Keeping your finger on the pulse Personalized Medicine potx

Individualized Therapy for Type 2 Diabetes: Clinical Implications of Pharmacogenetic Data 6 How to download free content 7 ESMO Meeting Report 13 Personalized Medicine News Lower Tox

Keeping your finger

on the pulse

Personalized Medicine

eNewsletter

Welcome to issue 5 of Adis in-touch Personalized Medicine

We must first apologize for the delay in sending you this issue but we have all

been very busy getting our journal content ready to appear on Springer’s new

platform You will be hearing more from us about this very soon

In this bumper issue Michelle Wilde, Commissioning Editor for Oncology at Adis,

reports back from the ESMO congress which took place in Vienna last month with

record numbers of attendees We also bring you an update on industry news as

well as an overview of recently published and upcoming relevant content from

Adis journals

As always, we are keen to hear your feedback and suggestions for future issues, so

please get in touch and share your thoughts!

Individualized Therapy for Type 2 Diabetes: Clinical Implications of Pharmacogenetic Data

6 How to download free content

7 ESMO Meeting Report

13 Personalized Medicine News

Lower Toxicity with Targeted Anticancer Agents in Phase I Trials

Antipsychotic-Associated Weight Gain: Genetic Link Identified

PARP Inhibitors: Mechanism of Action and Their Potential Role in the Prevention and Treatment of Cancer Genetic Interaction between NAT2, GSTM1, GSTT1, CYP2E1, and Environmental Factors is Associated with Adverse Reactions to Anti-Tuberculosis Drugs Influence of an Interaction between Lithium Salts and a Functional Polymorphism in SLC1A2 on the History of Illness in Bipolar Disorder

Cost Effectiveness of Genetic Testing for CYP2C19 Variants

to Guide Thienopyridine Treatment in Patients with Acute Coronary Syndromes

19 Articles coming soon

20 Upcoming Events

21 Opportunity to Publish

Jamie relocated to New Zealand in 2007 and joined Adis as a medical writer in the

Periodicals Writing Group

In total, he has authored almost 90

peer-reviewed publications both

as a researcher and medical writer

Jamie joined the Commissioning

Services Group at Adis in 2012 and

is now the Editor for BioDrugs and

Molecular Diagnosis & Therapy.

Adis welcomes Jamie Croxtall, the new Editor of

BioDrugs and Molecular Diagnosis & Therapy

Download our FREE

Glossary of terms used in Diabetes

and Genetics &

Polymorphisms of Estrogen Receptors and Risk of Depression:

Therapeutic Implications

Ryan, J and Ancelin, M.; Drugs 72(13):1725-1738, September 10, 2012.

Accumulating evidence suggests the involvement of estrogen in depression

Estrogen can modulate neurotransmitter turnover, enhancing the levels

of serotonin and noradrenaline (norepinephrine), and it is involved in

the regulation of serotonin receptor number and function Across the

female reproductive life, fluctuating estrogen levels and low levels have

been associated with depressed mood, and there is strong support for a

beneficial effect of estrogen-containing hormone treatment in depressed

peri-menopausal women Estrogen exerts its biological effects in large part

through intracellular activation of its principal receptors, estrogen receptor

α (ESR1) and estrogen receptor β (ESR2) Genetic variation in the estrogen

receptors may therefore modify estrogen signalling, thus influencing a

woman’s susceptibility to developing depression This review provides a

synthesis of studies that have examined the association between estrogen

receptor polymorphisms and depression-related mood disorders across the

lifetime The studies conducted to date have produced inconsistent findings,

which likely relates to the large heterogeneity in terms of the populations,

study design and depression measures used If it is confirmed that specific

estrogen receptor polymorphisms are associated with the risk of depression,

this could have important preventive and therapeutic implications, with the

potential to develop targeted estrogen receptor agonists and antagonists

Furthermore, it is possible that such therapies may be more effective in

treating particular people with depression based on their genetic profile,

which is an exciting prospect given that many people do not respond to

current antidepressant treatments

Molecular Characterization of Head and Neck Cancer: How Close to Personalized Targeted Therapy?

Worsham, M J., Ali, H., Dragovic, J and Schweitzer, V P.; Molecular Diagnosis & Therapy 16(4):209-222, August 1, 2012.

Molecular targeted therapy in head and neck squamous cell carcinoma (HNSCC) continues to make strides, and holds much promise Cetuximab remains the sole US FDA-approved molecular targeted therapy available for HNSCC, though several new biologic agents targeting the epidermal growth factor receptor (EGFR) and other pathways are currently in the regulatory approval pipeline While targeted therapies have the potential

to be personalized, their current use in HNSCC is not personalized This

is illustrated for EGFR-targeted drugs, where EGFR as a molecular target has yet to be individualized for HNSCC Future research needs to identify factors that correlate with response (or lack of one) and the underlying genotype–phenotype relationship that dictates this response Comprehensive exploration of genetic and epigenetic landscapes in HNSCC is opening new frontiers to further enlighten and mechanistically inform newer as well as existing molecular targets, and to set a course for eventually translating these discoveries into therapies for patients This opinion offers a snapshot

of the evolution of molecular subtyping in HNSCC and its current clinical applicability, as well as new emergent paradigms with implications for controlling this disease in the future

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Individualized Therapy for Gastroesophageal Reflux Disease:

Potential Impact of Pharmacogenetic Testing based on

CYP2C19

Furuta, T., Sugimoto, M and Shirai, N.; Molecular Diagnosis & Therapy 16(4):223-234,

August 1, 2012.

The main therapeutic agent for gastroesophageal reflux disease (GERD) is

a proton pump inhibitor (PPI) Plasma levels and the acid inhibitory effect

of PPIs depend on the activity of cytochrome P450 (CYP) 2C19, which is

polymorphic Genotypes of CYP2C19 are classified into three groups: rapid

metabolizers (RMs: *1/*1), intermediate metabolizers (IMs: *1/*X), and poor

metabolizers (PMs: *X/*X), where *1 and X represent the wild type and the

mutant allele, respectively RMs include ultra-rapid metabolizers, who possess

the CYP2C19*17 allele The pharmacokinetics and pharmacodynamics of

PPIs differ among different CYP2C19 genotype groups Plasma PPI levels

and intragastric pH values during PPI treatment are lowest in the RM

group, intermediate in the IM group, and highest in the PM group These

CYP2C19-genotype-dependent differences in the pharmacokinetics and

pharmacodynamics of PPIs influence the healing and recurrence of GERD

during PPI treatment, suggesting the need for CYP2C19 genotype-based

tailored therapy for GERD CYP2C19 pharmacogenetics should be taken into

consideration for the personalization of PPI-based therapy However, the

clinical usefulness of CYP2C19 genotype testing in GERD therapy should be

verified in clinical studies

Individualized Therapy for Type 2 Diabetes: Clinical Implications of Pharmacogenetic Data

Mannino, G C and Sesti, G.; Molecular Diagnosis & Therapy 16(5):285-302, October 1, 2012.

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, abnormally elevated hepatic glucose production, and reduced glucose-stimulated insulin secretion Treatment with antihyperglycemic agents is initially successful in type 2 diabetes, but it is often associated with a high secondary failure rate, and the addition of insulin is eventually necessary for many patients, in order to restore acceptable glycemic control and to reduce the risk of development and progression of disease complications

Notably, even patients who appear to have similar requirements of antidiabetic regimens show great variability in drug disposition, glycemic response, tolerability, and incidence of adverse effects during treatment

Pharmacogenomics is a promising area of investigation and involves the search for genetic polymorphisms that may explain the interindividual variability in antidiabetic therapy response The initial positive results portend that genomic efforts will be able to shed important light on variability in pharmacologic traits This review summarizes the current understanding of genetic polymorphisms that may affect the responses of subjects with T2DM

to antidiabetic treatment These genes belong to three major classes: genes involved in drug metabolism and transporters that influence pharmacokinetics (including the CYP superfamily and the OATP and OCT families); genes encoding drug targets and receptors (including PPARG, KATP, and incretin receptors); and genes involved in the causal pathway of T2DM that are able

to modify the effects of drugs (including adipokines, TCF7L2, IRS1, NOS1AP, and SLC30A8) In addition to these three major classes, available evidence

is reviewed for novel genes that have recently been proposed as possible modulators of therapeutic response in T2DM

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Meeting Report

The conference was hugely exciting, over 16,000 delegates attended with

2,000 abstracts presented that included data from more than 100,000

patients who had participated in well-designed clinical trials

Targeted therapies continue to be central to the move towards personalized

treatment of cancer patients In fact, it is increasingly apparent that we are

now entering a very important period of tumor sequencing and stratifying

in oncology This is being achieved through a more detailed classification

of tumor subtypes, through individualized genome profiling to identify the

presence of genetic alterations unique to a particular patient’s tumor and

quantification of gene expression (DNA and RNA and protein analysis) to

identify key oncogenic drivers The aim of this “precision medicine” is to

improve patient selection or, in other words, identify those patients who

are most likely to respond to a particular therapy

Dr Douglas Hanahan (Lausanne, Switzerland) gave an excellent keynote presentation on recent perspectives on the acquired hallmark capabilities

of cancer and implications for targeted therapies In addition to genetic and epigenetic changes in cancer cells, stromal cells in the tumor micro-environment also contribute to the hallmark capabilities Although we have drugs that target all of the hallmarks of cancer, targeting an individual hallmark is not very effective `Hallmark multi-targeting’ is required.Unfortunately, development of resistance to targeted therapy is currently the rule A wide range of adaptive resistance mechanisms can develop, including hallmark switching and activation of alternative pathways

A Report from the European Society

of Medical Oncology (ESMO)

Vienna, Austria, 28 Sept- 2 Oct, 2012

Michelle Wilde,

Oncology Commissioning Editor,

Adis Journals

Meeting Report - continued

Heterogeneity, in both inter- and intra-patient characteristics and tumor

genetics, was a big theme at this year’s ESMO congress The need for

accurate genomic characterization of tumors is essential for tailoring

treatment, determining resistance mechanisms, and for biomarker and

drug development Using single tumor biopsy samples is not sufficient

There was much discussion on how we deal with this in the clinic Current

thinking included the use of one drug that blocks many pathways,

combination therapy to block many targets, destroying resistant clones

before they develop, and optimising treatment duration to avoid

cultivating resistance

Central to this is the critical and difficult task of target/biomarker

identification, reproducibility and validation We need more predictive

biomarkers, biomarker-driven studies to assess combination therapies, and

comparisons of methods for diagnosis Biomarker-dependent therapy and

biomarker-guided patient selection is the way forward Multiple/composite

biomarkers will be increasingly needed to assess new generations of drugs

Bidirectional molecular data sharing will be key, and the availability of

results from negative studies is important for retrospective identification

of subpopulations likely to benefit

There were a number of indications for which actual and potential changing results were presented Some of these are detailed below

practice-Melanoma

Dr Keith T Flaherty (Boston, USA) explained that there is a wide range

of resistance mechanisms with BRAF inhibitors Although we have a

`druggable’ molecular alteration in melanoma (BRAF V600 mutation),

BRAF inhibitors have a limited duration of efficacy because the tumors upregulate other pathways, and MAPK reactivation is common Current evidence suggests that combination targeted therapy, rather than second-line therapy, could be the optimal approach to overcoming or delaying the development of resistance There are a wide range of BRAF inhibitor-containing combination therapies currently being investigated

Meeting Report - continued

Of particular excitement was the dual-therapy study in BRAF V600E

mutation-positive metastatic melanoma, reported by Dr Georgina Long

(Melanoma Institute Australia, and Westmead Hospital, University of

Sydney, Australia) The combination of dabrafenib 150mg twice daily

(an inhibitor of BRAF V600 mutations) and tremetinib 2mg once daily (a

selective MEK inhibitor) significantly increased progression-free survival

(PFS) [median 9.4 mo vs 5.8 mo; HR 0.39, 95% CI 0.25-0.62, p<0.0001]

and the confirmed response rate (76 vs 54%; p=0.03) compared with

dabrafenib monotherapy, and the duration of response was longer

with combination therapy (median 10.5 vs 5.6 mo) The 12-month

overall survival (OS) was 79% with the combination (crossover to the

combination was allowed on progression); however, the median OS had

not been reached.[1] Importantly, the incidence of hyperproliferative skin

lesions was lower with combination therapy; the incidence and severity of

pyrexia was greater, but this was manageable This combination is the first

kinase-kinase combination to show benefit in melanoma

Another possible future BRAF/MEK inhibitor combination could be

vemurafenib (BRAF inhibitor) plus GDC-0973 (MEK inhibitor)[2] Professor

Rene Gonzalez (Division of Medical Oncology, University of Colorado,

Aurora, USA) presented results from the BRIM7 study, a phase I dose

escalation trial of patients with unresectable or metastatic BRAF

V600-mutated melanoma The combination was tolerable with adverse events

being manageable Although tumor size reduction was reported, further

study is required

Lung cancer

We clearly know that lung cancer is not a single disease entity It remains important to first determine the histology of nonsmall-cell lung cancer (NSCLC), followed by identification of genetic mutations Excellent keynote presentations on the molecular characterization of lung cancer in multiple different diseases were given Professor Jean-Charles Soria (Institute Gustave Roussy, Villejuif, France) explained that molecular abnormalities that could allow the identification of new molecular subtypes of NSCLC and potential targets for the development of therapeutic agents have

been identified in many genes, in addition to the known EGFR (mutations) and ALK (translocations); these include FGFR1 and HER2 (amplifications), and ROS and RET (translocations), among many others Professor Soria

emphasised that for optimal management of patients with NSCLC and development of targeted therapies, characterization of the genomic changes that drive an individual patient’s disease is critical

At the same keynote, Dr Jeffrey Engelman (Massachusetts General Hospital, Charlestown, MA, USA) spoke about the evolution of lung cancers upon treatment with targeted therapies Development of resistance is the rule; the duration of response is months not years Dr Engelman explained that resistance may develop because of alterations in the gene target or amplification of the gene itself; bypass track resistance; or continuation

of proliferation despite the signalling pathway being inhibited While

we do not know how to overcome this, current and potential strategies include the use of combination therapies, pulsatile treatment and varying regimens; killing resistant clones before they develop; and stopping

treatment before resistance is cultivated An added complication is that,

in the case of EGFR mutations, these mutations can also be seen in

the resistant biopsy Furthermore, EGFR-resistant adenocarcinoma can

become small cell lung cancer We do not yet know why this is happening,

although epithelial-mesenchymal transition (EMT) is seen in many cancers

that acquire resistance

Both `microscopic’ and `macroscopic’ heterogeneity may also explain

clinical observations in NSCLC For example, cancers that progress on

EGFR inhibitor therapy will often flare when the inhibitor is discontinued;

it may be that we are selecting for a different clone of the cancer rather than the cancer histology changing Furthermore, different parts of a lesion can have different histologies, and there can be different resistance mechanisms within a sample Instead of repeat biopsies, other approaches such as serial monitoring of circulating tumor cells (CTCs), and monitoring for KRAS mutations in the serum may be more useful

We now have several targeted drugs for molecularly defined subsets of patients with NSCLC The most recent development is crizotinib, which

is now the standard of care for previously treated patients with advanced anaplastic lymphoma kinase-positive (ALK+) NSCLC As presented by

Dr Alice Shaw (Massachusetts General Hospital Cancer Center, Boston,

MA, USA), the phase III Profile 1007 study showed crizotinib to be significantly superior to standard second-line chemotherapy (pemetrexed

or docetaxel) in increasing the primary endpoint, PFS (median 7.7 mo vs

3 mo; HR 0.49; 95% CI 0.37-0.64, p<0.0001), as well as the secondary endpoint, objective response rate (65 vs 20%; p<0.0001), in patients with advanced ALK+ NSCLC who had received one previous platinum-based regimen.[3] Patient-reported outcomes based on lung cancer symptoms revealed significantly improved quality of life (QOL) with crizotinib Interim analysis of OS showed no statistically significant difference but data are immature and significant crossover occurred in the study There was a similar incidence of grade 3 and 4 treatment-related adverse events

As with all targeted therapies, patients develop resistance to crizotinib There are several ongoing trials of second-generation ALK inhibitors including AP26113

Meeting Report - continued