Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether.

Proc Natl Acad Sci U S A. 2016 10 04;113(40):11249-11254

Authors: Naon D, Zaninello M, Giacomello M, Varanita T, Grespi F, Lakshminaranayan S, Serafini A, Semenzato M, Herkenne S, Hernández-Alvarez MI, Zorzano A, De Stefani D, Dorn GW, Scorrano L

Abstract
The discovery of the multiple roles of mitochondria-endoplasmic reticulum (ER) juxtaposition in cell biology often relied upon the exploitation of Mitofusin (Mfn) 2 as an ER-mitochondria tether. However, this established Mfn2 function was recently questioned, calling for a critical re-evaluation of Mfn2's role in ER-mitochondria cross-talk. Electron microscopy and fluorescence-based probes of organelle proximity confirmed that ER-mitochondria juxtaposition was reduced by constitutive or acute Mfn2 deletion. Functionally, mitochondrial uptake of Ca2+ released from the ER was reduced following acute Mfn2 ablation, as well as in Mfn2-/- cells overexpressing the mitochondrial calcium uniporter. Mitochondrial Ca2+ uptake rate and extent were normal in isolated Mfn2-/- liver mitochondria, consistent with the finding that acute or chronic Mfn2 ablation or overexpression did not alter mitochondrial calcium uniporter complex component levels. Hence, Mfn2 stands as a bona fide ER-mitochondria tether whose ablation decreases interorganellar juxtaposition and communication.

PMID: 27647893 [PubMed - indexed for MEDLINE]

Role of Transporters in Drug Development.

J Clin Pharmacol. 2016 07;56 Suppl 7:S7-S10

Authors: Arya V, Kiser JJ

PMID: 27385180 [PubMed - indexed for MEDLINE]

Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease.

Sci Rep. 2016 05 04;6:25187

Authors: Bell CC, Hendriks DF, Moro SM, Ellis E, Walsh J, Renblom A, Fredriksson Puigvert L, Dankers AC, Jacobs F, Snoeys J, Sison-Young RL, Jenkins RE, Nordling Å, Mkrtchian S, Park BK, Kitteringham NR, Goldring CE, Lauschke VM, Ingelman-Sundberg M

Abstract
Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI.

PMID: 27143246 [PubMed - indexed for MEDLINE]

Big data from electronic health records for early and late translational cardiovascular research: challenges and potential.

Eur Heart J. 2017 Aug 29;:

Authors: Hemingway H, Asselbergs FW, Danesh J, Dobson R, Maniadakis N, Maggioni A, van Thiel GJ, Cronin M, Brobert G, Vardas P, Anker SD, Grobbee DE, Denaxas S, BigData@Heart Consortium

Abstract
Aims: Cohorts of millions of people's health records, whole genome sequencing, imaging, sensor, societal and publicly available data present a rapidly expanding digital trace of health. We aimed to critically review, for the first time, the challenges and potential of big data across early and late stages of translational cardiovascular disease research.
Methods and results: We sought exemplars based on literature reviews and expertise across the BigData@Heart Consortium. We identified formidable challenges including: data quality, knowing what data exist, the legal and ethical framework for their use, data sharing, building and maintaining public trust, developing standards for defining disease, developing tools for scalable, replicable science and equipping the clinical and scientific work force with new inter-disciplinary skills. Opportunities claimed for big health record data include: richer profiles of health and disease from birth to death and from the molecular to the societal scale; accelerated understanding of disease causation and progression, discovery of new mechanisms and treatment-relevant disease sub-phenotypes, understanding health and diseases in whole populations and whole health systems and returning actionable feedback loops to improve (and potentially disrupt) existing models of research and care, with greater efficiency. In early translational research we identified exemplars including: discovery of fundamental biological processes e.g. linking exome sequences to lifelong electronic health records (EHR) (e.g. human knockout experiments); drug development: genomic approaches to drug target validation; precision medicine: e.g. DNA integrated into hospital EHR for pre-emptive pharmacogenomics. In late translational research we identified exemplars including: learning health systems with outcome trials integrated into clinical care; citizen driven health with 24/7 multi-parameter patient monitoring to improve outcomes and population-based linkages of multiple EHR sources for higher resolution clinical epidemiology and public health.
Conclusion: High volumes of inherently diverse ('big') EHR data are beginning to disrupt the nature of cardiovascular research and care. Such big data have the potential to improve our understanding of disease causation and classification relevant for early translation and to contribute actionable analytics to improve health and healthcare.

PMID: 29370377 [PubMed - as supplied by publisher]

Influence of NKG2D Genetic Variants on Response to Anti-TNF Agents in Patients with Rheumatoid Arthritis.

Genes (Basel). 2018 Jan 25;9(2):

Authors: Iwaszko M, Świerkot J, Kolossa K, Jeka S, Wiland P, Bogunia-Kubik K

Abstract
A natural killer group 2 member D (NKG2D) acts as a powerful activating and co-stimulatory receptor on immune effector cells including NK and T cells. Disruptions within the NKG2D signalling pathway may trigger an exacerbated immune response and promote autoimmune reactions. The objective of the study was to evaluate a plausible role of polymorphisms within the NKG2D gene as a predictor of how effective anti-tumor necrosis factor (TNF) therapy is in rheumatoid arthritis (RA) patients. A total of 280 RA patients receiving anti-TNF therapy were genotyped for NKG2D rs2255336 (A > G), rs1049174 (C > G), and rs1154831 (C > A). Clinical response was evaluated according to the European League against Rheumatism (EULAR) criteria at the 12th and 24th week. Both the NKG2D rs225336 and rs1049174 polymorphisms were significantly associated with efficacy of TNF inhibitors. Inefficient therapy was more frequently observed in patients with rs2255336 GG or rs1049174 CC genotype as compared to other genotypes (p-value = 0.003 and p-value = 0.004, respectively). The presence of the rs2255336 G or the rs1049174 C allele correlated with a worse EULAR response (p-value = 0.002, p-value = 0.031, respectively). Moreover, patients carrying the rs2255336 or rs1049174 heterozygous genotype achieved better EULAR responses than patients with homozygous genotypes (p-value = 0.010 and p-value = 0.002, respectively). Data from the present study provides evidence that NKG2D polymorphisms may affect response to anti-TNF inhibitors in RA patients.

PMID: 29370129 [PubMed]

Pharmacogenetics of Risperidone-Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder.

Basic Clin Pharmacol Toxicol. 2018 Jan 25;:

Authors: Sukasem C, Vanwong N, Srisawasdi P, Ngamsamut N, Nuntamool N, Hongkaew Y, Puangpetch A, Chamkrachangpada B, Limsila P

Abstract
The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body weight and height. Genotyping was performed by Taqman real-time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852), and *41 (rs28371725), ATP-binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642), and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag-SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) -2548G>A (rs7799039), ghrelin gene (GHRL) -604G>A (rs27647), and brain-derived neurotrophic factor (BDNF) 196G>A (rs6265). Drug levels were analysed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results revealed that five percent of the patients presented with hyperglycaemia. Insulin resistance was detected in 16 percent of the patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (P=0.01 and P=0.03). There was no association of pharmacokinetic gene polymorphisms (CYP2D6 and ABCB1) and risperidone levels with insulin resistance. Multiple regression analysis indicated that BDNF 196 G>A polymorphism was significantly associated with insulin resistance (P=0.025). This finding suggested that BDNF 196 G>A polymorphism may be a genetic marker for predicting insulin resistance before initiating treatment in patients treated with risperidone. Because of the small sample size, further studies are needed to confirm these results. This article is protected by copyright. All rights reserved.

PMID: 29369497 [PubMed - as supplied by publisher]

Pharmacogenomics of chemically distinct classes of Keap1-Nrf2 activators identify common and unique gene, protein, and pathway responses in vivo.

Mol Pharmacol. 2018 Jan 24;:

Authors: Wible RS, Tran QT, Fathima S, Sutter CH, Kensler TW, Sutter TR

Abstract
The Keap1-Nrf2 signaling pathway is the subject of several clinical trials evaluating the effects of Nrf2 activation on the prevention of cancer, diabetes, and the treatment of chronic kidney disease and multiple sclerosis. 3H-1,2-dithiole-3-thione (D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are representative members of two distinct series of Nrf2 chemical activators. Previous reports have described activator-specific effects on Nrf2-dependent gene regulation and physiological outcomes. Here we used a robust chemical genomics approach to characterize expression profiles between D3T and CDDO-Im in liver from wild-type and Nrf2-null mice. At equally efficacious doses in wild-type mice, 406 genes show common RNA responses to both treatments. These genes enriched the Nrf2 regulated pathways of antioxidant defense and xenobiotic metabolism. Additionally, 197 and 745 genes were regulated uniquely in response to either D3T or CDDO-Im, respectively. Functional analysis of the D3T-regulated set showed a significant enrichment of Nrf2-regulated enzymes involved in cholesterol biosynthesis. This result was supported by Nrf2-dependent increases in LSS and CYP51 protein expression. CDDO-Im had no effect on cholesterol biosynthesis regardless of the dose tested. However, unlike D3T, CDDO-Im resulted in Nrf2-dependent elevation of Pparg, Ppara, and Klf13, as well as the coactivators Lpin1, Pgc1a, and Pgc1b; together indicating regulation of β-oxidation and lipid metabolic pathways. These findings provide novel insights into the pharmacodynamic action of these two activators of Keap1-Nrf2 signaling. Although both compounds modify Keap1 to affect canonical cytoprotective gene expression, additional unique sets of Nrf2-dependent genes were regulated by each agent with enrichment of selective metabolic pathways.  .

PMID: 29367259 [PubMed - as supplied by publisher]

Pharmacogenetic association of blood-lipid related genetic variants with 5-year progression of coronary artery calcification following the treatment with statin in the Heinz Nixdorf Recall study.

Atherosclerosis. 2017 Aug;263:e278

Authors: Pechlivanis S, Moebus S, Lehmann N, Mahabadi AA, Dykun I, Erbel R, Jöckel KH, Nöthen MM, Bachman HS

PMID: 29366052 [PubMed - in process]

Analysis of triglyceride-rich lipoprotein subfractions distribution by capillary isotachophoresis in non-dialysis patients with chronic kidney disease.

Atherosclerosis. 2017 Aug;263:e272

Authors: Cwiklinska A, Kowalski R, Cackowska M, Wieczorek E, Krol E, Kuchta A, Kortas-Stempak B, Dabkowski K, Gliwinska A, Szczepanska-Konkel M, Jankowski M

PMID: 29366031 [PubMed - in process]

Pharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long-acting injection: a case report.

BMC Psychiatry. 2017 Jul 03;17(1):238

Authors: Eum S, Schneiderhan ME, Brown JT, Lee AM, Bishop JR

Abstract
BACKGROUND: Given the complex nature of symptom presentation and medication regimens, psychiatric clinics may benefit from additional tools to personalize treatments. Utilizing pharmacogenetic information may be helpful in assessing unique responses to therapy. We report herein a case of wearing-off phenomena during treatment with aripiprazole long-acting injectable (LAI) and a proof of concept strategy of how pharmacogenetic information may be used to assess possible genetic factors and also hypothesize potential mechanisms for further study.
CASE PRESENTATION: A 51-year-old African American male with schizoaffective disorder was referred to a psychiatric clinic for medication management. After unsuccessful trials of multiple antipsychotics, oral aripiprazole was initiated (up to 30 mg/day) and transitioned to aripiprazole LAI with symptom improvement. At a high dose of aripiprazole LAI (400 mg Q3wks), the patient experienced breakthrough symptoms approximately 3 days prior to his next injection. Various considerations were examined to explain his atypical dose requirements, including but not limited to pharmacogenetic influences. Pharmacogenetic testing ruled out genetic influences on drug metabolism but noted a -141C Del variant in the dopamine-D2 receptor (DRD2) gene associated in prior studies of poor-response to antipsychotics. At this time, a new formulation, aripiprazole lauroxil, was explored due to its availability in higher dose options. Transition to the new formulation (882 mg Q4wks) greatly improved and stabilized the patient's symptoms with no breakthrough psychosis. Comparable daily dose equivalents were achieved with two different formulations due to the Q3wks vs Q4wks dosing strategies, although the two agents have some differences in pharmacokinetic profiles.
CONCLUSIONS: We report a case of a patient experiencing wearing-off symptoms with aripiprazole LAI who benefited from switching to aripiprazole lauroxil. Pharmacogenetic testing revealed normal activity for relevant metabolism pathways but a DRD2 -141C variant that may influence brain D2 expression and antipsychotic responsiveness. The clinical utility of DRD2 information and what to do with genotyping results has not been previously addressed, despite availability on clinical test panels. Our case report suggests further investigations of altered dosing strategies and receptor genotype sensitivities to pharmacokinetic factors may be helpful in understanding symptom re-emergence observed in some patients taking LAI antipsychotics.

PMID: 28673279 [PubMed - indexed for MEDLINE]

Drug metabolism in early infancy: opioids as an illustration.

Expert Opin Drug Metab Toxicol. 2018 Jan 24;:

Authors: van Donge T, Mian P, Tibboel D, van den Anker J, Allegaert K

Abstract
INTRODUCTION: Drug dosing in infants frequently depends on body weight as a crude indicator for maturation. Fentanyl (metabolized by Cytochrome P450 3A4) and morphine (glucuronidated by UDP-glucuronosyltransferase-2B7) served as model drugs to provide insight in maturation patterns of these enzymes and provide understanding of the impact of non-maturational factors to optimize dosing in infants. Areas covered: Systematic searches on metabolism and population pharmacokinetic (Pop-PK) models for fentanyl and morphine were performed. Pre- and post-model selection criteria were applied to assess and evaluate the validity of these models. It was observed that maturational changes have been rather well investigated, be it with variability in the maturational function estimates. The same holds true for Pop-PK models, where non-maturational covariates have also been reported (pharmacogenetics, disease state or external influences), although less incorporated in the PK models and with limited knowledge on mechanisms involved. Expert opinion: PK models for fentanyl and morphine are currently available. Consequently, we suggest that researchers should not continue to develop new models, but should investigate whether collected data fit in already existing models and provide additional value concerning the impact of (non)-maturational factors like drug-drug interactions or pharmacogenetics.

PMID: 29363349 [PubMed - as supplied by publisher]

Teratogenicity of systemic isotretinoin.

Minerva Pediatr. 2018 Feb;70(1):107-109

Authors: Holst H, Muhari-Stark E, Lava SA

PMID: 29363297 [PubMed - in process]

Innovative organotypic in vitro models for safety assessment: aligning with regulatory requirements and understanding models of the heart, skin, and liver as paradigms.

Arch Toxicol. 2018 Jan 23;:

Authors: Pridgeon CS, Schlott C, Wong MW, Heringa MB, Heckel T, Leedale J, Launay L, Gryshkova V, Przyborski S, Bearon RN, Wilkinson EL, Ansari T, Greenman J, Hendriks DFG, Gibbs S, Sidaway J, Sison-Young RL, Walker P, Cross MJ, Park BK, Goldring CEP

Abstract
The development of improved, innovative models for the detection of toxicity of drugs, chemicals, or chemicals in cosmetics is crucial to efficiently bring new products safely to market in a cost-effective and timely manner. In addition, improvement in models to detect toxicity may reduce the incidence of unexpected post-marketing toxicity and reduce or eliminate the need for animal testing. The safety of novel products of the pharmaceutical, chemical, or cosmetics industry must be assured; therefore, toxicological properties need to be assessed. Accepted methods for gathering the information required by law for approval of substances are often animal methods. To reduce, refine, and replace animal testing, innovative organotypic in vitro models have emerged. Such models appear at different levels of complexity ranging from simpler, self-organized three-dimensional (3D) cell cultures up to more advanced scaffold-based co-cultures consisting of multiple cell types. This review provides an overview of recent developments in the field of toxicity testing with in vitro models for three major organ types: heart, skin, and liver. This review also examines regulatory aspects of such models in Europe and the UK, and summarizes best practices to facilitate the acceptance and appropriate use of advanced in vitro models.

PMID: 29362863 [PubMed - as supplied by publisher]

Publisher Correction: Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model.

Sci Rep. 2018 Jan 23;8(1):1672

Authors: Bauer S, Wennberg Huldt C, Kanebratt KP, Durieux I, Gunne D, Andersson S, Ewart L, Haynes WG, Maschmeyer I, Winter A, Ämmälä C, Marx U, Andersson TB

Abstract
A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

PMID: 29362490 [PubMed - in process]

Interpersonal factors in the Pharmacokinetics and Pharmacodynamics of Voriconazole: Are CYP2C19 genotypes enough for us to make a clinical decision?

Curr Drug Metab. 2017 Dec 27;:

Authors: Zhong X, Tong X, Ju Y, Du X, Li Y

Abstract
Invasive mycoses are serious infections with high mortality and increasing incidence. Voriconazole, an important drug to treat invasive mycosis, is metabolized mainly by the cytochrome P450 family 2-subfamily C member 19 enzyme (CYP2C19) and is affected by the genotypes of CYP2C19. In this article, we review studies on how genotypes affect the pharmacokinetics and pharmacodynamics of voriconazole, and attempted to determine a method to deciding on dosage adjustments based on genotypes. The pharmacokinetics of voriconazole are influenced by various inter and intrapersonal factors, and for certain populations, such as geriatric patients and pediatric patients, these influences must be considered. CYP2C19 genotype represents the main part of the interpersonal variability related to voriconazole blood concentrations. Thus, monitoring the concentration of voriconazole is needed in clinical scenarios to minimize the negative influences of inter and intrapersonal factors. Several studies provided evidence on the stable trough concentration range from 1-2 to 4-6 mg/L, which were combined to consider the efficacy and toxicity. However, the therapeutic drug concentration needs to be narrowed down and evaluated by large-scale clinical trials. Though there is insufficient evidence on the relationship between CYP2C19 genotypes and clinical outcomes, there is a great potential for the initial voriconazole dose selection guiding by the CYP2C19 genotype. Finally, voriconazole therapeutic drug monitoring is essential to provide patient-specific dosing recommendations, leading to more effective anti-fungal regimens to increase clinical efficacy and reduce adverse drug reactions.

PMID: 29361899 [PubMed - as supplied by publisher]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/01/24

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/01/24

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Role of Perivascular Adipose Tissue in Health and Disease.

Compr Physiol. 2017 Dec 12;8(1):23-59

Authors: Fernández-Alfonso MS, Somoza B, Tsvetkov D, Kuczmanski A, Dashwood M, Gil-Ortega M

Abstract
Perivascular adipose tissue (PVAT) is cushion of fat tissue surrounding blood vessels, which is phenotypically different from other adipose tissue depots. PVAT is composed of adipocytes and stromal vascular fraction, constituted by different populations of immune cells, endothelial cells, and adipose-derived stromal cells. It expresses and releases an important number of vasoactive factors with paracrine effects on vascular structure and function. In healthy individuals, these factors elicit a net anticontractile and anti-inflammatory paracrine effect aimed at meeting hemodynamic and metabolic demands of specific organs and regions of the body. Pathophysiological situations, such as obesity, diabetes or hypertension, induce changes in its amount and in the expression pattern of vasoactive factors leading to a PVAT dysfunction in which the beneficial paracrine influence of PVAT is shifted to a pro-oxidant, proinflammatory, contractile, and trophic environment leading to functional and structural cardiovascular alterations and cardiovascular disease. Many different PVATs surrounding a variety of blood vessels have been described and exhibit regional differences. Both protective and deleterious influence of PVAT differs regionally depending on the specific vascular bed contributing to variations in the susceptibility of arteries and veins to vascular disease. PVAT therefore, might represent a novel target for pharmacological intervention in cardiovascular disease. © 2018 American Physiological Society. Compr Physiol 8:23-59, 2018.

PMID: 29357124 [PubMed - in process]

Vitamin D pathway gene polymorphisms and hepatocellular carcinoma in chronic hepatitis C-affected patients treated with new drugs.

Cancer Chemother Pharmacol. 2018 Jan 22;:

Authors: Cusato J, Boglione L, De Nicolò A, Favata F, Ariaudo A, Mornese Pinna S, Guido F, Avataneo V, Cantù M, Carcieri C, Cariti G, Di Perri G, D'Avolio A

Abstract
PURPOSE: Since HCV infection may lead to hepatocellular carcinoma (HCC) and vitamin D (deficiency) is related to cancer, we investigated if SNPs in genes involved in vitamin D pathway could predict HCV-related HCC presence in patients treated with new anti-HCV drugs.
METHODS: Patients with chronic hepatitis C and treated with direct-acting antivirals were enrolled. SNPs in VDR, CYP27B1, CYP24A1 and GC genes were assessed through real-time PCR. 258 patients were analyzed.
RESULTS: HCC was present in six patients, all taking sofosbuvir, all males and five/six had cirrhosis. HCV-RNA log levels at baseline were statistically different between patients with and without HCC. VDR FokI T > C SNP resulted associated with HCC: all the CC patients were free from HCC. An association between HCC presence and undetectable HCV-RNA at 1 month of therapy was suggested; cirrhosis was related to HCC. HCC risk factors were age, ribavirin administration, IL28Brs12979860CC and previous treatments; VDR FokICC, sex and insulin resistance were protective factors.
CONCLUSIONS: These data highlighted vitamin D pathway gene SNPs and HCC relationship in the Italian population; further studies are required.

PMID: 29356898 [PubMed - as supplied by publisher]

Not Everyone Fits the Mold: Intratumor and Intertumor Heterogeneity and Innovative Cancer Drug Design and Development.

OMICS. 2018 Jan;22(1):17-34

Authors: Dzobo K, Senthebane DA, Thomford NE, Rowe A, Dandara C, Parker MI

Abstract
Disruptive innovations in medicine are game-changing in nature and bring about radical shifts in the way we understand human diseases, their treatment, and/or prevention. Yet, disruptive innovations in cancer drug design and development are still limited. Therapies that cure all cancer patients are in short supply or do not exist at all. Chief among the causes of this predicament is drug resistance, a mechanism that is much more dynamic than previously understood. Drug resistance has limited the initial success experienced with biomarker-guided targeted therapies as well. A major contributor to drug resistance is intratumor heterogeneity. For example, within solid tumors, there are distinct subclones of cancer cells, presenting profound complexity to cancer treatment. Well-known contributors to intratumor heterogeneity are genomic instability, the microenvironment, cellular genotype, cell plasticity, and stochastic processes. This expert review explains that for oncology drug design and development to be more innovative, we need to take into account intratumor heterogeneity. Initially thought to be the preserve of cancer cells, recent evidence points to the highly heterogeneous nature and diverse locations of stromal cells, such as cancer-associated fibroblasts (CAFs) and cancer-associated macrophages (CAMs). Distinct subpopulations of CAFs and CAMs are now known to be located immediately adjacent and distant from cancer cells, with different subpopulations exerting different effects on cancer cells. Disruptive innovation and precision medicine in clinical oncology do not have to be a distant reality, but can potentially be achieved by targeting these spatially separated and exclusive cancer cell subclones and CAF subtypes. Finally, we emphasize that disruptive innovations in drug discovery and development will likely come from drugs whose effect is not necessarily tumor shrinkage.

PMID: 29356626 [PubMed - in process]