1 News, views, and events - straight to your inbox ISSUE 5 Keeping your finger on the pulse Personalized Medicine eNewsletter 2 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! Enjoy! The Adis in-touch team PersonalizedMed@adis.com Welcome Contents 3 Announcement 4 Featured Content Polymorphisms of Estrogen Receptors and Risk of Depression: Therapeutic Implications Molecular Characterization of Head and Neck Cancer: How Close to Personalized Targeted Therapy? Individualized Therapy for Gastroesophageal Reflux Disease: Potential Impact of Pharmacogenetic Testing based on CYP2C19 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 3 Announcement Jamie, originally from the UK, completed his PhD in Biochemistry at the University of Strathclyde in Glasgow in 1985. This was followed by a five-year stint at the Royal Post Graduate Medical School, London working on the hormonal control of gynaecological malignancies and other reproductive pathologies. In 1990, he joined the newly established William Harvey Research Institute at St. Bartholomew’s Hospital, London working on many aspects of cell signalling processes underlying tumour cell proliferation and inflammatory and cardiovascular diseases. 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 & Genomics Diabetes: http://bit.ly/DiabetesAdis Genetics & Genomics: http://bit.ly/GeneticsAdis 4 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. Featured Content Download any of the featured content for free before December 10th 2012 - Click on the links above and enter the voucher code 5F54NU during checkout to redeem this offer. 5 Featured Content Download any of the featured content for free before December 10th 2012 - Click on the links above and enter the voucher code 5F54NU during checkout to redeem this offer. 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. Adis in-touch is a free eNewsletter sent by email quarterly to all registered users. If you haven’t already signed-up to receive the eNewsletter from Adis, register now to make sure you receive future issues direct to your inbox. To sign-up, all you need to do is send us an email at: personalizedmed@adis.com quoting PM5. Register Now to keep your finger on the pulse 6 1. Click on one of the article titles on page 4 or 5 of this brochure to go through to the content page on AdisOnline.com 2. Click on the yellow ‘Buy This Article’ button on the right-hand column 3. Login to your existing AdisOnline. com account or register your details if you are a first-time user 4. When prompted, enter the voucher code 5F54NU into the dark grey box and click the button to check the code is valid. 5. Once the voucher has been validated, click to add this to the basket and complete the checkout process. How to download an article for free from our Featured Content 7 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 8 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 practice- changing results were presented. Some of these are detailed below. 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. 9 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 10 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 [...]... accompanying editorial, noting the difference between toxicity patterns involved in phase I trials of targeted agents and those of conventional chemotherapy drugs, comments that these studies highlight the need for the continued evolution of the design of phase I trials to meet the challenges encountered in the era of MTAs and personalized medicine. [3] The authors suggest that, due to the increasing number... available As further confirmation of the usefulness of prolonged VEGF inhibition, Dr Grothey reviewed the data on aflibercept, a soluble fusion protein and novel VEGF receptor antagonist This agent was recently approved by the US FDA as a treatment option in combination with FOLFIRI for patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen References 1 Long GV, Sosman... 0.0062) compared with second-line chemotherapy alone in patients with disease progression who had received bevacizumab as part of firstline therapy.[8] Dr Gianluca Masi (University Hospital of Pisa, Italy), who presented the results of this phase III trial, concluded that the continuation of bevacizumab in combination with second-line chemotherapy represents a new treatment option for these patients Mature... specific challenges to long-term administration of these drugs will need to be addressed Development of robust predictive biomarkers of response for optimal patient selection and rational combination strategies must be pursued if the full potential of these agents is to be realized Basu B, Sandhu SK, de Bono JS PARP inhibitors: mechanism of action and their potential role in the prevention and treatment of... reporting the highest number, and heterozygotes showing an intermediate phenotype The study confirmed the efficacy of lithium treatment in reducing the recurrence of illness in BD, and found an interaction between lithium treatment and the SLC1A2 −181A>C genotype, confirming previous studies reporting an interaction between lithium salts and the glutamatergic system 17 Personalized Medicine News - continued... approved by the US FDA in September 2012 as a monotherapy for patients with metastatic colorectal cancer who progressed with current standard therapies Other developments for patients with progressive metastatic colorectal cancer include continuation of treatment with bevacizumab beyond progression, and aflibercept, an antiangiogenic agent Continuation of bevacizumab administered with second-line chemotherapy... Institute, Boston, USA) and Xavier Pivot (Besancon, France), respectively In the HERA trial, there was no evidence of long term benefit in terms of disease-free survival (DFS) or OS of 2 versus 1y of trastuzumab administration The primary cardiac endpoint was similar in both groups but the secondary cardiac endpoint was higher in the 2 year arm In the PHARE study, noninferiority for DFS with 6 months’ treatment... Changing the Screening Paradigm? A 19 Upcoming Events Molecular Biotechnology and Bioinformatics Workshop November 19 – 23, 2012 Pune, India Pathogen Safety Summit 2012 November 26 – 28, 2012 Munich, Germany Diabetes, Cardiovascular & Renal Complications November 28 – 29, 2012 London, UK 8th Annual Personalized Medicine Conference November 28 – 29, 2012 Boston, MA, USA IDIBELL Cancer Conference on Personalized. .. and careful monitoring of patients at high risk of this complication Costa GNO, Magno LAV, Santana CVN, et al Genetic interaction between NAT2, GSTM1, GSTT1, CYP2E1, and environmental factors is associated with adverse reactions to antituberculosis drugs Mol Diagn Ther 2012; 16 (4): 241-250 Personalized Medicine News - continued Influence of an Interaction between Lithium Salts and a Functional Polymorphism... from these agents In an endeavour to enhance anti-tumour effects, PARP inhibitors have been combined with traditional cytotoxic therapy and radiotherapy; however, optimization of dosing schedules for these combination regimens remains key to maximizing benefit whilst mitigating the potential for increased toxicity With ongoing clinical experience of PARP inhibition, mechanisms of resistance to these therapies . straight to your inbox ISSUE 5 Keeping your finger on the pulse Personalized Medicine eNewsletter 2 Welcome to issue 5 of Adis in-touch Personalized Medicine. . to the content page on AdisOnline.com 2. Click on the yellow ‘Buy This Article’ button on the right-hand column 3. Login to your existing AdisOnline. com