Large-scale pharmacogenomic studies and drug response prediction for personalized cancer medicine

The response rate of most anti-cancer drugs is limited because of the high heterogeneity of cancer and the complex mechanism of drug action. Personalized treatment that stratifies patients into subgroups using molecular biomarkers is promising to improve clinical benefit. With the accumulation of preclinical models and advances in computational approaches of drug response prediction, pharmacogenomics has made great success over the last 20 years and is increasingly used in the clinical practice of personalized cancer medicine. In this article, we first summarize FDA-approved pharmacogenomic biomarkers and large-scale pharmacogenomic studies of preclinical cancer models such as patient-derived cell lines, organoids, and xenografts. Furthermore, we comprehensively review the recent developments of computational methods in drug response prediction, covering network, machine learning, and deep learning technologies and strategies to evaluate immunotherapy response. In the end, we discuss challenges and propose possible solutions for further improvement.     

Botanical candidates from Saudi Arabian flora as potential therapeutics for Plasmodium infection

Malaria is a lethal parasitic disease affecting over two hundred million people worldwide and kills almost half a million people per year. Until now, there is no curative treatment for this disease that has a substantial morbidity. The available chemotherapeutic agents are unable to completely control the infection with the continuous appearance of drug resistance. Consequently, the search for new therapeutic agents with high safety profiles and low side effects is of paramount importance. Several natural products have been investigated and proven to have antimalarial effects either in vivo or in vitro. A large number of plants have been studied globally for their antimalarial activities. However, studies that have been conducted in this field in Saudi Arabia are not enough. This article presents global and local research on the need for novel natural antimalarial agents with a particular emphasis on studies involving plants from Saudi Arabian flora.     

Predictive markers of safety and immunogenicity of adjuvanted vaccines

Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/.     

Plasmodium falciparum Carbonic Anhydrase is a Possible Target for Malaria Chemotherapy

Plasmodium falciparum is responsible for the majority of life-threatening cases of human malaria. The global emergence of drug-resistant malarial parasites necessitates identification and characterization of novel drug targets. Carbonic anhydrase (CA) is present at high levels in human red cells and in P. falciparum. Existence of at least three isozymes of the α class was demonstrated in P. falciparum and a rodent malarial parasite Plasmodium berghei. The major isozyme CA1 was purified and partially characterized from P. falciparum (PfCA1). A search of the malarial genome database yielded an open reading frame similar to the α-CAs from various organisms, including human. The primary amino acid sequence of the PfCA1 has 60% identity with a rodent parasite Plasmodium yoelii enzyme (PyCA). The single open reading frames encoded 235 and 252 amino acid proteins for PfCA1 and PyCA, respectively. The highly conserved active site residues were also found among organisms having α-CAs. The PfCA1 gene was cloned, sequenced and expressed in Escherichia coli. The purified recombinant PfCA1 enzyme was catalytically active. It was sensitive to acetazolamide and sulfanilamide inhibition. Kinetic properties of the recombinant PfCA1 revealed the authenticity to the wild type enzyme purified from P. falciparum in vitro culture. Furthermore, the PfCA1 inhibitors acetazolamide and sulfanilamide showed good antimalarial effect on the in vitro growth of P. falciparum. Our molecular tools developed for the recombinant enzyme expression will be useful for developing potential antimalarials directed at P. falciparum carbonic anhydrase.     

Antibodies to watch in 2014

The commercial pipeline of monoclonal antibodies is highly dynamic, with a multitude of transitions occurring during the year as product candidates advance through the clinical phases and onto the market. The data presented here add to that provided in the extensive “Antibodies to watch in 2014” report published in the January/February 2014 issue of mAbs. Recent phase transition data suggest that 2014 may be a banner year for first approvals of antibody therapeutics. As of May 2014, three products, ramucirumab (Cyramza®), siltuximab (Sylvant®) and vedolizumab (Entyvio^TM), had been granted first approvals in the United States, and four additional antibody therapeutics (secukinumab, dinutuximab, nivolumab, pembrolizumab) are undergoing regulatory review in either the US or the European Union. Other notable events include the start of first Phase 3 studies for seven antibody therapeutics (dupilumab, SA237, etrolizumab, MPDL3280A, bavituximab, clivatuzumab tetraxetan, blinatumomab). Relevant data for these product candidates are summarized, and metrics for antibody therapeutics development are discussed.     

SIRT1在宫颈癌细胞耐药中的作用及其机制研究

摘要目的：探讨沉默交配型信息调节因子2同源蛋白1（silentmatingtypeinformationregulation2homologyl,SIRTl）在宫颈癌化疗耐药中的作用及其机制。方法：体外培养人宫颈癌Hela细胞系和宫颈癌Hela／MMC耐药细胞亚系,westernblotting检测MMC对Hela和Hela／MMC细胞内SIRTl蛋白表达的影响;MTT法检测MMC及Nicotinamide对Hela和Hela／MMC细胞增殖的影响;AnnexinV-PI试验检测Hela／MMC细胞凋亡的亡的情况;RT—PCR方法检测耐药相关蛋白P—gP的mRNA表达情况。结果：正常情况下,Hela／MMC细胞中SIRTl的表达显著高于Hela细胞（P〈0．05）,MMC处理的Hela／MMC细胞中SIRTl的表达显著高于未经MMC处理（P〈0．05）。Nicotinamide对Hela和Hela／MMC细胞具有相似的生长抑制作用,Nicotinamide可使MMC诱导的Hela／MMC细胞凋亡增加,同时降低细胞内P-gP的mRNA表达（P〈0．05）。结论：SIRTl表达下调能显著减轻Hela／MMC细胞对MMC的耐药性,其作用可能与P—gp有关。     

嵌段共聚物聚乙二醇-聚苹果酸苄基酯载药胶束的制备及性质研究

目的：为构建聚合物胶束药物运载体系,制备嵌段共聚物聚乙二醇-聚苹果酸苄基酯载药胶束并测定其性质。方法：以L-天冬氨酸为原料,重氮化、环化后经开环聚合得到聚苹果酸苄基酯。氨基聚乙二醇通过酰胺键连接到β-聚苹果酸苄基酯上形成两亲性嵌段共聚物,喜树碱做药物模型制备载药胶束。动态光散射法测定胶束粒径、评价胶束稳定性,高效液相法测定喜树碱载药率和包封率,芘荧光法与动态光散射法测定临界胶束浓度。结果：喜树碱包封率72%,载药率6%,临界胶束浓度为40μg.mL-1。随着聚苹果酸苄基酯分子量减小,胶束稳定性增强。结论：聚乙二醇-聚苹果酸苄基酯在疏水链/亲水链分子量比值为2-4时在水中可自组装形成纳米胶束,可作为性能优良的聚合物药物载体。     

Association of multiple drug resistance-1 gene polymorphism with multiple drug resistance in breast cancer patients from an ethnic Saudi Arabian population

Chemotherapy has been used widely to treat cancer, both as a systemic therapy and as a local treatment. Unfortunately, many types of cancer are still refractory to chemotherapy. The mechanisms of anticancer drug resistance have been extensively explored but have not been fully characterized. This study analyzed the occurrences of polymorphism (SNP) in the MDR1 gene in breast cancer patients and determined a possible association with chemotherapy. The study group included one hundred breast carcinoma patients who subsequently received chemotherapy (the regimen generally consisted of commonly used drugs such as cyclophosphamide, adriamycin, 5-fluorouracil, docetaxel and their combinations). Blood samples from 100 healthy individuals are used, as controls were also genotyped for the MDR1 gene. This investigation revealed a significant correlation with response to various regimens of chemotherapy showing a low response to therapy with the CT/TT genotype at (exon 12) 1236 codon (p < 0.001). These findings demonstrate, for the first time, that the polymorphisms in (exon 12) 1236 codon of the MDR1 gene greatly influence the drug response in patients from the Arab population of Saudi Arabia.     

Can long range mechanical interaction between drugs and membrane proteins define the notion of molecular promiscuity? Application to P-glycoprotein-mediated multidrug resistance (MDR)

Background

Failure of treatment in over 90% of patients with metastatic cancer is due to acquired MDR. P-glycoprotein (Pgp) remains the archetypal drug membrane transporter expressed in many MDR cancer cells. Albeit the ATPase activity of Pgp is triggered by the presence of drug in the membrane, it is commonly assumed that when two drug molecules meet the same Pgp the protein cannot handle them efficiently due to steric effects and as a result the ATPase activity drops. However it is also possible that drug accumulating in the lipid-phase may affect the membrane in such a way that it imposes the mechanical closure of transporters by opposing the force mediated by ATP consumption. In this context, long range interactions between drug and membrane proteins could exist.

Methods

Recent data concerning Pgp structure have allowed us to formalize this hypothesis and we present a physico-mathematical model that is not based on predictive QSAR or other empirical methods applied to experimental data.

Results

Long range mechanical interactions between Pgp and drugs are predicted to occur at an external concentration of drug ~ 10–100 μM as previously determined experimentally at which concentration ~ 50% of transporters should be rendered inactive.

Conclusion

Distance interaction(s) between Pgp and drugs exist explaining an ill-defined effect concerning the ability of any drug to inhibit Pgp once a threshold concentration in the membrane has been reached.

General significance

Potential application of the theory in the field of pharmacology concentrating on the notion of molecular promiscuity and toxicity in drug discovery prediction is discussed.