohort.

BACKGROUND: Therapeutic drug monitoring (TDM) is increasingly performed for Infliximab (IFX) in patients with Crohn's disease (CD). Reactive TDM is a cost-effective strategy to empiric IFX dose escalation. The cost-effectiveness of proactive TDM is unknown. The aim of this study is to assess the cost-effectiveness of proactive vs reactive TDM in a simulated population of CD patients on IFX. METHODS: We developed a stochastic simulation model of CD patients on IFX and evaluated the expected health costs and outcomes of a proactive TDM strategy compared with a reactive strategy. The proactive strategy measured IFX concentration and antibody status every 6 months, or at the time of a flare, and dosed IFX to a therapeutic window. The reactive strategy only did so at the time of a flare. RESULTS: The proactive strategy led to fewer flares than the reactive strategy. More patients stayed on IFX in the proactive vs reactive strategy (63.4% vs 58.8% at year 5). From a health sector perspective, a proactive strategy was marginally cost-effective compared with a reactive strategy (incremental cost-effectiveness ratio of $146,494 per quality-adjusted life year), assuming a 40% of the wholesale price of IFX. The results were most sensitive to risk of flaring with a low IFX concentration and the cost of IFX. CONCLUSIONS: Assuming 40% of the average wholesale acquisition cost of biologic therapies, proactive TDM for IFX is marginally cost-effective compared with a reactive TDM strategy. As the cost of infliximab decreases, a proactive monitoring strategy is more cost-effective.

A Perspective on Thiazolidinone Scaffold Development as a New Therapeutic Strategy for Toxoplasmosis.

Toxoplasma gondii is one of the most successful parasites due to its ability to infect a wide variety of warm-blooded animals. It is estimated that one-third of the world's population is latently infected. The generic therapy for toxoplasmosis has been a combination of antifolates such as pyrimethamine or trimethoprim with either sulfadiazine or antibiotics such as clindamycin with a combination with leucovorin to prevent hematologic toxicity. This therapy shows limitations such as drug intolerance, low bioavailability or drug resistance by the parasite. There is a need for the development of new molecules with the capacity to block any stage of the parasite's life cycle in humans or in a different type of hosts. Heterocyclic compounds are promissory drugs due to its reported biological activity; for this reason, thiazolidinone and its derivatives are presented as a new alternative not only for its inhibitory activity against the parasite but also for its high selectivity-level with high therapeutic index. Thiazolidinones are an important scaffold known to be associated with anticancer, antibacterial, antifungal, antiviral, antioxidant, and antidiabetic activities. The molecule possesses an imidazole ring that has been described as an antiprotozoal agent with antiparasitic properties and less toxicity. Thiazolidinone derivatives have been reportedly as building blocks in organic chemistry and as scaffolds for drug discovery. Here we present a perspective of how structural modifications of the thiazolidinone core could generate new compounds with high anti-parasitic effect and less toxic results.

Drug Response Prediction by Globally Capturing Drug and Cell Line Information in a Heterogeneous Network.

One of the most important problem in personalized medicine research is to precisely predict the drug response for each patient. Due to relationships between drugs, recent machine learning-based methods have solved this problem using multi-task learning models. However, chemical relationships between drugs have not been considered. In addition, using very high dimensions of -omics data (e.g., genetic variant and gene expression) also limits the prediction power. A recent dual-layer network-based method was proposed to overcome these limitations by embedding gene expression features into a cell line similarity network and drug relationships in a chemical structure-based drug similarity network. However, this method only considered neighbors of a query drug and a cell line. Previous studies also reported that genetic variants are less informative to predict an outcome than gene expression. Here, we develop a novel network-based method, named GloNetDRP, to overcome these limitations. Besides gene expression, we used the genetic variant to build another cell line similarity network. First, we constructed a heterogeneous network of drugs and cell lines by connecting a drug similarity network and a cell line similarity network by known drug-cell line responses. Then, we proposed a method to predict the responses by exploiting not only the neighbors but also other drugs and cell lines in the heterogeneous network. Experimental results on two large-scale cell line data sets show that prediction performance of GloNetDRP on gene expression and genetic variant data is comparable. In addition, GloNetDRP outperformed dual-layer network- and typical multi-task learning-based methods.

Effective sustained release of 5-FU-loaded PLGA implant for improving therapeutic index of 5-FU in colon tumor.

In this study, a biodegradable implant composed of poly(lactide co-glycolide) (PLGA) and 5-fluorouracil (5-FU) was fabricated by mold method and used to impede the colon cancer via the local sustained release of 5-FU after transplanting into the peritoneal cavity. To optimize the 5-FU-implant, different factors such type of polymer, polymer-drug ratio, hydrophilic additives and organic solvents were investigated based on in vitro 5-FU release behavior. The optimized 5-FU-implant was subjected to evaluate the capacity of sustained release of 5-FU in vitro and in vivo. In addition, the pharmacokinetics and bio-distribution of 5-FU-implant were also tested in vivo after grafting into the peritoneal cavity in rat. Moreover, different doses of 5-FU-implants were compared against 5-FU injection for their antitumor activity in colon cancer model in nude mice and for their safety in health rat. The results revealed that the optimized 5-FU-implant possessed excellent sustained release of 5-FU for 2 week and no burst release were observed in vitro and in vivo. The pharmacokinetic behavior showed that higher concentration of 5-FU was found in peritoneal fluid when compared to plasma, which resulted in significantly improving antitumor activity as well as decreasing the side effect. It was proved that the 5-FU-implant was more efficacious and much safer than 5-FU bolus injection, which would be also used to overcome the reoccurrence of colon cancer after surgery.

Rationalizing Drug Response in Cancer Cell Lines.

Cancer cell lines (CCLs) play an important role in the initial stages of drug discovery allowing, among others, for the screening of drug candidates. As CCL panels continue to grow in size and diversity, many polymorphisms in genes encoding drug-metabolizing enzymes, transporters and drug targets, as well as disease-related genes have been linked to altered drug sensitivity. However, identifying the correlation between this variability and pharmacological responses remains challenging due to the heterogeneity of cancer biology and the intricate interplay between cell lines and drug molecules. Here, we propose a network-based strategy that exploits information on gene expression and somatic mutations of CCLs to group cells according to their molecular similarity. We then identify genes that are characteristic of each cluster and correlate their status with drug response. We find that CCLs with similar characteristic active network regions present specific responses to certain drugs, and identify a limited set of genes that might be directly involved in drug sensitivity or resistance.

A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody-Drug Conjugates (ADCs).

Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared with those of the cross-linker. Thus, the improved in vivo tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment. Mol Cancer Ther; 17(3); 650-60. ©2018 AACR.

Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial.

BACKGROUND: Panobinostat (a pan histone deacetylase inhibitor) is approved in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma who have received two or more previous lines of therapy. We aimed to improve the safety of this combination and investigate efficacy by incorporating low-dose thalidomide, using sub-cutaneous weekly bortezomib, and determining the maximum tolerated dose of panobinostat in this regimen. METHODS: We did a phase 1/2, multicentre, open-label trial (MUK six) at four hospitals in the UK, enrolling patients with relapsed, or relapsed and refractory, multiple myeloma aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 2 or less who had previously received 1-4 lines of therapy. Exclusion criteria included any antimyeloma treatment within 28 days of study drugs (except dexamethasone 160 mg >48 h before treatment). We used a rolling six escalation design to determine the maximum tolerated dose of panobinostat, and allocated patients to receive subcutaneous bortezomib 1·3 mg/m2, and oral thalidomide 100 mg, dexamethasone 20 mg, and panobinostat 10, 15, or 20 mg (escalated to 20 mg according to the escalation schedule). Treatment was given during a 21-day cycle (bortezomib on days 1 and 8; thalidomide every day; dexamethasone on days 1, 2, 8, and 9; and panobinostat on days 1, 3, 5, 8, 10, and 12) for 16 cycles in the absence of disease progression or unacceptable toxicity. Patients were permitted to come off study for autologous stem cell transplantation. The primary objective was to determine the maximum tolerated dose and recommended dose of panobinostat, and to estimate the proportion of patients with an overall response that was equal to a partial response or greater within 16 cycles of treatment at the recommended panobinostat dose in the modified intention-to-treat population. We assessed safety in all patients who received a trial drug (ie, bortezomib, thalidomide, dexamethasone, or panobinostat). This trial is registered at ClinicalTrials.gov, number NCT02145715, and with the ISRCTN registry, number ISRCTN59395590 and is closed to recruitment. FINDINGS: Between Jan 31, 2013, and Oct 30, 2014, we enrolled 57 eligible patients who received at least one dose of trial medication or any drug. One dose-limiting toxicity was reported (grade 3 hyponatremia at the 20 mg dose), therefore the maximum tolerated dose was not reached, and 20 mg was deemed to be the recommended dose. 46 patients were treated with panobinostat 20 mg (the intention-to-treat population). 42 patients (91%, 80% CI 83·4-96·2) of 46 achieved the primary endpoint of an overall response that was equal to a partial response or greater. Most adverse events were grade 1-2 with few occurrences of grade 3-4 diarrhoea or fatigue. The most common adverse events of grade 3 or worse in the safety population (n=57) were reduced neutrophil count (15 [26%]), hypophosphatemia (11 [19%]), and decreased platelet count (8 [14%]). 46 serious adverse events were reported in 27 patients; of 14 suspected to be related to the trial medication, seven (50%) were gastrointestinal disorders. INTERPRETATION: Panobinostat 20 mg in combination with bortezomib, thalidomide, and dexamethasone is an efficacious and well tolerated regimen for patients with relapsed multiple myeloma. FUNDING: Novartis and Myeloma UK.

Tiempo en rango terapéutico (TRT) en clínica de anticoagulación Reportes de eventos adversos y factores asociados a bajo TRT / Time in therapeutic range (TTR) in anticoagulation clinic Reports of adverse events and factors associated with low TTR

En el tratamiento de anticoagulación con warfarina, la reducción de eventos tromboembólicos debe ser valorada con el riesgo de sangrado. El tiempo de rango terapéutico (TRT) por el método de Rosenda al es una herramienta que valora la calidad en la monitorización de la terapia anticoagulante y se correlaciona con presencia de eventos tromboembólicos o sangrados. En este estudio se describe el tiempo de rango terapéutico (TRT R), los factores relacionados con menor (TRT R) y los efectos adversos presentados en la clínica de anticoagulación. Métodos y resultados: Estudio descriptivo de corte transversal entre el 1º de enero de 2011 y el 29 de febrero de 2012. Fueron evaluados 2232 resultados de INR de 319 pacientes. 98.550 días de seguimiento. 44% (108) hombres, 66% (211) mujeres, la edad promedio 60.3 años, siete visitas promedio/año, dosis semanal de warfarina 29.8 mg. La dosis semanal presenta una relación inversa con la edad, en menores de 45 años 37.9 mg y en mayores de 75 años 22.1 mg. El TRT R incrementó de 48-54%, respectivamente. Las indicaciones para anticoagulación: fibrilación auricular (FA) 38% (121), enfermedad tromboembólica venosa (ETEV) 35% (112), prótesis valvulares (PV) 17.5%(56) y embolia o trombosis arterial (EA) 9.5%(30). 228 pacientes (71%) presentaron un TRT R promedio del 64%. (40-100) INR mayor de 5 en 2.24% e INR menor de 1.5 en 10.9%. Sangrados menores: 16 pacientes (5%), sangrado mayor se presentó en dos pacientes (0.65%) y un evento adverso por embolia (0.32%). Los factores asociados a un TRT R bajo fueron: sexo masculino, enfermedad tromboembólica venosa, uso de warfarina genérica, edad menor de 55 años, tiempo menor de un año y menos de cinco visitas. Conclusiones: El tiempo de rango terapéutico TRT es una medición útil para establecer la eficacia de la terapia anticoagulante con warfarina. La meta de 60% en tiempo de rango terapéutico garantiza menos efectos adversos por sangrado o trombosis. Un número bajo de visitas y anticoagulación menor de un año están asociados a bajo TRT. (Acta Med Colomb 2016; 41: 42-48).

In the treatment of warfarin anticoagulation, reduction of thromboembolic events must be evaluated with the risk of bleeding. Time in therapeutic range (TTR) by the method of Rosendaal is a tool that values quality monitoring anticoagulant therapy and correlates with the presence of thromboembolic events or bleeding. In this study time therapeutic range (TTR), factors associated with lower (TTR) and adverse effects presented in the anticoagulation clinic are presented. Methods and Results: A descriptive cross-sectional study from 1° January 2011 and 29th February 2012. 2232 results of INR of 319 patients were assessed. 98550 days follow up. 44% (108) were men, 66% (211) women, average age 60.3 years, seven average visits/year, warfarin weekly dose of 29.8mg. The weekly dose has an inverse relationship with age; in patients under 45 years 37.9 mg., and in patients over 75 years, 22.1 mg. The TTR increased from 48 to 54%, respectively. Indications for anticoagulation: atrial fibrillation (AF) 38% (121), venous thromboembolic disease (VTE) 35% (112), prosthetic valves (PV) 17.5% (56) and emboli or arterial thrombosis (EA) 9.5% (30). 228 patients (71%) had a TTR average of 64%. (40-100), INR greater than 5 in 2.24% and INR less than 1.5 in 10.9%. Minor bleeding: 16 patients (5%), major bleeding occurred in two patients (0.65%) and oneadverse event of embolism (0.32%). The factors associated with low TTR were male gender, venous thromboembolic disease, use of generic warfarin, age less than 55 years, time shorter than one year and less than five visits. Conclusions: TTR is a useful measurement to establish the efficacy of anticoagulant therapy with warfarin. The goal of a 60% TTR ensures fewer adverse effects from bleeding or thrombosis. A low number of visits and anticoagulation less than a year are associated with low TTR. (ActaMed Colomb 2016; 41: 42-48).