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Posts Tagged ‘Pancreatic cancer’

Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Liver & Digestive Diseases Research, Medical and Population Genetics, Metabolomics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Nutrition and Phytochemistry, Proteomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , on October 24, 2012| 6 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

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Word Cloud By Danielle Smolyar

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Nature (2012) 

doi:10.1038/nature11547 Received 09 January 2012  Accepted 04 September 2012 

Published online 24 October 2012

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A andSF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2,MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Figures at a glance

Contributions

The research network comprising the Australian Pancreatic Cancer Genome Initiative, the Baylor College of Medicine Cancer Genome Project and the Ontario Institute for Cancer Research Pancreatic Cancer Genome Study (ABO collaboration) contributed collectively to this study as part of the International Cancer Genome Consortium. Biospecimens were collected at affiliated hospitals and processed at each biospecimen core resource centre. Data generation and analyses were performed by the genome sequencing centres, cancer genome characterization centres and genome data analysis centres. Investigator contributions are as follows: S.M.G., A.V.B., J.V.P., R.L.S., R.A.G., D.A.W., M.-C.G., J.D.M., L.D.S and T.J.H. (project leaders); A.V.B., S.M.G. and R.L.S. (writing team); A.L.J., J.V.P., P.J.W., J.L.F., C.L., M.A., O.H., J.G.R., D.T., C.X., S.Wo., F.N., S.So., G.K. and W.K. (bioinformatics/databases); D.K.M., I.H., S.I., C.N., S.M., A.Chr., T.Br., S.Wa., E.N., B.B.G., D.M.M., Y.Q.W., Y.H., L.R.L., H.D., R. E. D., R.S.M. and M.W. (sequencing); N.W., K.S.K., J.V.P., A.-M.P., K.N., N.C., M.G., P.J.W., M.J.C., M.P., J.W., N.K., F.Z., J.D., K.C., C.J.B., L.B.M., D.P., R.E.D., R.D.B., T.Be. and C.K.Y. (mutation, copy number and gene expression analysis); A.L.J., D.K.C., M.D.J., M.P., C.J.S., E.K.C., C.T., A.M.N., E.S.H., V.T.C., L.A.C., E.N., J.S.S., J.L.H., C.T., N.B. and M.Sc. (sample processing and quality control); A.J.G., J.G.K., R.H.H., C.A.I.-D., A.Cho., A.Mai., J.R.E., P.C. and A.S. (pathology assessment); J.W., M.J.C., M.P., C.K.Y. and mutation analysis team (network/pathway analysis and functional data integration); K.M.M., N.A.J., N.G.C., P.A.P.-M., D.J.A., D.A.L., L.F.A.W., A.G.R., D.A.T., R.J.D., I.R., A.V.P., E.A.M., R.L.S., R.H.H. and A.Maw. (functional screens); E.N., A.L.J., J.S.S., A.J.G., J.G.K., N.D.M., A.B., K.E., N.Q.N., N.Z., W.E.F., F.C.B., S.E.H., G.E.A., L.M., L.T., M.Sam., K.B., A.B., D.P., A.P., N.B., R.D.B., R.E.D., C.Y., S.Se., N.O., D.M., M-S.T., P.A.S., G.M.P., S.G., L.D.S., C.A.I.-D., R.D.S., C.L.W., R.A.M., R.T.L., S.B., V.C., M.Sca., C.B., M.A.T., G.T., A.S. and J.R.E. (sample collection and clinical annotation); D.K.C., M.P., C.J.S., E.S.H., J.A.L., R.J.D., A.V.P. and I.R. (preclinical models).

Competing financial interests

The authors declare no competing financial interests.

International Team Reports on Large-Scale Pancreatic Cancer Analysis

October 24, 2012

NEW YORK (GenomeWeb News) – A whole-exome sequencing and copy number variation study of pancreatic cancer published online today in Nature suggests that the disease sometimes involves alterations to genes and pathways best known for their role in axon guidance during embryonic development.

The work was conducted as part of the International Cancer Genome Consortium effort by researchers with the BCM Cancer Genome Project, the Australian Pancreatic Cancer Genome Initiative, and the Ontario Institute for Cancer Research Pancreatic Cancer Genome Study.

As they reported today, the investigators identified thousands of somatic mutations and copy number alterations in pancreatic ductal adenocarcinoma cancer, the most common form of pancreatic cancer. Some of the mutations affected known cancer genes and/or pathways implicated in pancreatic cancer in the past. Other genetic glitches pointed to processes not previously linked to the disease including mutations to axon guidance genes such as SLIT2, ROBO1, and ROBO2.

“This is a category of genes not previously linked to pancreatic cancer,” Baylor College of Medicine researcher William Fisher, a co-author on the new paper, said in a statement. “We are poised to jump on this gene list and do some exciting things.”

Pancreatic cancer is among the deadliest types of cancer, he and his colleagues explained, with a grim five-year survival rate of less than 5 percent. But despite its clinical importance, direct genomic studies of primary tumors had been stymied in the past due to difficulties obtaining large enough samples for such analyses.

“Genomic characterization of pancreatic ductal adenocarcinoma, which accounts for over 90 [percent] of pancreatic cancer, has so far focused on targeted polymerase chain reaction-based exome sequencing of primary and metastatic lesions propagated as xenografts or cell lines,” the study authors noted.

“A deeper understanding of the underlying molecular pathophysiology of the clinical disease is needed to advance the development of effective therapeutic and early detection strategies,” they added.

For the current study, researchers started with a set of tumor-normal samples from 142 individuals with stage I or stage II sporadic pancreatic ductal adenocarcinoma. Following a series of experiments to assess tumor cellularity and other features that can impact tumor analyses, they selected 99 patients whose samples were assessed in detail.

For whole-exome sequencing experiments, the investigators nabbed coding sequences from matched tumor and normal samples using either Agilent SureSelectII or Nimblegen capture kits before sequencing the exomes on SOLiD 4 or Illumina sequencing platforms. They also used Ion Torrent and Roche 454 platforms to validate apparent somatic mutations in the samples.

For its copy number analyses, meanwhile, the team tested the pancreatic cancer and normal tissue samples using Illumina HumanOmni1 Quad genotyping arrays.

When they sifted through data for the 99 most completely characterized pancreatic tumors, researchers uncovered 1,628 CNVs and roughly 2,000 non-silent, somatic coding mutations. More than 1,500 of the non-silent mutations were subsequently verified through additional sequencing experiments.

On average, each of the tumors contained 26 coding mutations. And despite the variability in mutations present from one tumor to the next, researchers identified 16 genes that were mutated in multiple tumor samples.

Some were well-known cancer players such as KRAS, which was mutated in more than 90 percent of the 142 pancreatic tumors considered initially. Several other genes belonged to cell cycle checkpoint, apoptosis, blood vessel formation, and cell signaling pathways, researchers reported, or to pathways involved in chromatin remodeling or DNA damage repair.

For example, some 8 percent of tumors contained mutations to ATM, a gene participating in a DNA damage repair pathway that includes the ovarian/breast cancer risk gene BRCA1.

Genes falling within axon guidance pathways turned up as well. That pattern was supported by the researchers analyses of data from published pancreatic cancer studies — including two studies based on mutagenesis screens in mouse models of the disease — and by their own gene expression experiments in mice.

The team also tracked down a few more pancreatic ductal adenocarcinoma cases involving mutations to axon guidance genes such as ROBO1, ROBO2, and SLIT2 through targeted testing on 30 more pancreatic cancer patients.

The findings are consistent with those found in some other cancer types, according to the study’s authors, who noted that there is evidence indicating that some axon guidance components feed into signaling pathways related to cancer development, such as the WNT signaling pathway. If so, they explained, it’s possible that mutations to axon guidance genes might influence the effectiveness of therapies targeting such downstream pathways or serve as potential treatment targets themselves.

Still, those involved in the study cautioned that more research is needed not only to explore such possibilities but also to distinguish between driver and passenger mutations in pancreatic cancer.

“The potential therapeutic strategies identified will … require testing in appropriate clinical trials that are specifically designed to target subsets of patients stratified according to well-defined molecular markers,” the study’s authors concluded.

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Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Liver & Digestive Diseases Research, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , on October 24, 2012| 7 Comments »

Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Article 10.4. Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Reporter: Aviva Lev-Ari, PhD, RN

Van Andel, Emory to Develop Early Pancreatic Cancer Dx

October 19, 2012
 

NEW YORK (GenomeWeb News) – Van Andel Institute and Emory University researchers will use a $2.3 million grant from the National Cancer Institute to fund an effort to develop new biomarker tools that can aid in the early diagnosis of pancreatic cancer.

The Van Andel and Emory team plan to use gene expression studies and a shotgun glycomics approach to try to develop useful diagnostic tests for a certain carbohydrate structure that is prevalent in most, but not all, pancreatic cancer tumors.

In a shotgun glycomics approach, all of the glycans from a sample are tagged with a fluorescent tag and separated from each other to create a tagged glycolipid library. This library will be developed through gene expression studies on the tumor tissue.

“One of the most common features of pancreatic cancers is the increased abundance of a carbohydrate structure called the CA 19-9 antigen,” Brian Haab, head of Van Andel’s Laboratory of Cancer Immunodiagnostics, said in a statement.

Because CA 19-9 is attached to many different proteins that the tumor secretes into the blood it is used to confirm diagnosis of and to manage disease progression of pancreatic cancer. Tests for this structure have not yet been useful for early detection or diagnosis, however, because around 20 to 30 percent off incipient tumors produce low levels of CA 19-9.

“The low levels are usually due to inherited genetic mutations in the genes responsible for the synthesis of CA 19-9,” Haab explained. “However, patients who produce low CA 19-9 produce alternate carbohydrate structures that are abnormally elevated in cancer.”

This study aims to characterize and identify these glycans to improve the ability to detect cancer in patients with low CA 19-9 levels.

The research will integrate the use affinity reagents, a type of proteins called lectins, as well as shotgun glycomics, to detect these glycan structures and develop a diagnostic test for pancreatic cancer.

Because pancreatic cancer tends to spread before it is diagnosed and because of its resistance to chemotherapy, it has one of the lowest survival rates of any major cancer. It will affect more than 43,000 Americans in 2012 and will kill more than 37,000, according to NCI.

“We anticipate these new approaches advancing pancreatic cancer diagnostics as well as benefiting other glycobiology research in cancer,” Haab said.

Researchers from the Fred Hutchinson Cancer Research Center, Palo Alto Research Center, the University of Georgia, and the University of Pittsburgh Medical Center also are participating in the project.

 

 

 

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Personalized Pancreatic Cancer Treatment Option

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Human Immune System in Health and in Disease, Imaging-based Cancer Patient Management, Liver & Digestive Diseases Research, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , on October 16, 2012| 6 Comments »

Personalized Pancreatic Cancer Treatment Option

Reporter: Aviva Lev-Ari, PhD, RN

Article-7.3.6. Personalized Pancreatic Cancer Treatment Option

Clovis on Track to Unveil Data on New Personalized Pancreatic Cancer Treatment Option by Year End

October 10, 2012
 

Drug developer Clovis Oncology is planning to report data from a clinical trial later this year that may yield a new treatment option for pancreatic cancer patients who are poor responders to gemcitabine.

Clovis is conducting a study, called LEAP, of 360 chemotherapy-naïve metastatic pancreatic cancer patients who are randomized to receive the current standard of care gemcitabine, or the investigational CO-101, a gemcitabine-lipid conjugate. The study investigators are hypothesizing that unlike gemcitabine, CO-101 won’t depend on the expression levels of the protein cellular transporter hENT1 to enter and destroy tumor cells.

Gemcitabine, currently the first-line standard chemotherapy treatment for metastatic pancreatic cancer patients, requires a transport mechanism to help it enter tumor cells. Previously published data suggest that patients with high hENT1 expression respond well to gemcitabine, while those with low expression — about two-thirds of pancreatic cancer patients — respond poorly to the chemotherapeutic.

LEAP researchers have prospectively collected biopsy samples and have enrolled both high- and low-hENT1 expressers. Study investigators will be blind to the hENT1 expression status of patients until the end of the trial. Clovis is working with Roche subsidiary Ventana Medical Systems to simultaneously develop and validate a companion diagnostic that can gauge low and high hENT1 expression. The primary outcome that study investigators are measuring in LEAP is overall survival in the hENT1-low population.

“The question really is whether the lipid, which facilitates entry into the cell through passive diffusion, is going to be able to deliver gemcitabine as efficiently as when a nucleoside transporter is present,” Clovis CEO Patrick Mahaffy told PGx Reporter. “The answer is we don’t know, but we’ll find out in the study.”

The study may reveal that since CO-101 doesn’t depend on hENT1 to enter tumor cells, all metastatic pancreatic cancer patients, regardless of low or high expression of this protein, derive a level of benefit from the new treatment. Still, Clovis is using a companion test to stratify patients after factoring in reimbursement and cost-effectiveness considerations, which currently are perhaps the biggest barriers to the adoption of personalized treatments.

“Nothing we know suggests that we would be better than gemcitabine … in the hENT1 high population. Given the evolving reimbursement environment and the fact that gemcitabine is generic and is priced as such, pending a successful outcome we anticipate that [CO-101] would be used primarily, if not solely, in the hENT1 low population where we anticipate poor outcomes for gemcitabine,” Mahaffy said. “We anticipate that gemcitabine would continue to be the favored product on price alone even if we were to show equivalence to CO-101 in the hENT1 high population.”

Clovis Oncology will commercialize CO-101 globally. The company is currently setting up commercialization infrastructure in the US for the drug, anticipating a launch as early as next year. Clovis won’t necessarily co-promote CO-101 and the companion test with Ventana. The test developer will be in charge of commercializing the test, and Clovis will market the drug with its sales representatives, who will also be educating oncologists about the need for a companion test.

Ventana will submit its premarket approval application for the hENT1 expression test at the same time that Clovis submits its new drug application for CO-101. The test will be marketed as not just a companion diagnostic to assess whether pancreatic cancer patients have low levels of hENT1 and would therefore respond to CO-101, but Ventana will also be able to market the diagnostic as a tool to determine which high-hENT1 expressing patients should be given gemcitabine.

“The [LEAP] trial will clinically validate the diagnostic both for determining response to both gemcitabine and CO-101,” Mahaffy said.

There are around 120,000 cases of pancreatic cancer each year in the US, EU, and Japan, and around 24 percent of patients survive for one year. Around 80 percent of pancreatic cancer patients receive gemcitabine as monotherapy or in combination with other cytotoxic agents. Based on the low incidence of metastatic pancreatic cancer, Clovis has garnered Orphan Drug status for CO-101 from US and European regulatory authorities.

Although a number of retrospective trials have demonstrated that hENT1 expression levels impact outcomes in pancreatic cancer patients in the metastatic and adjuvant setting, LEAP will be the first prospective validation of this observation. “That’s why this trial is so important to the pancreatic cancer community,” Mahaffy said. “Because not only are we going to learn about CO-101, but we’re going to learn prospectively about the role hENT1 plays in determining the outcome for patients’ treatment with gemcitabine alone.”

Testing for hENT1 expression status is not widely conducted by doctors in the care of pancreatic patients. “In fact, it’s not even widely known in the broader community setting,” noted Mahaffy, adding that academic oncologists are increasingly aware of the association between hENT1 expression and gemcitabine efficacy. After LEAP concludes and if the trial is successful, Clovis plans to initiate discussions with treatment guideline-setting bodies.

In addition to looking at CO-101 as a first-line metastatic pancreatic cancer treatment in hENT1-low patients, Clovis is also studying the drug-conjugate as a second-line treatment in metastatic pancreatic cancer (Phase II), as well as in non-small cell lung cancer (Phase I).

Personalized NSCLC Drug

In addition to CO-101, Clovis has a number of investigational agents in its pipeline that it is developing in molecularly defined patient subsets. For example, CO-1686 is a selective covalent inhibitor of EGFR mutations that the firm is exploring in patients with NSCLC. Currently Clovis is conducting a dose-finding Phase I/II trial involving CO-1686 in NSCLC patients with T790M mutations. Patients with these “gatekeeper” mutations become resistant to treatment to widely prescribed EGFR-inhibiting NSCLC drugs, Roche/Genentech’s Tarceva and AstraZeneca’s Iressa.

CO-1686 “is a very potent inhibitor of T790M … [mutations in] which occur in 50 percent of lung cancer patients, after treatment with Tarceva,” Mahaffy said. After the dose-finding portion of the Phase I/II trial, Clovis plans to initiate an expansion cohort looking at T790M mutation-positive patients who are resistant to Tarceva. “If we see the kind of results we hope to in that expansion cohort, we would initiate a registration study beginning in 2014 in Tarceva-failed patients with T790M mutations,” he said.

While CO-1686 is an inhibitor of T790M mutations and other activating mutations of EGFR, the drug doesn’t inhibit wild-type EGFR like Tarceva and Iressa do, which can make NSCLC patients prone to serious side effects. “What is interesting about [CO-1686] is it is a very potent inhibitor of activating mutations of EGFR, the same targets that Tarceva or Iressa address, but unlike those drugs, [CO-1686] does not inhibit wild-type EGFR,” Mahaffy said. With CO-1686, “we should see very limited rash and diarrhea side effects associated with Tarceva and Iressa.”

First, Clovis will study CO-1686 as a second-line treatment in NSCLC patients with T790M mutations. Eventually, Clovis plans to study the drug head-to-head against Tarceva in the first-line setting. “Given the activity of our drug in animal models so far, we think we may have the ability to demonstrate superiority in terms of efficacy and from the side effects of Tarceva,” Mahaffy said. “We would hope to demonstrate in addition to a cleaner safety profile, a longer duration of benefit, because we would prevent that primary resistance mechanism in T790M from emerging.”

Roche Molecular Systems has partnered with Clovis to develop a companion diagnostic for CO-1686.

Meanwhile, last year, the European Commission approved the use of Roche/Genentech’s Tarceva as a first-line treatment for NSCLC in patients with EGFR mutations (PGx Reporter 9/7/2012). Last month, UK’s National Institute for Health and Clinical Excellence issued a draft guidance recommending that the country’s National Health Service pay for Tarceva as an option for this patient population. The company is in discussions with the US Food and Drug Administration about launching Tarceva in this population (PGx Reporter 06/08/2011).

Additionally, Boehringer Ingelheim is developing afatinib, a drug intended for advanced NSCLC patients with EGFR mutation-positive tumors (PGx Reporter 6/6/2012). Boehringer is working with Qiagen to advance a companion test for its drug.

An NGS-Based Companion Dx?

Another drug in Clovis’ pipeline is an inhibitor of PARP 1 and PARP 2, called rucaparib, which the company licensed from Pfizer. Rucaparib is currently undergoing Phase I/II trials in breast and ovarian cancer. The company is investigating the efficacy and safety of the drug in patients who lack the ability to repair damaged DNA that cancer cells need to thrive.

Mahaffy highlighted that Clovis is currently continuing a dose-finding Phase I study initiated by Pfizer combining rucaparib with carboplatin, and is conducting a Phase I trial investigating the drug as a monotherapy. This latter study will include an extension cohort of ovarian cancer patients with germline BRCA mutations.

Clovis is among a handful of drug developers, including Abbott and AstraZeneca, that are advancing PARP inhibitors with a personalized medicine strategy, betting that patients with BRCA 1/2 mutations will respond better to this class of drugs than those without these mutations. Previous studies have demonstrated that the PARP 1 enzyme and the BRCA gene work in concert to repair DNA damage, enabling survival of cancer tumors. Patients with BRCA mutations can’t repair DNA damage in this way, so then PARP inhibitors can be more effective in stopping cancer growth.

Abbott and AstraZeneca are using a companion test developed by Myriad Genetics to study their PARP inhibitors in BRCA-mutated patients with these diseases. Myriad markets BRACAnalysis, a test that gauges germline BRCA mutations associated with hereditary breast and ovarian cancer. However, gene alternations other than germline BRCA 1/2 mutations are linked to faulty DNA repair and PARP inhibitor response. For example, Clovis estimates that around 15 percent of women with ovarian cancer harbor germline BRCA 1/2 mutations, but another 8 percent of patients have somatic mutations in BRCA. Meanwhile, germline BRCA 1/2 mutations comprise only 5 percent of breast cancers.

When Pfizer was developing rucaparib, it was working with MDxHealth to explore methylation-specific markers associated with DNA damage repair and response to PARP inhibiters (PGx Reporter 2/2/2011). According to MDxHealth both methylation and mutation testing can characterize BRCA gene activity. The company previously estimated that BRCA methylation appears in about 40 percent to 50 percent of triple-negative breast cancer patients, and in about 10 percent to 30 percent in sporadic breast cancers.

Clovis has an open contract with MDxHealth looking at methylation profiles in breast and ovarian cancer, and will continue to explore this approach, specifically for methylated BRCA in triple-negative breast cancer. Additionally, Clovis is “considering the opportunity to look at both germline and somatic mutations of BRCA, based on a tissue-based assay,” Mahaffy said.

Beyond this, in August, Clovis and Foundation Medicine announced they are working together to investigate other genetic defects related to DNA repair deficiency.

“We went with Foundation Medicine … because it will allow us to reach a broader population,” Mahaffy said. For example, in ovarian cancer, Foundation Medicine’s next-generation sequencing platform could identify other mechanisms of DNA repair deficiencies that could potentially increase the intent-to-treat population for rucaparib from 15 percent of ovarian cancer patients with germline BRCA mutations to as much as 50 percent of the population that has somatic mutations in 28 additional genes that have been described as conferring “BRCA-ness” or as having a BRCA-like effect on DNA repair.

Clovis plans to develop a companion test for rucaparib on Foundation Medicine’s Foundation One targeted NGS platform. However, one challenge for Clovis is that the FDA hasn’t yet elucidated how it plans to regulate NGS-based tests. “Clearly, there is a seismic shift underway, and we may be one of the first to have plans to go forward on a premarket approval path with next-gen sequencing,” Mahaffy said. “But clearly the FDA and everyone else knows this tidal wave is coming.”

Clovis hopes to initiate a registration trial in the second half of next year looking at rucaparib as a maintenance therapy in ovarian cancer patients sensitive to platinum-based chemotherapy who have alterations in BRCA and deficiencies in other DNA repair genes. Foundation Medicine and Clovis have separately initiated discussions with the FDA about getting taking NGS-based tests through regulatory approval, Mahaffy said.

      Turna Ray is the editor of GenomeWeb’s Pharmacogenomics Reporter. She covers pharmacogenomics, personalized medicine, and companion diagnostics. E-mail her here or follow her GenomeWeb Twitter account at @PGxReporter.

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Pancrealipase DR for Exocrine Pancreatic Insufficieny (EPI)

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Health Economics and Outcomes Research, International Global Work in Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Genetics & Pharmaceutical, tagged , , , , , , on May 30, 2012| Leave a Comment »

Pancrealipase DR for Exocrine Pancreatic Insufficieny (EPI).

via Pancrealipase DR for Exocrine Pancreatic Insufficieny (EPI).

Reported by: Dr. V.S.Karra, Ph.D

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Battle of Steve Jobs and Ralph Steinman with Pancreatic cancer: How we lost

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Medical and Population Genetics, tagged , , , , , , , , , , , , , , , on May 21, 2012| 3 Comments »

Author: Ritu Saxena, Ph.D.

Recently, two world renowned innovators, Steve Jobs-the CEO of Apple Inc. and Dr. Steinman-winner of 2011 Nobel prize in Physiology or medicine lost their life battle against Pancreatic cancer. Although both Jobs and Steinman suffered from the same disease, they were diagnosed with two fundamentally different forms of cancer of pancreas.

Steve lived with the disease for 8 years, a relatively long time for Pancreatic cancer patients to survive. The reason is attributed to the rare form of cancer of pancreas he suffered from-referred to as pancreatic neuroendocrine tumor. Steinman, on the other hand died due to a more common form of pancreatic cancer, the adenocarcenoma.

Neuroendocrine tumors arise from islands of hormone-producing cells (islets), that happen to be in that organ. Jobs learned in 2003 that he had an extremely rare form of this cancer, an islet-cell neuroendocrine tumor. In his email to  Apple employees in 2004, Steven Jobs wrote “I have some personal news that I need to share with you, and I wanted you to hear it directly from me,” Jobs said in the message, which he sent from his hospital bed. “I had a very rare form of pancreatic cancer called an islet cell neuroendocrine tumor, which represents about 1 percent of the total cases of pancreatic cancer diagnosed each year, and can be cured by surgical removal if diagnosed in time (mine was). I will not require any chemotherapy or radiation treatments.”

About 2,500 cases of pancreatic islet cell tumors are seen in the United States each year, according to the University of Southern California’s Center for Pancreatic and Biliary Diseases. These tumors, which are derived from neuroendocrine cells, tend to be slow growing and are treatable even after they have metastasized, said the center’s Web site.  http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2004/08/02/MNGMJ816F41.DTL&ao=all

The management strategy of neuroendrocrine tumors (NET) like any other disease is supposed to be curative where possible. As suggested by several researchers including Ramage et al (http://www.ncbi.nlm.nih.gov/pubmed/15686165, ), surgery is the only curative option currently available for NETs. The updated guidelines published for the NET management state the over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, because of the uncommon nature of the disease, there remain few randomised trials in the field, hence all evidence mentioned in the research article is considered relatively weak compared with other more common cancers. For patients who are diagnosed early enough to be candidates for surgery, the aim is to keep the patient disease- and symptom-free for as long as possible. For patients suffering from advanced-stage NETs, operative therapy is rarely curative and chemotherapy could be used on metastasized NETs. http://www.ncbi.nlm.nih.gov/pubmed/22052063.

As reported in a story covered by CNN in 2008, there was a lot of speculation when he appeared rail-thin at the unveiling of the new iPhone. Jobs eventually said in January 2009 that doctors said he dropped so much weight because of “a hormone imbalance that has been ‘robbing’ me of the proteins my body needs to be healthy. Sophisticated blood tests have confirmed this diagnosis.” http://tech.fortune.cnn.com/2008/06/13/steve-jobs-life-after-the-whipple/ This statement explains how symptoms of hormonal excess in NET patients must be controlled before surgical procedure is followed. Also, recommended management of the symptoms of hormonal hypersecretion depends on the hormone secreted. For example, glucose levels in patients with insulinomas should be stabilized with diet and/or diazoxide. Gastrin hypersecretion in patients with gastrinomas may be managed with proton pump inhibitors (PPIs). http://www.neuroendocrinetumor.com/health-care-professional/net-treatment-options.jsp

Steinman, on the other hand, suffered from adenocarcenoma that arises from the pancreatic cells themselves, referred to as the “far more common form of pancreatic cancer” by Jobs. He further wrote in his memo “…(adenocarcenoma) is currently not curable and usually carries a life expectancy of around one year after diagnosis. I mention this because when one hears ‘pancreatic cancer’ (or Googles it), one immediately encounters this far more common and deadly form, which, thank God, is not what I had.”

Dr. Steinman won the 2011 Nobel Prize for Medicine or Physiology for his early-career landmark discovery about the immune system in the 1970s when he first described ‘dendritic cells’ with the help of his mentor Zanvil Cohn at Rockefeller University. Unfortunately, he died just three days before the official announcement. http://www.scientificamerican.com/article.cfm?id=steinman-nobel-laureate-explains-discovery-dendritic-cells. He had been suffering from pancreatic cancer for four years, had been undergoing treatment using a pioneering immunotherapy based on his own research. Dendritic cells from his body were deployed to mount an assault on his cancer. His early research at Rockefeller, began as an attempt to understand the primary white cells of the immune system — the large “eating” macrophages and the exquisitely specific lymphocytes, which operate in a variety of ways to spot, apprehend and destroy infectious microorganisms and tumor cells. Steinman’s subsequent research pointed to dendritic cells as important and unique accessories in the onset of several immune responses, including clinically important situations such as rejection of graft, resistance to tumors, autoimmune diseases and infections including AIDS. http://newswire.rockefeller.edu/2011/10/03/rockefeller-university-scientist-ralph-steinman-honored-today-with-nobel-prize-for-discovery-of-dendritic-cells-dies-at-68/

The standard of care in the United States for the treatment of locally advanced pancreatic cancer is a combination of low-dose chemotherapy given simultaneously with radiation treatments to the pancreas and surrounding tissues. Radiation treatments are designed to lower the risk of local growth of the cancer, thereby minimizing the symptoms that local progression causes (back or belly pain, nausea, loss of appetite, intestinal blockage, jaundice). http://www.medicinenet.com/pancreatic_cancer/page6.htm#advanced

Research Efforts on Pancreatic Cancer: The untimely passing of the geniuses reminds us how important research in the area of pancreatic cancer is which lead to finding new therapeutic targets that might stem reliable therapies. A recent example is the report published in Science Daily stating that the protein RGL2 might be a promising therapeutic target for pancreatic cancer. http://www.sciencedaily.com/releases/2010/11/101105101400.htm. The conclusion was derived via research published in November in the Journal of Biological Chemistry by a team led by Channing Der, PhD from UNC Lineberger Cancer Center. http://www.jbc.org/content/285/45/34729.long   For almost three decades, scientists and physicians have known that a gene called the KRAS oncogene is mutated in virtually all pancreatic cancers, making it an important target for scientists looking for a way to stop the growth of pancreatic cancer tumors. The problem is that the KRAS gene triggers cancer cell growth in numerous ways, through multiple cell signaling pathways, and scientists have had difficulty determining which one will be the most promising to block — an important first step in designing a drug for use in patients. Dr. Der said that “We are particularly optimistic about RGL2 because we know that this protein is a critical component of KRAS signaling to another class of proteins called Ral GTPases, which are essential for the growth of almost all pancreatic tumors.”

Another groundbreaking research was published in the journal Nature talks about discovering the link between a gene and the prognosis of Pancreatic Ductal Adenocarcenoma. The team found that when a gene involved in protein degradation is switched-off through chemical tags on the DNA’s surface, pancreatic cancer cells are protected from the bodies’ natural cell death processes, become more aggressive, and can rapidly spread. Their research study proposed USP9X to be a major tumour suppressor gene with prognostic and therapeutic relevance in pancreatic cancer. http://www.sanger.ac.uk/about/press/2012/120429.html http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature11114.pdf

Although, most of the research efforts are concentrated on the more common form of cancer, pancreatic adenocarcenoma, similar research efforts are needed for developing cure for the uncommon form, the one Steve Jobs suffered from, neuroendocrine cancer.

What we lost to the disease is more than the two geniuses, we lost the possibility of further innovation that might have changed the world in ways we could not imagine. The loss, though, sheds light on the importance of finding a cure for the disease and its different types. Hope the research community is able to interpret and find answers to the enigma of Pancreatic cancer and its diverse forms in which it strikes.

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Early Biomarker for Pancreatic Cancer Identified

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Uncategorized, tagged , , , , , , on May 17, 2012| 4 Comments »

Early Biomarker for Pancreatic Cancer Identified

Reporter: Prabodh Kandala, PhD

Article 10.5. Early Biomarker for Pancreatic Cancer Identified

Researchers at the University of California, San Diego School of Medicine and Moores Cancer Center have identified a new biomarker and therapeutic target for pancreatic cancer, an often-fatal disease for which there is currently no reliable method for early detection or therapeutic intervention.

Pancreatic ductal adenocarcinoma, or PDAC, is the fourth-leading cause of cancer-related death. Newly diagnosed patients have a median survival of less than one year, and a 5-year survival rate of only 3 to 5 percent. Therefore, biomarkers that can identify early onset of PDAC and which could be viable drug targets are desperately needed.

‘”We found that a kinase called PEAK1 is turned on very early in pancreatic cancer,” said first author Jonathan Kelber, PhD, a postdoctoral researcher in the UCSD Department of Pathology and Moores Cancer Center. “This protein was clearly detected in biopsies of malignant tumors from human patients — at the gene and the protein levels — as well as in mouse models.”

PEAK1 is a type of tyrosine kinase — an enzyme, or type of protein, that speeds up chemical reactions and acts as an “on” or “off” switch in many cellular functions. The fact that PEAK1 expression is increased in human PDAC and that its catalytic activity is important for PDAC cell proliferation makes it an important candidate as a biomarker and therapeutic target for small molecule drug discovery.

In addition to showing that levels of PEAK1 are increased during PDAC progression, the scientists found that PEAK1 is necessary for the cancer to grow and metastasize.

“PEAK1 is a critical signaling hub, regulating cell migration and proliferation,” said Kelber. “We found that if you knock it out in PDAC cells, they form significantly smaller tumors in preclinical mouse models and fail to metastasize efficiently.”

The research team, led by principal investigator Richard Klemke, PhD, UCSD professor of pathology, studied a large, on-line data base of gene expression profiles to uncover the presence of PEAK1 in PDAC. These findings were corroborated at the protein level in patient biopsy samples from co-investigator Michael Bouvet, MD, and in mouse models developed by Andrew M. Lowy, MD, both of the UCSD Department of Surgery at Moores Cancer Center.

While many proteins are upregulated in cancers of the pancreas, there has been limited success in identifying candidates that, when inhibited, have potential as clinically approved therapeutics. However, the researchers found that inhibition of PEAK1-dependent signaling sensitized PDAC cells to existing chemotherapies such as Gemitabine, and immunotherapies such as Trastuzumab.

“Survival rates for patients with pancreatic cancer remain low,” said Bouvet. “Therefore, earlier detection and novel treatment strategies are very important if we are going to make any progress against pancreatic cancer. Since current therapies are often ineffective, our hope is that the findings from this research will open up a new line of investigation to bring a PEAK1 inhibitor to the clinic.”

Abstract:

Early biomarkers and effective therapeutic strategies are desperately needed to treat pancreatic ductal adenocarcinoma (PDAC), which has a dismal 5-year patient survival rate. Here, we report that the novel tyrosine kinase PEAK1 is upregulated in human malignancies, including human PDACs and pancreatic intraepithelial neoplasia (PanIN). Oncogenic KRas induced a PEAK1-dependent kinase amplification loop between Src, PEAK1, and ErbB2 to drive PDAC tumor growth and metastasis in vivo. Surprisingly, blockade of ErbB2 expression increased Src-dependent PEAK1 expression, PEAK1-dependent Src activation, and tumor growth in vivo, suggesting a mechanism for the observed resistance of patients with PDACs to therapeutic intervention. Importantly, PEAK1 inactivation sensitized PDAC cells to trastuzumab and gemcitabine therapy. Our findings, therefore, suggest that PEAK1 is a novel biomarker, critical signaling hub, and new therapeutic target in PDACs. Cancer Res; 72(10); 2554–64. ©2012 AACR.

http://cancerres.aacrjournals.org/content/72/10/2554

http://www.sciencedaily.com/releases/2012/05/120515070305.htm

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