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Posts Tagged ‘type 2 DM’


LIK 066, Novartis, for the treatment of type 2 diabetes

Curator: Larry H. Bernstein, MD, FCAP

 

LIK 066, Novartis, for the treatment of type 2 diabetes
Dr. Anthony Crasto

imgf000135_0001

lik 066

 

LIK-066, a new flozin on the horizon

 

Sodium glucose transporter-2 inhibitor
SGLT 1/2 inhibitor
Novartis Ag innovator
Clinical trial……..https://clinicaltrials.gov/ct2/show/NCT01915849
https://clinicaltrials.gov/ct2/show/NCT02470403

 

  • 10 Jun 2015 Novartis initiates enrolment in a phase II trial for Type 2 diabetes mellitus in USA (NCT02470403)
  • 02 Apr 2014 Novartis terminates a phase II trial in Type-2 diabetes mellitus in USA, Poland, Argentina, Hungary, Puerto Rico and South Africa (NCT01824264)
  • 01 Jan 2014 Novartis completes a phase II trial in Type 2 diabetes mellitus in USA (NCT01915849)

LIK-066 is in phase II clinical studies at Novartis for the treatment of type 2 diabetes.
In June 2014, the EMA’s PDCO adopted a positive opinion on a pediatric investigation plan (PIP) for LIK-066 for type 2 diabetes.
Diabetes mellitus is a metabolic disorder characterized by recurrent or persistent hyperglycemia (high blood glucose) and other signs, as distinct from a single disease or condition. Glucose level abnormalities can result in serious long-term complications, which include cardiovascular disease, chronic renal failure, retinal damage, nerve damage (of several kinds), microvascular damage and obesity.

 

Type 1 diabetes, also known as Insulin Dependent Diabetes Mellitus (IDDM), is characterized by loss of the insulin-producing β-cells of the islets of Langerhans of the pancreas leading to a deficiency of insulin. Type-2 diabetes previously known as adult- onset diabetes, maturity-onset diabetes, or Non-Insulin Dependent Diabetes Mellitus (NIDDM) – is due to a combination of increased hepatic glucose output, defective insulin secretion, and insulin resistance or reduced insulin sensitivity (defective responsiveness of tissues to insulin). Chronic hyperglycemia can also lead to onset or progression of glucose toxicity characterized by decrease in insulin secretion from β-cell, insulin sensitivity; as a result diabetes mellitus is self-exacerbated [Diabetes Care, 1990, 13, 610].
Chronic elevation of blood glucose level also leads to damage of blood vessels. In diabetes, the resultant problems are grouped under “microvascular disease” (due to damage of small blood vessels) and “macro vascular disease” (due to damage of the arteries). Examples of microvascular disease include diabetic retinopathy, neuropathy and nephropathy, while examples of macrovascular disease include coronary artery disease, stroke, peripheral vascular disease, and diabetic myonecrosis.
Diabetic retinopathy, characterized by the growth of weakened blood vessels in the retina as well as macular edema (swelling of the macula), can lead to severe vision loss or blindness. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US. Diabetic neuropathy is characterized by compromised nerve function in the lower extremities. When combined with damaged blood vessels, diabetic neuropathy can lead to diabetic foot. Other forms of diabetic neuropathy may present as mononeuritis or autonomic neuropathy. Diabetic nephropathy is characterized by damage to the kidney, which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of l adult kidney failure worldwide. A high glycemic diet (i.e., a diet that consists of meals that give high postprandial blood sugar) is known to be one of the causative factors contributing to the development of obesity.
Type 2 diabetes is characterized by insulin resistance and/or inadequate insulin secretion in response to elevated glucose level. Therapies for type 2 diabetes are targeted towards increasing insulin sensitivity (such as TZDs), hepatic glucose utilization (such as biguanides), directly modifying insulin levels (such as insulin, insulin analogs, and insulin secretagogues), increasing increttn hormone action (such as exenatide and sitagliptin), or inhibiting glucose absorption from the diet (such as alpha glucosidase inhibitors) [Nature 2001 , 414, 821-827], glucose is unable to diffuse across the cell membrane and requires transport proteins. The transport of glucose into epithelial cells is mediated by a secondary active cotransport system, the sodium-D-glucose co-transporter (SGLT), driven by a sodium- gradient generated by the Na+/K+-ATPase. Glucose accumulated in the epithelial cell is further transported into the blood across the membrane by facilitated diffusion through GLUT transporters [Kidney International 2007, 72, S27-S35].
SGLT belongs to the sodium/glucose co-transporter family SLCA5. Two different SGLT isoforms, SGLT1 and SGLT2, have been identified to mediate renal tubular glucose reabsorption in humans [Curr. Opinon in Investigational Drugs (2007): 8(4), 285-292 and references cited herein]. Both of them are characterized by their different substrate affinity. Although both of them show 59% homology in their amino acid sequence, they are functionally different. SGLT1 transports glucose as well as galactose, and is expressed both in the kidney and in the intestine, while SGLT2 is found exclusively in the S1 and S2 segments of the renal proximal tubule.
As a consequence, glucose filtered in the glomerulus is reabsorbed into the renal proximal tubular epithelial cells by SGLT2, a low-affinity/high-capacity system, residing on the surface of epithelial cell lining in S1 and S2 tubular segments. Much smaller amounts of glucose are recovered by SGLT1 , as a high-affinity/low-capacity system, on the more distal segment of the proximal tubule. In healthy human, more than 99% of plasma glucose that is filtered in the kidney glomerulus is reabsorbed, resulting in less than 1 % of the total filtered glucose being excreted in urine. It is estimated that 90% of total renal glucose absorption is facilitated by SGLT2; remaining 10 % is likely mediated by SGLT1 [J. Parenter. Enteral Nutr. 2004, 28, 364-371].
SGLT2 was cloned as a candidate sodium glucose co-transporter, and its tissue distribution, substrate specificity, and affinities are reportedly very similar to those of the low-affinity sodium glucose co-transporter in the renal proximal tubule. A drug with a mode of action of SGLT2 inhibition will be a novel and complementary approach to existing classes of medication for diabetes and its associated diseases to meet the patient’s needs for both blood glucose control, while preserving insulin secretion. In addition, SGLT2 inhibitors which lead to loss of excess glucose (and thereby excess calories) may have additional potential for the treatment of obesity.
Indeed small molecule SGLT2 inhibitors have been discovered and the anti-diabetic therapeutic potential of such molecules has been reported in literature [T-1095 (Diabetes, 1999, 48, 1794-1800, Dapagliflozin (Diabetes, 2008, 57, 1723-1729)].

 

PATENT

WO 2011048112
https://www.google.com/patents/WO2011048112A1?cl=en
Gregory Raymond Bebernitz, Mark G. Bock, Dumbala Srinivas Reddy, Atul Kashinath Hajare, Vinod Vyavahare, Sandeep Bhausaheb Bhosale, Suresh Eknath Kurhade, Videsh Salunkhe, Nadim S. Shaikh, Debnath Bhuniya, P. Venkata Palle, Lili Feng, Jessica Liang,
Patentscope, Espacenet

 

PATENT

SEE  INDIAN PATENT
IN 2009DE02173
Glycoside derivatives and uses thereof

REFERENCES

Pediatric investigation plan (PIP) decision: (S)-Pyrrolidine-2-carboxylic acid compound with (2S,3R,4R,5S,6R)-2-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2:1) ( LIK066) (EMEA-001527-PIP01-13)
European Medicines Agency (EMA) Web Site 2014, July 24
Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) assessment of LIK066 in healthy subjects and in patients with type 2 diabetes mellitus (T2DM) (NCT01407003)
ClinicalTrials.gov Web Site 2011, August 07
WO2012140597
WO2011048112
IN 2009DE02173

 

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Mirogabalin for diabetic neuropathy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Mirogabalin

by DR ANTHONY MELVIN CRASTO Ph.D

 

Mirogabalin, A-2000700, DS-5565
1138245-13-2, C12H19NO2, 209.28
[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid
2-[(1R,5S,6S)-6-(aminomethyl)-3-ethyl-6-bicyclo[3.2.0]hept-3-enyl]acetic acid
UNII-S7LK2KDM5U
Originator
Daiichi Sankyo
Therapeutic Claim
Treatment of fibromyalgia

Phase III clinical trials at Daiichi Sankyo for the treatment of pain associated with fibromyalgia

 

Class
Analgesic drugs (small molecules)
Mechanism of action
CACNA2D1 protein modulators

 

Mirogabalin (DS-5565) is a drug developed by Daiichi Sankyo and related to drugs such as gabapentin and pregabalin. Similarly to these drugs, mirogabalin binds to the α2δ calcium channels (1 and 2), but with significantly higher potency than pregabalin. It has shown promising results in Phase II clinical trials for the treatment of diabeticperipheral neuropathic pain,[1][2] and is currently in Phase III trials.

Mirogabalin, a voltage-dependent calcium channel subunit alpha-2/delta-1 ligand, is in phase III clinical trials at Daiichi Sankyo for the treatment of pain associated with fibromyalgia. The company is also conducting phase III clinical studies for the treatment of chronic pain and pain associated with diabetic peripheral neuropathy.

PATENTS

WO 2009041453

https://www.google.co.in/patents/EP2192109A1

JP 2010241796

WO 2012169475

WO 2012169474

WO2015005298

https://patentscope.wipo.int/search/en/detail.jsf

 

In the present invention, compounds having formula (IX) prepared via the process F from Step A (and / or its enantiomer) may be very produced as pure compounds. Compounds of formula (IX) which can be obtained by the present invention typically have a quality below.

The content of the diastereomer represented by the formula (X): 0.1% less than the content of the enantiomers represented by the formula (XI): 1.0% less than the formula (XII) and the double bond represented by the formula (XIII) The total content of regioisomers: less than 0.5% (Note that each content is calculated from the area percentage of the free form of formula (IX) (VII) in the by test High Performance Liquid Chromatography) [formula 23] [of 24]

 

 Next, the present invention is described by examples in detail, the present invention is, which however shall not be construed as limited thereto.
The internal standard substance in a magnetic resonance spectra (NMR), and using tetramethylsilane and abbreviations indicate the multiplicity, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and brs = It shows a broad singlet.
In the name of the compound, “R” and “S” indicate the absolute configuration at the asymmetric carbon. Furthermore, “RS” and “SR” indicates that the asymmetric carbon atom is racemic. In addition, “(1RS, and 5SR) -” if such a can shows the relative arrangement of the 1-position and the 5-position, as well shows only one of the diastereomers, its diastereomers are racemic We show that.
In the name of the compound, “E” and “Z” indicates the arrangement of positional isomers in the structure of the compound having a position isomerism.
“EZ” and “ZE” indicates that it is a mixture of regioisomers. Way more notation, is in accordance with the conventions in this area of the normal.

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Pharmacogenomics

Writer and Curator: Larry H. Bernstein, MD, FCAP

 

Implementation and utilization of genetic testing in personalized medicine

NS Abul-Husn, AO Obeng, SC Sanderson, O Gottesman, S A Scott
Pharmacogenomics and Personalized Medicine 2014:7 227–240
http://dx.doi.org/10.2147/PGPM.S48887

Clinical genetic testing began over 30 years ago with the availability of mutation detection for sickle cell disease diagnosis. Since then, the field has dramatically transformed to include gene sequencing, high-throughput targeted genotyping, prenatal mutation detection, preimplantation genetic diagnosis, population-based carrier screening, and now genome-wide analyses using microarrays and next-generation sequencing. Despite these significant advances in molecular technologies and testing capabilities, clinical genetics laboratories historically have been centered on mutation detection for Mendelian disorders. However, the ongoing identification of deoxyribonucleic acid (DNA) sequence variants associated with common diseases prompted the availability of testing for personal disease risk estimation, and created commercial opportunities for direct-to-consumer genetic testing companies that assay these variants. This germline genetic risk, in conjunction with other clinical, family, and demographic variables, are the key components of the personalized medicine paradigm, which aims to apply personal genomic and other relevant data into a patient’s clinical assessment to more precisely guide medical management. However, genetic testing for disease risk estimation is an ongoing topic of debate, largely due to inconsistencies in the results, concerns over clinical validity and utility, and the variable mode of delivery when returning genetic results to patients in the absence of traditional counseling. A related class of genetic testing with analogous issues of clinical utility and acceptance is pharmacogenetic testing, which interrogates sequence variants implicated in interindividual drug response variability. Although clinical pharmacogenetic testing has not previously been widely adopted, advances in rapid turnaround time genetic testing technology and the recent implementation of preemptive genotyping programs at selected medical centers suggest that personalized medicine through pharmacogenetics is now a reality. This review aims to summarize the current state of implementing genetic testing for personalized medicine, with an emphasis on clinical pharmacogenetic testing.

Pharmacogenomic knowledge gaps and educational resource needs among physicians in selected specialties

Katherine A Johansen Taber, Barry D Dickinson
Pharmacogenomics and Personalized Medicine 2014:7 145–162
http://dx.doi.org/10.2147/PGPM.S63715

Background: The use of pharmacogenomic testing in the clinical setting has the potential to improve the safety and effectiveness of drug therapy, yet studies have revealed that physicians lack knowledge about the topic of pharmacogenomics, and are not prepared to implement it in the clinical setting. This study further explores the pharmacogenomic knowledge deficit and educational resource needs among physicians.
Materials and methods: Surveys of primary care physicians, cardiologists, and psychiatrists were conducted.
Results: Few physicians reported familiarity with the topic of pharmacogenomics, but more reported confidence in their knowledge about the influence of genetics on drug therapy. Only a small minority had undergone formal training in pharmacogenomics, and a majority reported being unsure what type of pharmacogenomic tests were appropriate to order for the clinical situation. Respondents indicated that an ideal pharmacogenomic educational resource should be electronic and include such components as how to interpret pharmacogenomic test results, recommendations for prescribing, population subgroups most likely to be affected, and contact information for laboratories offering pharmacogenomic testing.
Conclusion: Physicians continue to demonstrate pharmacogenomic knowledge gaps, and are unsure about how to use pharmacogenomic testing in clinical practice. Educational resources that are clinically oriented and easily accessible are preferred by physicians, and may best support appropriate clinical implementation of pharmacogenomics.

Developing genomic knowledge bases and databases to support clinical management: current perspectives

Vojtech Huser, Murat Sincan, James J Cimino
Pharmacogenomics and Personalized Medicine 2014:7 275–283
http://dx.doi.org/10.2147/PGPM.S49904

Personalized medicine, the ability to tailor diagnostic and treatment decisions for individual patients, is seen as the evolution of modern medicine. We characterize here the informatics resources available today or envisioned in the near future that can support clinical interpretation of genomic test results. We assume a clinical sequencing scenario (germline whole-exome sequencing) in which a clinical specialist, such as an endocrinologist, needs to tailor patient management decisions within his or her specialty (targeted findings) but relies on a genetic counselor to interpret off-target incidental findings. We characterize the genomic input data and list various types of knowledge bases that provide genomic knowledge for generating clinical decision support. We highlight the need for patient-level databases with detailed lifelong phenotype content in addition to genotype data and provide a list of recommendations for personalized medicine knowledge bases and databases. We conclude that no single knowledge base can currently support all aspects of personalized recommendations and that consolidation of several current resources into larger, more dynamic and collaborative knowledge bases may offer a future path forward.

 

Tumor Heterogeneity: Mechanisms and Bases for a Reliable Application of Molecular Marker Design

Salvador J. Diaz-Cano
Int. J. Mol. Sci. 2012, 13, 1951-2011; http://dx.doi.org/10.3390/ijms13021951

Tumor heterogeneity is a confusing finding in the assessment of neoplasms, potentially resulting in inaccurate diagnostic, prognostic and predictive tests. This tumor heterogeneity is not always a random and unpredictable phenomenon, whose knowledge helps designing better tests. The biologic reasons for this intratumoral heterogeneity would then be important to understand both the natural history of neoplasms and the selection of test samples for reliable analysis. The main factors contributing to intratumoral heterogeneity inducing gene abnormalities or modifying its expression include: the gradient ischemic level within neoplasms, the action of tumor microenvironment (bidirectional interaction between tumor cells and stroma), mechanisms of intercellular transference of genetic information (exosomes), and differential mechanisms of sequence-independent modifications of genetic material and proteins. The intratumoral heterogeneity is at the origin of tumor progression and it is also the byproduct of the selection process during progression. Any analysis of heterogeneity mechanisms must be integrated within the process of segregation of genetic changes in tumor cells during the clonal expansion and progression of neoplasms. The evaluation of these mechanisms must also consider the redundancy and pleiotropism of molecular pathways, for which appropriate surrogate markers would support the presence or not of heterogeneous genetics and the main mechanisms responsible. This knowledge would constitute a solid scientific background for future therapeutic planning.

Systematic evaluation of connectivity map for disease indications

Jie Cheng, Lun Yang, Vinod Kumar and Pankaj Agarwal
Genome Medicine 2014, 6:95 http://genomemedicine.com/content/6/12/95

Background: Connectivity map data and associated methodologies have become a valuable tool in understanding drug mechanism of action (MOA) and discovering new indications for drugs. One of the key ideas of connectivity map (CMAP) is to measure the connectivity between disease gene expression signatures and compound-induced gene expression profiles. Despite multiple impressive anecdotal validations, only a few systematic evaluations have assessed the accuracy of this aspect of CMAP, and most of these utilize drug-to-drug matching to transfer indications across the two drugs.
Methods: To assess CMAP methodologies in a more direct setting, namely the power of classifying known drug-disease relationships, we evaluated three CMAP-based methods on their prediction performance against a curated dataset of 890 true drug-indication pairs. The disease signatures were generated using Gene Logic BioExpress system and the compound profiles were derived from the Connectivity Map database (CMAP, build 02, http://www.broadinstitute.org/CMAP/).
Results: The similarity scoring algorithm called eXtreme Sum (XSum) better than the standard Kolmogorov-Smirnov (KS) statistic in terms of the area under curve and can achieve a four-fold enrichment at 0.01, false positive rate level, with AUC = 2.2E-4, P value = 0.0035.
Conclusion: Connectivity map can significantly enrich true positive drug-indication pairs given an effective matching algorithm.

Pharmacogenetics of Statin-Induced Myopathy: A Focused Review of the Clinical Translation of Pharmacokinetic Genetic Variants

Jasmine A Talameh and Joseph P Kitzmiller
J Pharmacogenomics Pharmacoproteomics 2014, 5:2 http://dx.doi.org/10.4172/2153-0645.1000128

Statins are the most commonly prescribed drugs in the United States and are extremely effective in reducing major cardiovascular events in the millions of Americans with hyperlipidemia. However, many patients (up to 25%) cannot tolerate or discontinue statin therapy due to statin-induced myopathy (SIM). Patients will continue to experience SIM at unacceptably high rates or experience unnecessary cardiovascular events (as a result of discontinuing or decreasing their statin therapy) until strategies for predicting or mitigating SIM are identified. A promising strategy for predicting or mitigating SIM is pharmacogenetic testing particularly of pharmacokinetic genetic variants as SIM is  related to statin exposure. Data is emerging on the association between pharmacokinetic genetic variants and SIM.
A current, critical evaluation of the literature on pharmacokinetic genetic variants and SIM for potential translation to clinical practice is lacking. This review focuses specifically on pharmacokinetic genetic variants and their association with SIM clinical outcomes. We also discuss future directions, specific to the research on pharmacokinetic genetic variants, which could speed the translation into clinical practice. For simvastatin, we did not find sufficient evidence to support the clinical translation of pharmacokinetic genetic variants other than SLCO1B1. However, SLCO1B1 may also be clinically relevant for pravastatin- and pitavastatin-induced myopathy, but additional studies assessing SIM clinical outcome are needed. CYP2D6*4 may be clinically relevant for atorvastatin-induced myopathy, but mechanistic studies are needed. Future research efforts need to incorporate statin-specific analyses, multi-variant analyses, and a standard definition of SIM. As the use of statins is extremely common and SIM continues to occur in a significant number of patients, future research investments in pharmacokinetic genetic variants have the potential to make a profound impact on public health.

Benefits of Pharmacogenetics in the Management of Hypertension

Clara Torrellas, Juan Carlos Carril and Ramón Cacabelos
J Pharmacogenomics Pharmacoproteomics 2014, 5:2 http://dx.doi.org/10.4172/2153-0645.1000126

Introduction: Hypertension, suffered by 35% of the population, stands out as the main risk factor for cardiovascular disorders with the highest death rate worldwide. Only a small number of patients with hypertension gets efficient control over blood pressure (BP) with appropriate drug therapy.  harmacogenetics, as a tool to identify antihypertensive therapeutic response-associated polymorphisms, could help to reduce this problem.
Objectives: We present here an epidemiological study of the prevalence of hypertension and its pharmacological treatment to demonstrate the error rate that physicians can commit when the patient´s pharmacogenetic profile is unknown.
Method: The sample consisted of 1115 individuals of which 332 met criteria for hypertension. We recorded each patient´s drug prescription prior to their visit to EuroEspes Biomedical Research Center, and analyzed their pharmacogenetic profile.
Results: About 30% of patients were hypertensive, of whom only 40.4% were receiving an active ingredient for hypertension control. Among them, CYP3A4/5 and CYP2C9 were the major metabolizing enzymes. Antagonists of angiotensin II receptors, followed by calcium-blocking agents and beta-adrenergic antagonists were the most commonly-prescribed drug categories. However, 61% of hypertensive patients were not taking suitable antihypertensive agents for their metabolism according to their genetic idiosyncrasy. Furthermore, the highest error rate was determined for CYP2C9.
Conclusion: The introduction of changes in the management of hypertension in the Spanish population could be useful to promote the prevention and treatment of high blood pressure in a more efficient way. The integration of pharmacogenetic testing into routine clinical procedures could optimize the therapeutic response, guiding the physician in the choice of the correct antihypertensive drug and the correct dose. The control of BP arises as an area of particular interest in assessing the validity and utility of pharmacogenetic testing/intervention.

Pharmacogenomics Study of Clopidogrel by RFLP based Genotyping of CYP2C19 in Cardiovascular Disease Patients in North-East Population of India

Prasanthi SV, Vinayak S Jamdade, Nityanand B Bolshette, Ranadeep Gogoi and Mangala Lahkar
J Pharmacogenomics Pharmacoproteomics 2014, 5:3 http://dx.doi.org/10.4172/2153-0645.1000132

Introduction and Objective: Pharmacogenetics is a genetically determined variability in drug responses. The genes and their allelic variants which affect our response to drugs are the main routes in development of pharmacogenetics. Clopidogrel is an antiplatelet drug, used against athero-thrombotic events in cardiovascular patients. The objective of our study was to identify the CYP2C19 Single Nucleotide Polymorphisms, responsible for altering the metabolism of clopidogrel, at gene level. And to document the prevalence of CYP2C19 gene mutations in clopidogrel treated cardiovascular disease patients in Assam population, Guwahati Medical College & Hospital, in North- East India.
Patients and Methods: We have studied 60 patients who received clopidogrel from Gauhati medical college and hospital Assam. Genomic DNA was extracted by using Hipura blood genomic DNA extracting mini preparation kit by following the manufacturer’s instructions.RFLP analysis was done by DNA amplification which was carried out by using set of primers and resulting ampicons of CYP2C19*2;CYP2C19*3 and CYP2C19*17 were subjected for Restriction digestion with SmaI, BamHI and Lwe0I respectively.
Results: We found that CYP2C19*2 had allelic frequency of ~40% in Gauhati Medical College and Hospital, Assam, North East India. None of the samples were mutated with CYP2C19*3 andCYP2C19*17 allele. Other CYP2C19 variant alleles with reduced or absent enzymatic activity have been identified. Conclusion: We found that loss of functional allele CYP2C19*2 had higher carriage frequency; whereas, CYP2C19*3 and *17 alleles were not found in cardiovascular patients who were taking clopidogrel. Personalized therapy targeting patients who carry these genetic variants might help to improve the clinical outcome.

Role of cytochrome P450 genotype in the steps toward personalized drug therapy

Larisa H Cavallari, Hyunyoung Jeong, Adam Bress
Pharmacogenomics and Personalized Medicine 2011:4 123–136
http://dx.doi.org/10.2147/PGPM.S15497

Genetic polymorphism for cytochrome 450 (P450) enzymes leads to interindividual variability in the plasma concentrations of many drugs. In some cases, P450 genotype results in decreased enzyme activity and an increased risk for adverse drug effects. For example, individuals with the CYP2D6 loss-of-function genotype are at increased risk for ventricular arrhythmia if treated with usual does of thioridazine. In other cases, P450 genotype may influence the dose of a drug required to achieve a desired effect. This is the case with warfarin, with lower doses often necessary in carriers of a variant CYP2C9*2 or *3 allele to avoid supratherapeutic anticoagulation. When a prodrug, such as clopidogrel or codeine, must undergo hepatic biotransformation to its active form, a loss-of-function P450 genotype leads to reduced concentrations of the active drug and decreased drug efficacy. In contrast, patients with multiple CYP2D6 gene copies are at risk for opioid-related toxicity if treated with usual doses of codeine-containing analgesics. At least 25 drugs contain information in their US Food and Drug Administration-approved labeling regarding P450 genotype. The CYP2C9, CYP2C19, and CYP2D6 genes are the P450 genes most often cited. To date, integration of P450 genetic information into clinical decision making is limited. However, some institutions are beginning to embrace routine P450 genotyping to assist in the treatment of their patients. Genotyping for P450 variants may carry less risk for discrimination compared with genotyping for disease-associated variants. As such, P450 genotyping is likely to lead the way in the clinical implementation of pharmacogenomics. This review discusses variability in the CYP2C9, CYP2C19, and CYP2D6 genes and the implications of this for drug efficacy and safety.

Asthma pharmacogenetics and the development of genetic profiles for personalized medicine

Victor E Ortega, Deborah A Meyers, Eugene R Bleecker
Pharmacogenomics and Personalized Medicine 2015:8 9–22
http://dx.doi.org/10.2147/PGPM.S52846

Human genetics research will be critical to the development of genetic profiles for personalized or precision medicine in asthma. Genetic profiles will consist of gene variants that predict individual disease susceptibility and risk for progression, predict which pharmacologic therapies will result in a maximal therapeutic benefit, and predict whether a therapy will result in an adverse response and should be avoided in a given individual. Pharmacogenetic studies of the glucocorticoid, leukotriene, and β2-adrenergic receptor pathways have focused on candidate genes within these pathways and, in addition to a small number of genome-wide association studies, have identified genetic loci associated with therapeutic responsiveness. This review summarizes these pharmacogenetic discoveries and the future of genetic profiles for personalized medicine in asthma. The benefit of a personalized, tailored approach to health care delivery is needed in the development of expensive biologic drugs directed at a specific biologic pathway. Prior pharmacogenetic discoveries, in combination with additional variants identified in future studies, will form the basis for future genetic profiles for personalized tailored approaches to maximize therapeutic benefit for an individual asthmatic while minimizing the risk for adverse events.

Clinical application of high throughput molecular screening techniques for pharmacogenomics

Arun P Wiita, Iris Schrijver
Pharmacogenomics and Personalized Medicine 2011:4 109–121
http://dx.doi.org/10.2147/PGPM.S15302

Genetic analysis is one of the fastest-growing areas of clinical diagnostics. Fortunately, as our knowledge of clinically relevant genetic variants rapidly expands, so does our ability to detect these variants in patient samples. Increasing demand for genetic information may necessitate the use of high throughput diagnostic methods as part of clinically validated testing. Here we provide a general overview of our current and near-future abilities to perform large-scale genetic testing in the clinical laboratory. First we review in detail molecular methods used for high throughput mutation detection, including techniques able to monitor thousands of genetic variants for a single patient or to genotype a single genetic variant for thousands of patients simultaneously. These methods are analyzed in the context of pharmacogenomic testing in the clinical laboratories, with a focus on tests that are currently validated as well as those that hold strong promise for widespread clinical application in the near future. We further discuss the unique economic and clinical challenges posed by pharmacogenomic markers. Our ability to detect genetic variants frequently outstrips our ability to accurately interpret them in a clinical context, carrying implications both for test development and introduction into patient management algorithms. These complexities must be taken into account prior to the introduction of any pharmacogenomic biomarker into routine clinical testing.

Clinical implementation of RNA signatures for pharmacogenomic decision-making

Weihua Tang, Zhiyuan Hu, Hind Muallem, Margaret L Gulley
Pharmacogenomics and Personalized Medicine 2011:4 95–107
http://dx.doi.org/10.2147/PGPM.S14888

RNA profiling is increasingly used to predict drug response, dose, or toxicity based on analysis of drug pharmacokinetic or pharmacodynamic pathways. Before implementing multiplexed RNA arrays in clinical practice, validation studies are carried out to demonstrate sufficient evidence of analytic and clinical performance, and to establish an assay protocol with quality assurance measures. Pathologists assure quality by selecting input tissue and by interpreting results in the context of the input tissue as well as the technologies that were used and the clinical setting in which the test was ordered. A strength of RNA profiling is the array-based measurement of tens to thousands of RNAs at once, including redundant tests for critical analytes or pathways to promote confidence in test results. Instrument and reagent manufacturers are crucial for supplying reliable components of the test system. Strategies for quality assurance include careful attention to RNA preservation and quality checks at pertinent steps in the assay protocol, beginning with specimen collection and proceeding through the variousphases of transport, processing, storage, analysis, interpretation, and reporting. Specimen quality is checked by probing housekeeping transcripts, while spiked and exogenous controls serve as a check on analytic performance of the test system. Software is required to manipulate abundant array data and present it for interpretation by a laboratory physician who reports results in a manner facilitating therapeutic decision-making. Maintenance of the assay requires periodic documentation of personnel competency and laboratory proficiency. These strategies are shepherding genomic arrays into clinical settings to provide added value to patients and to the larger health care system.

Dysregulation of the homeobox transcription factor gene HOXB13: role in prostate cancer

Brennan Decker, Elaine A Ostrander
Pharmacogenomics and Personalized Medicine 2014:7 193–201
http://dx.doi.org/10.2147/PGPM.S38117

Prostate cancer (PC) is the most common noncutaneous cancer in men, and epidemiological studies suggest that about 40% of PC risk is heritable. Linkage analyses in hereditary PC families have identified multiple putative loci. However, until recently, identification of specific risk alleles has proven elusive. Cooney et al used linkage mapping and segregation analysis to identify a putative risk locus on chromosome 17q21-22. In search of causative variant(s) in genes from the candidate region, a novel, potentially deleterious G84E substitution in homeobox transcription factor gene HOXB13 was observed in multiple hereditary PC families. In follow-up testing, the G84E allele was enriched in cases, especially those with an early diagnosis or positive family history of disease. This finding was replicated by others, confirming HOXB13 as a PC risk gene. The HOXB13 protein plays diverse biological roles in embryonic development and terminally differentiated tissue. In tumor cell lines, HOXB13 participates in a number of biological functions, including coactivation and localization of the androgen receptor and FOXA1. However, no consensus role has emerged and many questions remain. All HOXB13 variants with a proposed role in PC risk are predicted to damage the protein and lie in domains that are highly conserved across species. The G84E variant has the strongest epidemiological support and lies in a highly conserved MEIS protein-binding domain, which binds cofactors required for activation. On the basis of epidemiological and biological data, the G84E variant likely modulates the interaction between the HOXB13 protein and the androgen receptor, as well as affecting FOXA1-mediated transcriptional programming. However, further studies of the mutated protein are required to clarify the mechanisms by which this translates into PC risk.

Patient selection and targeted treatment in the management of platinum-resistant ovarian cancer

Christopher P Leamon, Chandra D Lovejoy, Binh Nguyen
Pharmacogenomics and Personalized Medicine 2013:6 113–125
http://dx.doi.org/10.2147/PGPM.S24943

Ovarian cancer (OC) has the highest mortality rate of any gynecologic cancer, and patients generally have a poor prognosis due to high chemotherapy resistance and late stage disease diagnosis. Platinum-resistant OC can be treated with cytotoxic chemotherapy such as paclitaxel, topotecan, pegylated liposomal doxorubicin, and gemcitabine, but many patients eventually relapse upon treatment. Fortunately, there are currently a number of targeted therapies in development for these patients who have shown promising results in recent clinical trials. These treatments often target the vascular endothelial growth factor pathway (eg, bevacizumab and aflibercept), DNA repair mechanisms (eg, iniparib and olaparib), or they are directed against folate related pathways (eg, pemetrexed, farletuzumab, and vintafolide). As many targeted therapies are only effective in a subset of patients, there is an increasing need for the identification of response predictive biomarkers. Selecting the right patients through biomarker screening will help tailor therapy to patients and decrease superfluous treatment to those who are biomarker negative; this approach should lead to improved clinical results and decreased toxicities. In this review the current targeted therapies used for treating platinum-resistant OC are discussed. Furthermore, use of prognostic and response predictive biomarkers to define OC patient populations that may benefit from specific targeted therapies is also highlighted.

Pharmacogenetics in breast cancer: steps toward personalized medicine in breast cancer management

Sarah Rofaiel, Esther N Muo1, Shaker A Mousa
Pharmacogenomics and Personalized Medicine 2010:3 129–143
http://dx.dpi.org:/10.2147/PGPM.S10789

There is wide individual variability in the pharmacokinetics, pharmacodynamics, and tolerance to anticancer drugs within the same ethnic group and even greater variability among different ethnicities. Pharmacogenomics (PG) has the potential to provide personalized therapy based on individual genetic variability in an effort to maximize efficacy and reduce adverse effects. The benefits of PG include improved therapeutic index, improved dose regimen, and selection of optimal types of drug for an individual or set of individuals. Advanced or metastatic breast cancer is typically treated with single or multiple combinations of chemotherapy regimens including anthracyclines, taxanes, antimetabolites, alkylating agents, platinum drugs, vinca alkaloids, and others. In this review, the PG of breast cancer therapeutics, including tamoxifen, which is the most widely used therapeutic for the treatment of hormone-dependent breast cancer, is reviewed. The pharmacological activity of tamoxifen depends on its conversion by cytochrome P450 2D6 (CYP2D6) to its abundant active metabolite, endoxifen. Patients with reduced CYP2D6 activity, as a result of either their genotype or induction by the coadministration of other drugs that inhibit CYP2D6 function, produce little endoxifen and hence derive limited therapeutic benefit from tamoxifen; the same can be said about the different classes of therapeutics in breast cancer. PG studies of breast cancer therapeutics should provide patients with breast cancer with optimal and personalized therapy

Novel treatment strategies in triple-negative breast cancer: specific role of poly(adenosine diphosphate-ribose) polymerase inhibition

M William Audeh
Pharmacogenomics and Personalized Medicine 2014:7 307–316
http://dx.doi.org/10.2147/PGPM.S39765

Inhibitors of the poly(adenosine triphosphate-ribose) polymerase (PARP)-1 enzyme induce synthetic lethality in cancers with ineffective DNA (DNA) repair or homologous repair deficiency, and have shown promising clinical activity in cancers deficient in DNA repair due to germ-line mutation in BRCA1 and BRCA2. The majority of breast cancers arising in carriers of BRCA1 germ-line mutations, as well as half of those in BRCA2 carriers, are classified as triple-negative breast cancer (TNBC). TNBC is a biologically heterogeneous group of breast cancers characterized by the lack of immunohistochemical expression of the ER, PR, or HER2 proteins, and for which the current standard of care in systemic therapy is cytotoxic chemotherapy. Many “sporadic” cases of TNBC appear to have indicators of DNA repair dysfunction similar to those in BRCA-mutation carriers, suggesting the possible utility of PARP inhibitors in a subset of TNBC. Significant genetic heterogeneity has been observed within the TNBC cohort, creating challenges for interpretation of prior clinical trial data, and for the design of future clinical trials. Several PARP inhibitors are currently in clinical development in BRCA-mutated breast cancer. The use of PARP inhibitors in TNBC without BRCA mutation will require biomarkers that identify cancers with homologous repair deficiency in order to select patients likely to respond. Beyond mutations in the BRCA genes, dysfunction in other genes that interact with the homologous repair pathway may offer opportunities to induce synthetic lethality when combined with PARP inhibition.

Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways

Sarah R Hosford, Todd W Miller
Pharmacogenomics and Personalized Medicine 2014:7 203–215
http://dx.doi.org/10.2147/PGPM.S52762

Breast cancers expressing estrogen receptor α, progesterone receptor, or the human epidermal growth factor receptor 2 (HER2) proto-oncogene account for approximately 90% of cases, and treatment with antiestrogens and HER2-targeted agents has resulted in drastically improved survival in many of these patients. However, de novo or acquired resistance to antiestrogen and HER2-targeted therapies is common, and many tumors will recur or progress despite these treatments. Additionally, the remaining 10% of breast tumors are negative for estrogen receptor α, progesterone receptor, and HER2 (“triple-negative”), and a clinically proven tumor-specific drug target for this group has not yet been identified. Therefore, the identification of new therapeutic targets in breast cancer is of vital clinical importance. Preclinical studies elucidating the mechanisms driving resistance to standard therapies have identified promising targets including cyclin-dependent kinase 4/6, phosphoinositide 3-kinase, poly adenosine diphosphate–ribose polymerase, Src, and histone deacetylase. Herein, we discuss the clinical potential and status of new therapeutic targets in breast cancer.

Overview of diagnostic/targeted treatment combinations in personalized medicine for breast cancer patients

Anna Tessari, Dario Palmieri, Serena Di Cosimo
Pharmacogenomics and Personalized Medicine 2014:7 1–19
http://dx.doi.org/10.2147/PGPM.S53304

Breast cancer includes a body of molecularly distinct subgroups, characterized by different presentation, prognosis, and sensitivity to treatments. Significant advances in our understanding of the complex architecture of this pathology have been achieved in the last few decades, thanks to new biotechnologies that have recently come into the research field and the clinical practice, giving oncologists new instruments that are based on biomarkers and allowing them to set up a personalized approach for each individual patient. Here we review the main treatments available or in preclinical development, the biomolecular diagnostic and prognostic approaches that changed our perspective about breast cancer, giving an overview of targeted therapies that represent the current standard of care for these patients. Finally, we report some examples of how new technologies in clinical practice can set in motion the development of new drugs.

Human ABC transporter ABCG2/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer therapeutics

Kohji Noguchi, Kazuhiro Katayama, Yoshikazu Sugimoto
Pharmacogenomics and Personalized Medicine 2014:7 53–64
http://dx.doi.org/10.2147/PGPM.S38295

Adenosine triphosphate (ATP)-binding cassette (ABC) transporter proteins, such as ABCB1/P-glycoprotein (P-gp) and ABCG2/breast cancer resistance protein (BCRP), transport various structurally unrelated compounds out of cells. ABCG2/BCRP is referred to as a “half-type” ABC transporter, functioning as a homodimer, and transports anticancer agents such as irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), gefitinib, imatinib, methotrexate, and mitoxantrone from cells. The expression of ABCG2/BCRP can confer a multidrug-resistant phenotype on cancer cells and affect drug absorption, distribution, metabolism, and excretion in normal tissues, thus modulating the in vivo efficacy of chemotherapeutic agents. Clarification of the substrate preferences and structural relationships of ABCG2/BCRP is essential for our understanding of the molecular mechanisms underlying its effects in vivo during chemotherapy. Its single-nucleotide polymorphisms are also involved in determining the efficacy of chemotherapeutics, and those that reduce the functional activity of ABCG2/BCRP might be associated with unexpected adverse effects from normal doses of anticancer drugs that are ABCG2/BCRP substrates. Importantly, many recently developed molecular-targeted cancer drugs, such as the tyrosine kinase inhisbitors, imatinib mesylate, gefitinib, and others, can also interact with ABCG2/BCRP. Both functional single-nucleotide polymorphisms and inhibitory agents of ABCG2/BCRP modulate the in vivo pharmacokinetics and pharmacodynamics of these molecular cancer treatments, so the pharmacogenetics of ABCG2/BCRP is an important consideration in the application of molecular-targeted chemotherapies.

Bosutinib: a SRC–ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Fuad El Rassi, Hanna Jean Khoury
Pharmacogenomics and Personalized Medicine 2013:6 57–62
http://dx.doi.org/10.2147/PGPM.S32145

Bosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia. This review of bosutinib summarizes the mode of action, pharmacokinetics, efficacy and safety data, as well as the patient-focused perspective through quality-of-life data. Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia, especially in the chronic phase, with resistance or intolerance to prior tyrosine kinase inhibitors. Bosutinib has distinct but manageable adverse events. In the absence of T315I and V299L mutations, there are no absolute contraindications for the use of bosutinib in this patient population.

Toward precision medicine with next-generation EGFR inhibitors in non-small-cell lung cancer
Timothy A Yap, Sanjay Popat
Pharmacogenomics and Personalized Medicine 2014:7 285–295
http://dx.doi.org/10.2147/PGPM.S55339

The use of genomics to discover novel targets and biomarkers has placed the field of oncology at the forefront of precision medicine. First-generation epidermal growth factor receptor (EGFR) inhibitors have transformed the therapeutic landscape of EGFR mutant non-small-cell lung carcinoma through the genetic stratification of tumors from patients with this disease. Somatic EGFR mutations in lung adenocarcinoma are now well established as predictive biomarkers of response and resistance to small-molecule EGFR inhibitors. Despite early patient benefit, primary resistance and subsequent tumor progression to first-generation EGFR inhibitors are seen in 10%–30% of patients with EGFR mutant non-small-cell lung carcinoma. Acquired drug resistance is also inevitable, with patients developing disease progression after only 10–13 months of antitumor therapy. This review details strategies pursued in circumventing T790M-mediated drug resistance to EGFR inhibitors, which is the most common mechanism of acquired resistance, and focuses on the clinical development of second-generation EGFR inhibitors, exemplified by afatinib (BIBW2992). We discuss the rationale, mechanism of action, clinical efficacy, and toxicity profile of afatinib, including the LUX-Lung studies. We also discuss the emergence of third-generation irreversible mutant-selective inhibitors of EGFR and envision the future management of EGFR mutant lung adenocarcinoma.

ALK-driven tumors and targeted therapy: focus on crizotinib

Carlos Murga-Zamalloa, Megan S Lim
Pharmacogenomics and Personalized Medicine 2014:7 87–94
http://dx.doi.org/10.2147/PGPM.S37504

Receptor tyrosine kinases have emerged as promising therapeutic targets for a diverse set of tumors. Overactivation of the tyrosine kinase anaplastic lymphoma kinase (ALK) has been reported in several types of malignancies such as anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, neuroblastoma, and non-small-cell lung carcinoma. Further characterization of the molecular role of ALK has revealed an oncogenic signaling signature that results in tumor dependence on ALK. ALK-positive tumors display a different behavior than their ALK-negative counterparts; however, the specific role of ALK in some of these tumors remains to be elucidated. Although more studies are required to establish selective targeting of ALK as a definitive therapeutic option, initial trials have shown extraordinary results in the majority of cases.

Non-small-cell lung cancer: molecular targeted therapy and personalized medicine – drug resistance, mechanisms, and strategies

Marybeth Sechler, AD Cizmic, S Avasarala, M Van Scoyk, C Brzezinski, et al.
Pharmacogenomics and Personalized Medicine 2013:6 25–36
http://dx.doi.org/10.2147/PGPM.S26058

Targeted therapies for cancer bring the hope of specific treatment, providing high efficacy and in some cases lower toxicity than conventional treatment. Although targeted therapeutics have helped immensely in the treatment of several cancers, like chronic myelogenous leukemia, colon cancer, and breast cancer, the benefit of these agents in the treatment of lung cancer remains limited, in part due to the development of drug resistance. In this review, we discuss the mechanisms of drug resistance and the current strategies used to treat lung cancer. A better understanding of these drug-resistance mechanisms could potentially benefit from the development of a more robust personalized medicine approach for the treatment of lung cancer.

ERCC1 and XRCC1 as biomarkers for lung and head and neck cancer

Alec Vaezi, Chelsea H Feldman, Laura J Niedernhofer
Pharmacogenomics and Personalized Medicine 2011:4 47–63
http://dx.doi.org/10.2147/PGPM.S20317

Advanced stage non-small cell lung cancer and head and neck squamous cell carcinoma are both treated with DNA damaging agents including platinum-based compounds and radiation therapy. However, at least one quarter of all tumors are resistant or refractory to these genotoxic agents. Yet the agents are extremely toxic, leading to undesirable side effects with potentially no benefit. Alternative therapies exist, but currently there are no tools to predict whether the first-line genotoxic agents will work in any given patient. To maximize therapeutic success and limit unnecessary toxicity, emerging clinical trials aim to inform personalized treatments tailored to the biology of individual tumors. Worldwide, significant resources have been invested in identifying biomarkers for guiding the treatment of lung and head and neck cancer. DNA repair proteins of the nucleotide excision repair pathway (ERCC1) and of the base excision repair pathway (XRCC1), which are instrumental in clearing DNA damage caused by platinum drugs and radiation, have been extensively studied as potential biomarkers of clinical outcomes in lung and head and neck cancers. The results are complex and contradictory. Here we summarize the current status of single nucleotide polymorphisms, mRNA, and protein expression of ERCC1 and XRCC1 in relation
to cancer risk and patient outcomes.

Optimizing response to gefitinib in the treatment of non-small-cell lung cancer

Pietro Carotenuto, Cristin Roma, Anna Maria Rachiglio, Raffaella Pasquale, et al.
Pharmacogenomics and Personalized Medicine 2011:4 1–9
http://dx.doi.org:/10.2147/PGPM.S6626

The epidermal growth factor receptor (EGFR) is expressed in the majority of non-small-cell lung cancer (NSCLC). However, only a restricted subgroup of NSCLC patients respond to treatment with the EGFR tyrosine kinase inhibitor (EGFR TKI) gefitinib. Clinical trials have demonstrated that patients carrying activating mutations of the EGFR significantly benefit from treatment with gefitinib. In particular, mutations of the EGFR TK domain have been shown to increase the sensitivity of the EGFR to exogenous growth factors and, at the same time, to EGFR TKIs such as gefitinib. EGFR mutations are more frequent in patients with particular clinical and pathological features such as female sex, nonsmoker status, adenocarcinoma histology, and East Asian ethnicity. A close correlation was found between EGFR mutations and response to gefitinib in NSCLC patients. More importantly, randomized Phase III studies have shown the superiority of gefitinib compared with chemotherapy in EGFR mutant patients in the first-line setting. In addition, gefitinib showed a good toxicity profile with an incidence of adverse events that was significantly lower compared with chemotherapy. Therefore, gefitinib is a major breakthrough for the management of EGFR mutant NSCLC patients and represents the first step toward personalized treatment of NSCLC.

Pharmacogenomics of drug metabolizing enzymes and transporters: implications for cancer therapy

Jing Li, Martin H Bluth
Pharmacogenomics and Personalized Medicine 2011:4 11–33
http://dx.doi.org:/10.2147/PGPM.S18861

The new era of personalized medicine, which integrates the uniqueness of an Individual with respect to the pharmacokinetics and pharmacodynamics of a drug, holds promise as a means to provide greater safety and efficacy in drug design and development. Personalized medicine is particularly important in oncology, whereby most clinically used anticancer drugs have a narrow therapeutic window and exhibit a large interindividual pharmacokinetic and pharmacodynamics variability. This variability can be explained, at least in part, by genetic variations in the genes encoding drug metabolizing enzymes, transporters, or drug targets. Understanding of how genetic variations influence drug disposition and action could help in tailoring cancer therapy based on individual’s genetic makeup. This review focuses on the pharmacogenomics of drug metabolizing enzymes and drug transporters, with a particular highlight of examples whereby genetic variations in the metabolizing enzymes and transporters influence the pharmacokinetics and/or response of chemotherapeutic agents.

Transcriptome-wide signatures of tumor stage in kidney renal clear cell carcinoma: connecting copy number variation, methylation and transcription factor activity
Qi Liu, Pei-Fang Su, Shilin Zhao and Yu Shyr
Genome Medicine 2014, 6:117 http://genomemedicine.com/content/6/12/117

Background: Comparative analysis of expression profiles between early and late stage cancers can help to understand cancer progression and metastasis mechanisms and to predict the clinical aggressiveness of cancer. The observed stage-dependent expression changes can be explained by genetic and epigenetic alterations as well as transcription dysregulation. Unlike genetic and epigenetic alterations, however, activity changes of transcription factors, generally occurring at the post-transcriptional or post-translational level, are hard to detect and quantify.
Methods: Here we developed a statistical framework to infer the activity changes of transcription factors by simultaneously taking into account the contributions of genetic and epigenetic alterations to mRNA expression variations.
Results: Applied to kidney renal clear cell carcinoma (KIRC), the model underscored the role of methylation as a significant contributor to stage-dependent expression alterations and identified key transcription factors as potential drivers of cancer progression.
Conclusions: Integrating copy number, methylation, and transcription factor activity signatures to explain stage-dependent expression alterations presented a precise and comprehensive view on the underlying mechanisms during KIRC progression.

Developments in renal pharmacogenomics and applications in chronic kidney disease

Ariadna Padullés, Inés Rama, Inés Llaudó, Núria Lloberas
Pharmacogenomics and Personalized Medicine 2014:7 251–266
http://dx.doi.org/10.2147/PGPM.S52763

Chronic kidney disease (CKD) has shown an increasing prevalence in the last century. CKD encompasses a poor prognosis related to a remarkable number of comorbidities, and many patients suffer from this disease progression. Once the factors linked with CKD evolution are distinguished, it will be possible to provide and enhance a more intensive treatment to high-risk patients. In this review, we focus on the emerging markers that might be predictive or related to CKD progression physiopathology as well as those related to a different pattern of response to treatment, such as inhibitors of the renin–angiotensin system (including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers; the vitamin D receptor agonist; salt sensitivity hypertension; and progressive kidney-disease markers with identified genetic polymorphisms). Candidate-gene association studies and genome-wide association studies have analyzed the genetic basis for common renal diseases, including CKD and related factors such as diabetes and hypertension. This review will, in brief, consider genotype-based pharmacotherapy, risk prediction, drug target recognition, and personalized treatments, and will mainly focus on findings in CKD patients. An improved understanding will smooth the progress of switching from classical clinical medicine to gene-based medicine.

 

 

 

 

 

 

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Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases


Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases

Author and Curator: Larry H Bernstein, MD, FCAP

This introduction is to a thorough evaluation of a rich source of research literature on the genomic influences, which may have variable strength in the biological causation of atherosclerosis, microvascular disease, plaque formation, not necessarily having expressing, except in a multivariable context that includes the environment, dietary factors, level of emotional stress, sleep habits, and the daily activities of living for affected individuals.  The potential of genomics is carried in the DNA, copied to RNA, and this is most well studied in the micro RNAs (miRNA).  The miRNA has been explored for the appearance in the circulation of specific miRNAs that might be associated with myocyte or endothelial cell injury, and they are also being used as targets for therapeutics by the creation of silencing RNAs (siRNA).  The extent to which there is evidence of success in these studies is limited, but is being translated from animal studies to human disease.  There is also a long history of the measurement of  circulating enzymes and isoenzymes (alanine amino transferase, creatine kinase, and lactate dehydrogenase, not to leave out the adenylate kinase species specific to myocardium), and more recently the release of troponins I and T, and the so far still not fully explored ischemia modified albumin, or of miRNAs for the diagnosis of myocardial infarction.

There is also a significant disagreement about the value of measuring high sensitivity C reactive protein (hs-CRP), which has always been a marker for systemic inflammatory disease, in both chronic rheumatic and infectious diseases having a broad range, so that procalcitonin has appeared to be better for that situation, and for early diagnosis of sepsis. The hs-CRP has been too easily ignored because of

1. the ubiquitous elevations in the population
2. the expressed concerns that one might not be inclined to treat a mild elevation without other risk factors, such as, LDL cholesterolemia, low HDL, absent diabetes or obesity.  Nevertheless, hs-CRP raises an reasonable argument for preventive measures, and perhaps the use of a statin.

There has been a substantial amount of work on the relationship of obesity to both type 2 diabetes mellitus (T2DM) and to coronary vascular disease and stroke.  Here we bring in the relationship of the vascular endothelium, adipose tissue secretion of adiponectin, and platelet activation.  A whole generation of antiplatelet drugs addresses the mechanism of platelet activation, adhession, and interaction with endothelium.   Very interesting work has appeared on RESISTIN, that could bear some fruit in the treatment of both obesity and T2DM.

It is important to keep in mind that epigenomic gene rearrangements or substitutions occur throughout life, and they may have an expression late in life.  Some of the known epigenetic events occur with some frequency, but the associations are extremely difficult to pin down, as well as the strength of the association.  In a population that is not diverse, epigenetic changes are passed on in the population in the period of childbearing age.  The establishment of an epigenetic change is diluted in a diverse population.  There have been a number of studies with different findings of association between cardiovascular disease and genetic mutations in the Han and also in the Uyger Chinese populations, which are distinctly different populations that is not part of this discussion.

This should be sufficient to elicit broad appeal in reading this volume on cardiovascular diseases, and perhaps the entire series.  Below is a diagram of this volume in the series.

PART 1 – Genomics and Medicine
Introduction to Genomics and Medicine (Vol 3)
Genomics and Medicine: The Physician’s View
Ribozymes and RNA Machines
Genomics and Medicine: Genomics to CVD Diagnoses
Establishing a Patient-Centric View of Genomic Data
VIDEO:  Implementing Biomarker Programs ­ P Ridker PART 2 – Epigenetics – Modifiable
Factors Causing CVD
Diseases Etiology
   Environmental Contributors
Implicated as Causing CVD
   Diet: Solids and Fluid Intake
and Nutraceuticals
   Physical Activity and
Prevention of CVD
   Psychological Stress and
Mental Health: Risk for CVD
   Correlation between
Cancer and CVD
PART 3  Determinants of CVD – Genetics, Heredity and Genomics Discoveries
Introduction
    Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)
     Functional Characterization of CV Genomics: Disease Case Studies @ 2013 ASHG
     Leading DIAGNOSES of CVD covered in Circulation: CV Genetics, 3/2010 – 3/2013
     Commentary on Biomarkers for Genetics and Genomics of CVD
PART 4 Individualized Medicine Guided by Genetics and Genomics Discoveries
    Preventive Medicine: Cardiovascular Diseases
    Walking and Running: Similar Risk Reductions for Hypertension, Hypercholesterolemia,
DM, and possibly CAD
https://pharmaceuticalintelligence.com/2013/04/04/walking-and-running-similar-risk-reductions-for-hypertension-hypercholesterolemia-dm-and-possibly-cad/
    Prevention of Type 2 Diabetes: Is Bariatric Surgery the Solution?
https://pharmaceuticalintelligence.com/2012/08/23/prevention-of-type-2-diabetes-is-bariatric-surgery-the-solution/
Gene-Therapy for CVD
Congenital Heart Disease/Defects
   Medical Etiologies: EBM – LEADING DIAGNOSES, Risks Pharmacogenomics for Cardio-
vascular Diseases
   Signaling Pathways     Response to Rosuvastatin in
Patients With Acute Myocardial Infarction:
Hepatic Metabolism and Transporter Gene
Variants Effect
https://pharmaceuticalintelligence.com/2014/
01/02/response-to-rosuvastatin-in-patients-
with-acute-myocardial-infarction-hepatic-
metabolism-and-transporter-gene-variants-effect/
   Proteomics and Metabolomics      Voltage-Gated Calcium Channel and Pharmaco-
genetic Association with Adverse Cardiovascular
Outcomes: Hypertension Treatment with Verapamil
SR (CCB) vs Atenolol (BB) or Trandolapril (ACE)
https://pharmaceuticalintelligence.com/2014/01/02/
voltage-gated-calcium-channel-and-pharmacogenetic-
association-with-adverse-cardiovascular-outcomes-
hypertension-treatment-with-verapamil-sr-ccb-vs-
atenolol-bb-or-trandolapril-ace/
      SNPs in apoE are found to influence statin response
significantly. Less frequent variants in
PCSK9 and smaller effect sizes in SNPs in HMGCR
https://pharmaceuticalintelligence.com/2014/01/02/snps-in-apoe-are-found-to-influence-statin-response-significantly-less-frequent-variants-in-pcsk9-and-smaller-effect-sizes-in-snps-in-hmgcr/

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How Might Sleep Apnea Lead to Serious Health Concerns like Cardiac and Cancer?

Author: Larry H Bernstein, MD, FCAP  

What is the link between sleep apnea and cardiovascular disease and is the treatment of obstructive sleep apnea (OSA) by continuous positive airway pressure in patients (CPAP) with heart failure to improve left ventricular systolic function sufficient?  There are statistics incicating the benefit of CPAP and improvement of LVSF in those patients on CPAP with CHF.  But that observation does not get at why the patients benefit, or whether the OSA is sufficient.  Don’t expect a randomized clinical trial of any design to be brought to bear on the subject, considering the ethical issues involved.  We’ll return to that in a moment.
In a recent study researchers in Spain followed thousands of patients at sleep clinics and found that those with the most severe forms of sleep apnea had a 65 percent greater risk of developing cancer of any kind. The second study, of about 1,500 government workers in Wisconsin, showed that those with the most disordered sleep had five times the rate of dying from cancer as people without the sleep disorder (apnea not specified). Both research teams only looked at cancer diagnoses and outcomes in general.  If I lump the two studies, assuming that all patients with the most disordered sleep had OSA and were on CPAP, what does this tell us?  The heart and lung function together as a cardiopulmonary oxygenation unit!  A problem disrupting oxygenation, such as autonomically controlled sleep disruption or, oronasal obstruction (ASSOCIATED WITH SNORING), would be expected to have an effect on alertness during the day, predisposition to CHF from strain on the CP circulation as well as ventilatory impairment and peripheral oxygenation.  It appears that an association with ANY cancer, unspecified, is a long reach.
In both studies the researchers ruled out the possibility that the usual risk factors for cancer, like
  1. age
  2. smoking
  3. alcohol use
  4. physical activity
  5. weight
The association between cancer and disordered breathing at night remained
  • even after they adjusted for confounding variables.
This led to the conclusion that cancer might be linked to (intermittent) lack of oxygen supply interrupting aerobic cell activity over long periods of time.  The conclusion is drawn that from two associations
  • the research on positive outcome from CPAP in OSA and
  • a possible link between breathing and cardiac and cancer clearly
demonstrates the importance of regular breathing exercises (other wise known as ‘Pranayama’ in India) as part of our every day life.
This answers the first observation I posed. That is, the use of CPAP, while enormously important, is not sufficient.  Regular breathing exercises would seem to be helpful, although not a standard part of current treatment. This would be especially important if the movement of the abdominal muscles and diaphragm were synchronized with the expansion of the nthorax for maximum air flow.  This observation is familiar from working with a certified exercise physiologist.   The other part of this is an optimum time for walking and carrying out basic muscle and flexibility exercises several times a week, which has been shown repeatedly by studies on health benefits.
It is not my place to raise some questions about the way the studies were carried out.  The patients who have sleep apnea would be expected to have an increased body mass index (BMI), and while not sarcopenic, more likely to have excess body fat, abdominal distribution in males, and hip distribution in females, amd more importantly, unseen fat in the abdominal peritoneum.  This is related to type 2 diabetes with a metabolic syndrome, a separate indicator of CVD risk.   The metabolic syndrome involves TNF-alpha (once also known as cachexin), IL-1, IL-6, C-reactive protein, and in the case of fat signaling, adipokines, as well as insulin resistance and, as a result, some counter-regulatory secretion of glucocorticosteroids.  This metabolic picture would result in the following:
  1. impaired glucose utilization
  2. some excess and uncompensated gluconeogenesis
  3. the impaired lactate reentry at the end of glycolysis
  4. an effect on allosteric PFK
Features 1-4 look like what Warburg called a Pasteur Effect, not at the clellular level, but in the whole individual.   While obesity and type 2 diabetes are occuring in the young and adolescent population, the consequences might not be seen until years later.  The consequences could be in a middle aged person falling asleep at a meeting, or a series of automabile accidents related to falling asleep at the wheel.
At a time that clinical laboratory measurements are so accurate, and
  • the associations between type 2 diabetes,
  • measurement of wt/ht^2,
  • arm strength,
  • skin fold thickness,

are common measures of fitness, they don’t appear to have any place in these studies. If that is the case, then how is it possible to make sense of a relationship between SEVERITY of sleep disturbance and health outcome.

English: The Cycle of Obstructive Sleep Apnea ...

English: The Cycle of Obstructive Sleep Apnea – OSA (Photo credit: Wikipedia)

English: The graph shows the correlation betwe...

English: The graph shows the correlation between body mass index (BMI) and percent body fat (%BF) for men in NCHS’ NHANES III 1994 data. The body fat percent shown uses the method from Romero-Corral et al. to convert NHANES BIA to %BF (June 2008). “Accuracy of body mass index in diagnosing obesity in the adult general population”. International Journal of Obesity 32 (6) : 959–956. DOI:10.1038/ijo.2008.11. PMID 18283284. (Photo credit: Wikipedia)

English: Body mass index, BMI, body size, body...

English: Body mass index, BMI, body size, body weight, mortality Italiano: indice di massa corporea, IMC, altezza corporea, peso corporeo, mortalità (Photo credit: Wikipedia)

Italiano: biometria, epidemiologia, rischio, p...

Italiano: biometria, epidemiologia, rischio, peso corporeo umano, mortalità, indice di massa corporea, IMC, body mass index, BMI, prospective studies collaboration (Photo credit: Wikipedia)

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