Personalized Cancer Medicine Research Articles

Cancer biomarkers and personalized cancer medicine.

The development of cancer biomarkers has brought the treatment of cancer from the tumor type-based to molecular target-based,and the latter marks the introduction of personalized cancer medicine (PCM). However,each individual tumor has unique molecular information,and the real PCM should be focused on single individuals and their specific molecular identities.

Advances in the treatment of castration-resistant prostate cancer: emphasis in new hormonal therapies

Prostate cancer represents the second cancer-related cause of death in North American and Chilean men. The main treatment for incurable stages of disease is surgical or pharmacological castration. However, with time and despite the addition of anti-androgens, the disease progresses to a clinical state that has been commonly referred to as “hormone refractory”. In recent years, the concept of hormone refractoriness has been challenged and replaced by “castration resistance”, acknowledging that further and optimal hormonal manipulation can be attained, beyond achieving testosterone levels at castration range. The purpose of this review is to summarize the recent therapeutic breakthroughs in the management of metastatic castrate resistant prostate cancer (mCRPC), with greater emphasis in the newer hormonal therapy agents such as Abiraterone and Enzalutamide. Future combination and sequential treatment strategies are contextualized in the current era of personalized cancer medicine and genomic characterization of prostate cancer.

Routine multiplexed mutational analysis of colorectal cancers (CRCs): A single-institution experience.

599 Background: Colorectal tumors harbor mutations in genes that play key roles in CRC carcinogenesis and that may enable prioritization of appropriate anti-cancer therapy. KRAS testing is part of standard of care testing prior to initiation of anti-epidermal growth factor receptor antibodies. Other mutations are emerging as significant drivers, but they are not yet part of routine screening. Methods: As part of Vanderbilt-Ingram Cancer Center’s Personalized Cancer Medicine Initiative, we developed a clinical algorithm to genotype patient’s colorectal tumors using a SNaPshot-based assay (multiplexed PCR, primer extension, and capillary electrophoresis) designed to detect 65 somatic mutations in 7 genes (KRAS, BRAF, AKT1, PIK3CA, SMAD4, PTEN, and NRAS) important in CRC carcinogenesis. Adult patients with metastatic CRC were consented for genotyping of tumor tissue. Mutational profiling was performed in Vanderbilt’s CLIA-certified Molecular Diagnostics Laboratory. Results were reported in the electronic medical record for clinical use. Results: Study enrolled from May 2012 to February 2014. SNaPshot results were available from 126 patients. 49 tumors (38.9%) were wildtype for all mutations tested. 58 (46.0%) tumors had a KRAS mutation, including one with two KRAS mutations; the most common was G12D (n=23), but two had a Q61H mutation and two had a K117N mutation, which are not included in some commercial KRAS tests. Ten (8.9%) tumors carried the V600E BRAF mutation. Nine (7.1%) tumors harbored a PIK3CA mutation. Three (2.4%) tumors had mutations in SMAD4. Four (3.2%) tumors had a NRAS mutation. One (0.8%) tumor had a PTEN mutation. Nine (7.1%) tumors harbored double mutations, the most common being KRAS and PIK3CA double mutations (N=6). 24 (19%) subjects subsequently were treated on clinical trial therapy, including 6 subjects on therapy based on the SNaPshot results. Not surprisingly, RAS results impacted use of anti-EGFR therapy. Conclusions: 61% of the tumors carried at least one mutation in the seven genes tested, suggesting that trials of tumor genotyping-based treatment assignment are feasible. Study was supported by Vanderbilt University Medical Center.

Analysis of individual protein regions provides novel insights on cancer pharmacogenomics.

The promise of personalized cancer medicine cannot be fulfilled until we gain better understanding of the connections between the genomic makeup of a patient's tumor and its response to anticancer drugs. Several datasets that include both pharmacologic profiles of cancer cell lines as well as their genomic alterations have been recently developed and extensively analyzed. However, most analyses of these datasets assume that mutations in a gene will have the same consequences regardless of their location. While this assumption might be correct in some cases, such analyses may miss subtler, yet still relevant, effects mediated by mutations in specific protein regions. Here we study such perturbations by separating effects of mutations in different protein functional regions (PFRs), including protein domains and intrinsically disordered regions. Using this approach, we have been able to identify 171 novel associations between mutations in specific PFRs and changes in the activity of 24 drugs that couldn't be recovered by traditional gene-centric analyses. Our results demonstrate how focusing on individual protein regions can provide novel insights into the mechanisms underlying the drug sensitivity of cancer cell lines. Moreover, while these new correlations are identified using only data from cancer cell lines, we have been able to validate some of our predictions using data from actual cancer patients. Our findings highlight how gene-centric experiments (such as systematic knock-out or silencing of individual genes) are missing relevant effects mediated by perturbations of specific protein regions. All the associations described here are available from http://www.cancer3d.org.

Personalized cancer medicine: present status and future perspectives

결핵은 결핵균에 의하여 발생하는 질환이다. 따라서, 진단 은 결핵균을 증명하거나 결핵균에 의해 손상된 조직소견을 확인하면 된다. 치료도 결핵균을 죽일 수 있는 항균제를 사 용하면 대부분 해결된다. 암이라는 진단은 결핵과 다르다. 우리나라에 흔한 ‘위암’의 경우, 위장에는 대부분 선암이 발생하지만 악성림프종이나 육종 등도 생긴다. 반대로 ‘선암’은 위장뿐만 아니라, 유방, Most cancers have oncogenes and tumor suppressor genes. First successful drug targeting a oncogene is imatinib. It was very effective for chronic myelogenous leukemia as well as gastrointestinal stromal tumors. Many other targeted agents showed good response: trastuzumab for breast cancer, epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer, etc. Tests for EGFR and ALK gene mutation are routinely recommended for adenocarcinoma of lung cancer for selection of anticancer treatment. In addition, large-scale genomic data generation (next generation sequencing) is feasible in a clinical setting and gives us high hope for personalized cancer medicine. However, there are many hurdles to overcome. Driver genes must be distinguished from the passenger genes that are present in tumor DNA. In case of targeted cancer therapy, emergence of drug resistance due to tumor cell heterogeneity and clonal evolution is difficult to manage. Genetic testing for cancer risk showed some success in preventing familial breast or ovarian cancers, but it cannot be generalized in other tumors. Application of genetic information in cancer medicine showed promise but evidence-based approach is needed in clinical practice.

Oncotyrol – Center for Personalized Cancer Medicine: Methods and Applications of Health Technology Assessment and Outcomes Research

The Oncotyrol - Center for Personalized Cancer Medicine is an international and interdisciplinary alliance combining research and commercial competencies to accelerate the development, evaluation and translation of personalized healthcare strategies in cancer. The philosophy of Oncotyrol is to collaborate with relevant stakeholders and advance knowledge "from bench to bedside to population and back". Oncotyrol is funded through the COMET Excellence Program by the Austrian government via the national Austrian Research Promotion Agency (FFG). This article focuses on the role of health technology assessment (HTA) and outcomes research in personalized cancer medicine in the context of Oncotyrol. Oncotyrol, which currently comprises approximately 20 individual projects, has four research areas: Area 1: Biomarker and Drug Target Identification; Area 2: Assay Development and Drug Screening; Area 3: Innovative Therapies; Area 4: Health Technology Assessment and Bioinformatics. Area 4 translates the results from Areas 1 to 3 to populations and society and reports them back to Area 3 to inform clinical studies and guidelines, and to Areas 1 and 2 to guide further research and development. In a series of international expert workshops, the Oncotyrol International Expert Task Force for Personalized Cancer Medicine developed the Methodological Framework for Early Health Technology Assessment and Decision Modeling in Cancer and practical guidelines in this field. Further projects included applications in the fields of sequential treatment of patients with chronic myeloid leukemia (CML), benefit-harm and cost-effectiveness evaluation of prostate cancer screening, effectiveness and cost-effectiveness of multiple cervical cancer screening strategies, and benefits and cost-effectiveness of genomic test-based treatment strategies in breast cancer. An interdisciplinary setting as generated in Oncotyrol provides unique opportunities such as systematically coordinating lab and bench research, product development, clinical studies and decision science/HTA and transparent joint planning of research and development with a partnership of researchers, manufacturers and health policy decision makers. However, generating a joint research and legal framework with numerous partners from different sectors can be challenging, particularly in the starting period of such an endeavor. The journey to translational personalized medicine through multidisciplinary collaborations may still be long and difficult, but it is evident that it must be continued to turn vision into reality.

The Prognostic Value of Microsatellite Instability, KRAS, BRAF and PIK3CA Mutations in Stage II Colon Cancer Patients.

In the era of personalized cancer medicine, identifying mutations within patient tumors plays an important role in defining high-risk stage II colon cancer patients. The prognostic role of BRAF V600E mutation, microsatellite instability (MSI) status, KRAS mutation and PIK3CA mutation in stage II colon cancer patients is not settled. We retrospectively analyzed 186 patients with stage II colon cancer who underwent an oncological resection but were not treated with adjuvant chemotherapy. KRAS mutations, PIK3CA mutation, V600E BRAF mutation and MSI status were determined. Survival analyses were performed. Mutations were found in the patients with each mutation in the following percentages: 23% (MSI), 35% (KRAS), 19% (BRAF) and 11% (PIK3CA). A trend toward worse overall survival (OS) was seen in patients with an MSI (5-year OS 74% versus 82%, adjusted hazard ratio [HR] 1.8, 95% confidence interval [CI] 0.6-4.9) and a KRAS-mutated tumor (5-year OS 77% versus 82%, adjusted HR 1.7, 95% CI 0.8-3.5). MSI and BRAF-mutated tumors tended to correlate with poorer disease-free survival (DFS) (5-year DFS 60% versus 78%, adjusted HR 1.6, 95% CI 0.5-2.1 and 5-year DFS 57% versus 77%, adjusted HR 1.1, 95% CI 0.4-2.6 respectively). In stage II colon cancer patients not treated with adjuvant chemotherapy, BRAF mutation and MSI status both tended to have a negative prognostic effect on disease-free survival. KRAS and MSI status also tended to be correlated with worse overall survival.

Progressive Multifocal Leukoencephalopathy with Negative JC Virus PCR following Treatment of Follicular Lymphoma: Implications for Biologics in the Era of Targeted Cancer Therapy.

Anticancer therapy predisposes patients to infections by the immunosuppression that results from treatment. Although 85% of patients with progressive multifocal leukoencephalopathy (PML) have concurrent HIV/AIDS, PML can also develop in patients after they receive chemotherapy for cancer. The case herein describes a 69-year-old man with history of follicular lymphoma who presented with progressive dysarthria and right-sided paralysis. He received rituximab one year prior to presentation. PET scan suggested no recurrence of lymphoma. Cerebrospinal fluid (CSF) analysis was negative and showed fewer than 500 copies/mL of JC virus. However, brain biopsy showed chromatin margination and viropathic change within oligodendrocytes, confirming PML. He was started on mirtazapine and mefloquine with some clinical improvement. To our knowledge, this is the first case of rituximab-associated PML in a patient with negative JC virus PCR from the CSF. Recognition of PML in the differential of oncology patients with CNS symptoms is an important consideration as we enter the era of targeted therapy and personalized cancer medicine involving biologics. Furthermore, screening of patients for presence of subclinical JC viremia prior to the use of biologics may be an important component of assessing patient candidacy for these agents.

Signaling Pathway Profiling of Hepatocellular Carcinoma Cell Lines by Reverse-Phase Protein Array (RPPA) for Personalized Cancer Medicine

Signaling Pathway Profiling of Hepatocellular Carcinoma Cell Lines by Reverse-Phase Protein Array (RPPA) for Personalized Cancer Medicine

FIGO's staging classification for cancer of the ovary, fallopian tube, and peritoneum: abridged republication.

Over the past quarter of a century, several scientific developments have challenged traditional concepts in ovarian cancer. First, it was recognized that ovarian cancer is not a homogeneous disease, but rather a group of diseases-each with different morphology and biological behavior. Approximately 90% of ovarian cancers are carcinomas (malignant epithelial tumors) and, based on histopathology, immunohistochemistry, and molecular genetic analysis, at least five main types are currently distinguished: high-grade serous carcinoma (HGSC, 70%); endometrioid carcinoma (EC,10%); clear-cell carcinoma (CCC,10%); mucinous carcinoma (MC, 3%); and low-grade serous carcinoma (LGSC, <5%) [1,2]. These tumor types (which account for 98% of ovarian carcinomas) can be reproducibly diagnosed by light microscopy and are inherently different diseases, as indicated by differences in epidemiologic and genetic risk factors; precursor lesions; patterns of spread; and molecular events during oncogenesis, response to chemotherapy, and prognosis [2,3]. Much less common are malignant germ cell tumors and potentially malignant sex cord-stromal tumors. The biomarker expression profile within a given histotype is consistent across stages. Ovarian cancers differ primarily based on histologic type. In the era of personalized cancer medicine, reproducible histopathologic diagnosis of tumor cell type is a sine qua non for successful treatment. Different tumor histotypes respond differently to chemotherapy. The International Federation of Gynecology and Obstetrics (FIGO) Committee on Gynecologic Oncology unanimously agreed that histologic type should be designated at staging. The finding of high-grade serous tubal intraepithelial carcinoma (STIC), in patients with BRCA mutation undergoing risk-reducing salpingo-oophorectomy (RRSO)[4] also influenced the new FIGO staging. Although STIC is capable of metastasizing and, therefore, cannot be considered a true carcinoma in situ , compelling evidence for a tubal origin of BRCA-positive HGSC has accumulated over the past decade [5,6]. The relative proportion of HGSCs of ovarian and tubal derivation is unknown, mainly because tumor growth in advanced-stage cancers conceals the primary site. Even in cases involving BRCA mutation, evidence of a tubal origin of HGSCs is incomplete and a multicentric origin of these tumors cannot be excluded. The process of the proposed changes to the staging of ovarian, fallopian tube, and primary peritoneal cancer started three years ago under the leadership of the Chair of the FIGO Committee on Gynecologic Oncology, Professor Lynette Denny. The proposal was sent to all relevant gynecologic oncology organizations and societies worldwide. The new staging was reached by consensus of those participating in the FIGO meeting held in Rome, Italy, on October 7, 2012 and approved two weeks later. The following is the consensus agreement that resulted from these efforts and represents new criteria for staging of these gynecologic cancer (Table 1). Table 1 2014 FIGO ovarian, fallopian tube, and peritoneal cancer staging system and corresponding TNM

Promoting Precision Cancer Medicine through a Community-Driven Knowledgebase

Increasing efforts are being dedicated towards improving cancer care via personalized medicine. These efforts depend to a large degree on the availability of a knowledge foundation. Unfortunately, existing knowledge linking cancer drugs and potential efficacy biomarkers is in its infancy; and where links are known, they are frequently unstructured and poorly documented. We have developed a new open-access knowledgebase for precision cancer medicine (the PCM Wiki and Knowledgebase). This knowledgebase was constructed using an innovative, two-pronged approach involving a structured knowledgebase at the back-end, and an intuitive knowledge-sharing interface and user-friendly query engine in front. The knowledgebase was seeded with several patient case reports and information was mined via text-mining and literature review by human curators. Using our novel Wiki-based platform to present and share knowledge stored in the PCM knowledgebase, users are able to suggest corrections, propose additions or point to errors in the knowledgebase. The result is a community-driven evolving knowledgebase holding integrated and consolidated knowledge of markers and indications for personalized cancer medicine. We suggest that the PCM Knowledgebase and Wiki could serve as an important tool for the advancement of clinical trials and care in the field of precision cancer medicine.

Tissue-specific selection of optimal reference genes for expression analysis of anti-cancer drug-related genes in tumor samples using quantitative real-time RT-PCR

Gene transcription analysis in clinical tumor samples can help with diagnosis, prognosis, and treatment of cancers. We aimed to identify the optimal reference genes for reliable expression analysis in various tumor samples by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Using a one-step TaqMan-based qRT-PCR, 5 commonly used reference genes (ACTB, GAPDH, RPLPO, GUSB, and TFRC) and 10 anticancer drug-related genes (TYMS, RRM1, TUBB3, STMN1, TOP2A, EGFR, VEGFR2, HER2, ERCC1, and BRCA1) were analyzed in 327 tissue samples from lung, rectal, colon, gastric, esophageal, and breast tumors. According to the expression stability assessments obtained by using three programs (geNorm, NormFinder, and BestKeeper) and a comprehensive ranking method, the optimal reference genes for lung, gastric, esophageal, and breast tumors were RPLPO, GAPDH, ACTB, and ACTB, respectively. For rectal tumors, a combination of the 3 most stable genes (GUSB, ACTB, and RPLPO) was suitable for qRT-PCR, whereas for colon tumors, a combination of the 4 most stable genes (GAPDH, ACTB, GUSB, and RPLPO) was optimal for qRT-PCR. Based on the expression data of target genes normalized against selected reference genes, the principal component analysis revealed 4 expression patterns in 6 different tissues. One pattern was observed in gastric, rectal, and colon tumor tissues, which are gastrointestinal tumors. Expressions in the breast, lung, and esophageal tissues were separately represented as one pattern. Our results could facilitate the practice of personalized cancer medicine based on the gene expression profile of the patients.

Reverse phase protein arrays: mapping the path towards personalized medicine.

Reverse phase protein array (RPPA) technology evolved from the advent of miniaturized immunoassays and gene microarray technology. Reverse phase protein arrays provide either a low throughput or high throughput methodology for quantifying proteins and their post-translationally modified forms in both cellular and non-cellular samples. As the demand for patient tailored therapies increases so does the need for precise and sensitive technology to accurately profile the molecular circuitry driving an individual patient's disease. RPPAs are currently utilized in clinical trials for profiling and comparing the functional state of protein signaling pathways, either temporally within tumors, between patients, or within the same patients before/after treatment. RPPAs are generally employed for quantifying large numbers of samples on one array, under identical experimental conditions. However, the goal of personalized cancer medicine is to design therapies based on the molecular portrait of a patient's tumor, which in turn result in more efficacious treatments with less toxicity. Therefore, RPPAs are also being validated for low throughput assays of individual patient samples. This review explores RPPA technology in the cancer research field, concentrating on its role as a fundamental tool for deciphering protein signaling networks and its emerging role in personalized medicine.

Novel Points of Attack for Targeted Cancer Therapy

New molecular insight reveals novel points of attack for targeted cancer therapy. The recent advances in cancer genomics and novel insight into the complex biology of cancer make the promise of personalized, targeted cancer medicine closer than ever. The massive parallel sequencing endeavours performed by The Cancer Genome Atlas, the International Cancer Genome Consortium and by numerous individual investigators have provided a comprehensive genomic characterization of a wide range of cancers. The joint efforts enabled by the improved sequencing technology have demonstrated that individual cancers comprise mutational repertoires with only a few frequently recurrent driver genes. Thus, the identification of new drug targets and novel drugs have accelerated and renewed the hopes of personalized cancer therapy achieving clinical reality for a wider range of cancers. Together with cost-effective sequencing technology to perform comprehensive mutational profiling of each individual cancer, this provides the basis for a personalized cancer medicine revolution within the next few years. The aim of this MiniReview is to provide an overview of the history and evolution of targeted cancer therapy, exemplified by molecularly targeted drugs successfully implemented in the clinic. Furthermore, we aim to highlight novel molecular targets for therapeutic intervention, as well as the main present challenges including inter- and intratumor heterogeneity and cellular plasticity in addition to the importance of the tumor micro-environment. Many cancer patients already receive some form of tailored therapy, and recent evidence suggests that novel and highly innovative, targeted approaches are on their way into the clinic.

Combined downregulation of microRNA-133a and microRNA-133b predicts chemosensitivity of patients with esophageal squamous cell carcinoma undergoing paclitaxel-based chemotherapy.

microRNA-133a (miR-133a) and miR-133b, located on chromosome 18 in the same bicistronic unit, have been commonly identified as being downregulated in esophageal squamous cell carcinoma (ESCC). The aim of this study was to investigate the correlation of miR-133a/b expression with efficacy of paclitaxel-based chemotherapy and clinical outcome of ESCC patients. miR-133a expression and miR-133b expression were examined in 100 newly diagnosed ESCC patients prior to treatment by quantitative real-time PCR. Then, the patients received four cycles of paclitaxel-based chemotherapy, the short-term treatment efficacy was evaluated, and a 3-year follow-up was performed. Expression levels of miR-133a and miR-133b were both significantly lower in ESCC tissues compared to adjacent noncancerous tissues (both P < 0.001). In addition, combined miR-133a/b downregulation was found to be closely correlated with advanced tumor stage (P = 0.02) and poor differentiation (P = 0.01). Moreover, the response rate of ESCC patients to paclitaxel-based chemotherapy was significantly higher in combined miR-133a/b downregulation group compared with other groups (P = 0.02). Furthermore, univariate and multivariate Cox analyses revealed that tumor stage and combined expression of miR-133a/b were independent prognosis factors in ESCC patients. Our data offer the convincing evidence that combined expression of miR-133a and miR-133b may predict chemosensitivity of patients with ESCC undergoing paclitaxel-based chemotherapy, implying its importance in applying 'personalized cancer medicine' in the clinical treatment of ESCC. We also identified combined expression of miR-133a and miR-133b as an effective prognostic marker of this malignancy.

Abstract 1537: Prospective mutational characterization of Japanese patients with non-small cell lung cancer by next-generation sequencing

Abstract Background: Detection of tumor genetic alterations is critically needed for lung cancer clinic as well as for the development of molecular targeted therapeutics. Here we report the results of a broad spectrum of genetic alterations identified in Japanese patients with non-small cell lung cancer (NSCLC) by ultra-deep targeted sequencing. Material and Methods: Highly multiplexed amplicon sequencing was performed using genomic DNA extracted from snap-frozen tumor specimens. TruSeq amplicon cancer panel was used for the detection of somatic mutations in 48 cancer related genes followed by ultra-deep sequencing (Illumina) at an average coverage of approximately 3,400x. ALK, ROS1 and RET translocations and EGFR, MET, PIK3CA, FGFR1 and FGFR2 amplifications were also detected by multiplex RT-PCR and quantitative PCR, respectively. Results: Between July 2011 and March 2013, 279 consecutive patients were enrolled in this prospective study at Shizuoka Cancer Center: median age 69 years (range: 38-92); male 66%; never smoker 25.8%; histology: adenocarcinoma 70.6%, squamous cell carcinoma (SQ) 25.1%, others 4.3%; pathological stage: I 58.1%, II 22.6%, III 15.4%, IV 3.9%. TP53 mutation was most frequently detected (35.9%) in all patients, particularly in SQ (59.2%). Mutations in genes such as CTNNB1 (4.0%), SMAD4 (1.5%), GNAS (1.0%), STK11 (1.0%), HRAS (0.5%) and PTPN11 (0.5%) were also detected in addition to major mutations in genes such as EGFR (44.8%), KRAS (18.4%) and PIK3CA (4.5%) in adenocarcinoma. PIK3CA (19.7%), HRAS (2.8%), APC (1.4%), FGFR2 (1.4%), FGFR3 (1.4%) and SMAD4 (1.4%) mutations were identified in SQ and notably, 40.9% of SQ patients harbored concurrent gene mutations, suggesting the genetic complexity of this histological subset. In EGFR mutation, deletion in exon 19 (42.6%) and L858R point mutation in exon 21 (41.5%) were frequently observed. As for PIK3CA mutation, the majority (92.8% of all PIK3CA mutant SQ cases) was detected in exon 9 (residues E542 and E545) in SQ but in contrast, mutations in exon 1 and 20 (residues G106 and H1047, respectively) were more frequently detected (33.3% combined of all PIK3CA mutant adenocarcinoma cases) in adenocarcinoma. Conclusions: We managed to detect a wide range of genetic alterations and to identify additional actionable mutations along with popular driver mutations in NSCLC by next-generation sequencing technology. These data should be incorporated into lung cancer clinic to implement personalized cancer medicine. Citation Format: Hirotsugu Kenmotsu, Yasuhiro Koh, Masakuni Serizawa, Mitsuhiro Isaka, Tomohiro Maniwa, Haruyasu Murakami, Keita Mori, Masahiro Endo, Takashi Nakajima, Yasuhisa Ohde, Toshiaki Takahashi, Nobuyuki Yamamoto. Prospective mutational characterization of Japanese patients with non-small cell lung cancer by next-generation sequencing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1537. doi:10.1158/1538-7445.AM2014-1537

120IN - Adapting Organisation and Research Infrastructures at Gustave Roussy for Todays Clinical Research Programmes

ABSTRACT Integration of basic-transltional-clinical research to create an interactive continuum, within one infrastuctural approach, has been the focus over the recent years at the Gustave Roussy Comprehensive Cancer Center. This continuum of cancer research activities is to articulate with cancer care and to advance with a key mission of the institute: to create tomorrows medicine. In order to achieve this a number of basic decisions had to be taken: 1) Adapt your clinical research infrastructures to the importance of creating a critical mass activity in early drug development. This was achieved by the creation of a department of drug development and treatment innovations harbouring all early clnical trial activities including the organizational nad monitoring aspects. 2) Develop and advance personalized cancer medicine by conducting clinical trials in this domain. This requested the creation of a molecular portrait platform that can deliver within in context of clinical requirements in terms of quality and speed. For this a whole floor of a 6000 M2 new translational research building was reserved and equipped, including bioinformatics. 3) Develop adequate infrastructural support in persons and platforms to participate in the revolution in immunotherapy of cancer. For this dedicated immunotherapists were recruted and an immunotherapy-monitoring platform was created. 4) Develop hi-tech platforms to accomodate on the one hand clinical trial requirements in personalized cancer medicine as indicated under points 1-2-3, as well as basic research platforms that a mutualized by all groups 5) Develop a model where a CCC will evolve into a Cancer Campus by creating and/or expanding large scale preclinical research facilities that will be a prerequisite to attract research branches of pharma, biotech, hi-tech and othe private companies to install themselves onto a cancer-center-surrounding biopark: cancer campus 6) Find the money All the above will provide the environment that will attrackt the best researchers and clinicians and research-clinicians to meet the expectations of society regarding advances to be made in cancer care, which is and remains the endgoal of all we do. Disclosure: The author has declared no conflicts of interest.

Basic cancer research: why it is essentiel for the future of cancer therapy

The last decade has witnessed significant progress in cancer understanding and ther-apy: we can now identify the genetic drivers of individual tumours, and tailor drugs able to specifically intercept the driver mutations. While all agree that personalized cancer medicine is a clear outcome of the resources dedicated to cancer research over the last 50 years, some critics question the necessity for continuous investments in sub-fields other than clinical research and drug development. Herein, scientists from the European Association for Cancer Research (EACR) argue that the new ways to diagnose and treat cancer present important and hitherto unaddressed challenges for fundamental research of cancer. Allocating the resources needed for basic studies will likely fuel the next wave of achievements in the long way to conquer cancer.

20IN - How to Design the Trials to Meet the Perspectives of Personalised Cancer Medicine

ABSTRACT In the current era of stratified medicine and biomarker driven therapies, the focus has shifted from predictions based on the traditional anatomic staging systems to guide the choice of treatment for an individual patient to an integrated approach using the genetic makeup of the tumor and the genotype of the patient. Starting from early phase trials for initial marker validation to larger definitive trials, clinical trial designs utilized in the developmental pathway for biomarkers and biomarker-directed therapies are rapidly evolving. Two critical issues that need careful consideration are the choice of the clinical trial design (based on the strength of the preliminary evidence, marker prevalence etc.), and biomarker assay related issues surrounding the marker assessment methods such as the reliability and reproducibility of the assay. While assessing the safety profile and establishing the maximum tolerated dose remains the primary focus of Phase I trials for all agents, establishing a preliminary efficacy signal and/or identification of subsets of patients most likely to benefit from the new treatment are increasingly assessed as part of Phase I trials of targeted therapeutics. The choice of endpoints, patient selection, model-based versus rule-based design algorithms and inclusion of expansion cohorts need careful consideration in this setting. Phase II trials have at least 3 main purposes: assess the regimen / drug under investigation for evidence of efficacy; evaluate the patient population for a phase III study (i.e., identify genomic-defined patient subsets) and finally, to more fully assess the toxicity profile in a larger number of patients than that of a phase I study. While most of the prospective designs for biomarker-directed therapy were primarily developed for marker validation in phase III setting, they have evolved since then to be applicable in an initial marker validation phase II setting. Designs for biomarker validation (initial and definitive) are broadly classified into enrichment, all-comers, hybrid or adaptive (with various adaptation strategies). This talk will provide numerous examples of cancer clinical trials that utilize a design strategy aiming at personalized medicine. Disclosure: The author has declared no conflicts of interest.

Long non-coding RNAs in cancer: implications for personalized therapy.

Long non-coding RNAs (lncRNAs, pseudogenes and circRNAs) have recently come into light as powerful players in cancer pathogenesis and it is becoming increasingly clear that they have the potential of greatly contributing to the spread and success of personalized cancer medicine. In this concise review, we briefly introduce these three classes of long non-coding RNAs. We then discuss their applications as diagnostic and prognostic biomarkers. Finally, we describe their appeal as targets and as drugs, while pointing out the limitations that still lie ahead of their definitive entry into clinical practice.