From Genetic Engineering and Biotechnology News: GEN News Highlights: Mar 29, 2012

http://www.genengnews.com/gen-news-highlights/cancer-cell-line-encyclopedia-released-to-aid-drug-discovery-and-clinical-trials/81246560/

Mar 29, 2012 Cancer Cell Line Encyclopedia Released to Aid Drug Discovery and Clinical Trials http://www.nature.com/nature/journal/v483/n7391/full/nature11003.html

http://www.broadinstitute.org/ccle/home

http://www.nature.com/nature/journal/v483/n7391/full/nature11005.html

Scientists have made a catalogue of genetic and molecular data on nearly 1,000 cancer cell lines publicly available. They hope it will aid the design of anticancer therapeutics and clinical trials. The Cancer Cell Line Encyclopedia (CCLE) has been drafted by a team led by researchers at the Broad Institute, Harvard Medical School, and the Novartis Institutes for Biomedical Research. It comprises a compilation of gene expression, chromosomal copy number, and massively parallel sequencing data from 947 human cancer cell lines used in drug research and development.

The cell lines were acquired from commercial vendors in the U.S., Europe, Japan, and Korea and represent what the researchers say is a diverse picture of cancer as a disease by including subtypes of both common and rare forms of cancer. Each cell line has been genetically characterized through a series of high-throughput analyses at the Broad Institute, including global RNA-expression patterns and DNA sequence variations in about 1,600 cancer-associated genes. Pharmacologic profiling for several drugs was possible in about half of the cell lines. Algorithms were developed to predict drug responses based on the genetic and molecular makeup of cancer cells.

The Broad Institute’s Levi A. Garraway, Ph.D., and colleagues report on the CCLE in a paper in Nature titled “The CancerCell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity.” The paper runs alongside another study, led by researchers at the Wellcome Trust Sanger Institute, Harvard Medical School, and Dana Farber Cancer Institute, which involved screening a panel of several hundred diverse cancer cell lines with 130 drugs under clinical and preclinical investigation to help identify new biomarkers of drug response. This paper is titled “Systematic identification of genomic markers of drug sensitivity in cancer cells.”

Outlining their development of the CCLE, Dr. Garraway’s team describe proof-of-principal studies in which the resource was coupled with pharmacological profiles for 24 anticancer drugs to identify genetic, lineage, and gene-expression-based predictors of drug sensitivity. Interestingly, the results suggested that cell lineage is a major predictive feature for response of cells to a number of compounds, including that of hematological lineage cell lines to HDAC inhibitor panobinostat.

The results similarly indicated that enhanced sensitivity of some NRAS-mutant cell lines to MEK inhibitors relates to a dependence on aryl hydrocarbon receptor (AHR) function and that in some instances elevated AHR may serve as a mechanistic biomarker for enhanced MEK inhibitor sensitivity. Further analyses indicated that multiple myeloma may respond to IGF1 receptor inhibitors, while SLFN11 expression was identified as the top correlate of sensitivity to irinotecan therapy. In fact all three Ewing’s sarcoma cell lines screened showed high SLFN11 expression and sensitivity to irinotecan.

“Ewing’s sarcomas also exhibited the highest SLFN11 expression among 4,103 primary tumor samples spanning 39 lineages, suggesting that topoisomerase I inhibitors might offer an effective treatment option for this cancer type,” the authors write. “Towards this end, several ongoing trials in Ewing’s sarcoma are examining irinotecan-based combinations or the addition of topotecan to standard regimen.”

The authors aim to build on the CCLE resource by adding in analyses based on deeper sequencing, metabolic activity profiles and epigenetic modifications. The current knowledge base represents what the authors claim is just the tip of the iceberg in terms of potential. “With this initial effort, we have taken some critical first steps,” comments co-author Todd Golub, Ph.D., director of the Broad Institute’s cancer program and Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute. “The challenge now is to greatly expand the number of compounds tested across the panel of cell lines.”

The published work by the Sanger Institute-led team separately identified a strong association between the EWS-FLI1 rearrangement characteristic of Ewing’s sarcoma tumors and sensitivity to the PARP inhibitor olaparib (AZD2281) and a structurally distint PARP inhibitor AG-014699. PARP inhibitors are known to be active against BRCA1- and BRCA2-mutant cancers, and the effectiveness of these drugs against the EWS-FLI1-carrying Ewing’s sarcoma cells was comparable to that in BRCA-deficient cells.

“The observation of PARP inhibitor sensitivity by EWS-FLI1-positive Ewing’s sarcoma cell lines points to the likelihood of new potent gene-drug associations, as novel chemical and genomic space are explored,” write Massachusetts General Hospital Cancer Center lead author Cyril H. Benes, M.D., et. al. “By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.”

Combination Targeted Therapy Well Tolerated, Effective for Refractory Ewing’s Sarcoma Tumors http://www.newswise.com/articles/combination-targeted-therapy-well-tolerated-effective-for-refractory-ewing-s-sarcoma-tumors

Released: 3/27/2012 1:00 PM EDT Embargo expired: 3/31/2012 2:30 PM EDT Source: American Association for Cancer Research (AACR)

This abstract will be presented at an AACR press conference on Saturday, March 31 at 1:30 p.m. CT in room CC20 A/B/C of the Hyatt McCormick Conference Center. Reporters who cannot attend in person may participate by calling in with the following information: U.S. & Canada: (888) 647-7462 International: (201) 604-0169

Newswise — CHICAGO — A combination of targeted therapies may be effective against relapsed or recurrent Ewing’s sarcoma or desmoplastic small-round-cell tumors, according to results of a phase I trial presented at the AACR Annual Meeting 2012, held here March 31 – April 4, and published simultaneously in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“Ewing’s sarcoma (EWS) is the second most common bone malignancy striking children, adolescents and young adults in the prime of their lives,” said lead researcher Aung Naing, M.D., assistant professor in the department of investigational cancer therapeutics in the division of cancer medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas. “More treatment options are needed for this disease, because relapse of the disease is quite frequent.

“When tested in the treatment of the EWS family of tumors, single-agent insulin growth factor-1 receptor (IGF-1R) inhibitors and the mTOR inhibitors given as monotherapy have produced variable outcomes.”

The researchers evaluated a subset of 20 patients, including 17 with EWS and three with desmoplastic small-round-cell tumors (DSRCT), who were treated as part of an expansion cohort from a phase I study of an IGF-1R inhibitor, cixutumumab, and the mTOR inhibitor temsirolimus.

All patients had been pretreated heavily before enrolling in the study. Researchers assigned patients to four-week cycles of 6 mg/kg cixutumumab and 25 mg to 37.5 mg of temsirolimus.

At a median follow-up of 8.9 months, they observed prolonged stable disease lasting more than six months and two complete responses in 29 percent of the patients with EWS. Notably, in one patient who had previously demonstrated a marked clinical response to a different IGF-1R targeted antibody before acquiring resistance, combining IGF-1R inhibition and mTOR inhibition induced a complete response, which provides strong evidence for synergy between mTOR and IGF-1R antagonists. Four responders developed grade 3 mucositis, myelosuppression or hyperglycemia, which were treated with supportive therapy.

“This study demonstrated early evidence that this combination can be considered for patients with relapsed and recurrent diseases,” Naing said. “Further studies in larger numbers of patients with EWS and DSRCT as well as additional investigation into underlying resistance mechanisms in individual patients are needed.”

Press registration for the AACR Annual Meeting 2012 is free to qualified journalists and public information officers: http://www.aacr.org/PressRegistration.

Follow the AACR on Twitter: @aacr#aacrFollow the AACR on Facebook: http://www.facebook.com/aacr.org

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About the AACR Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR’s membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for patient benefit. The AACR actively communicates with legislators and policy makers about the value of cancer research and related biomedical science in saving lives from cancer.

For more information about the AACR, visit www.AACR.org.

Presenter: Aung Naing, M.D.

Abstract Number: LB-124/CCR-12-0061

Title: Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing’s Sarcoma Family Tumors

Author Block: Aung Naing, Patricia LoRusso, Vivek Subbiah, Siqing Fu, David Hong, Peter Anderson, Robert Benjamin, Joseph Ludwig, Helen X. Chen, Austin Doyle, Razelle Kurzrock. UT MD Anderson Cancer Ctr., Houston, TX, Karmanos Cancer Institute, Detroit, MI, CTEP National Cancer Insititute, Rockville, MD, National Cancer Institute, Rockville, MD

Background: Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at insulin growth factor-1 receptor (IGF-1R), on the basis of preclinical data suggesting that the combination could overcome resistance in Ewing’s sarcoma (EWS).

Methods: Patients received cixutumumab, 6 mg/kg IV weekly, and temsirolimus, 25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Median follow up was 8.9 months.

Results: Twenty patients (17 with EWS, 3 with desmoplastic small-round-cell tumor [DSCRT]) were enrolled. Twelve patients (60%) were men; median age, 24 years; median number of prior therapies, 6. Six patients previously received an IGF-1R inhibitor and two, temsirolimus. The most frequent toxicities, at least possibly drug-related, were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%) (mostly grade 1-2). Seven of 20 patients (35%) achieved stable disease (SD) >5 months or complete/partial (CR/PR) responses (duration = 5.6, 5.7, 8, 2 +, 18+, 15, 22+ months). Tumor regression of over 20% (100%, 100%, 27%, 23%, 23%) occurred in 5/17 (29%) EWS patients with time to treatment failure lasting 22, 2+, 15, 18 and 8 months, respectively. Biopsy samples of one patient taken at the time of emergence of resistance to a different IGF-1R inhibitor, demonstrated upregulation of mTOR pathway proteins, as determined by morphoproteomic analysis of the resistant tumor; and this particular patient achieved a CR with a time to treatment failure of 22 months on our trial. A second patient with EWS had a PR with prior IGF-1R treatment and then had a mixed response with remarkable regression in three lung modules after instituting cixutumumab and temsirolimus, but progression in a fourth lesion. Morphoproteomic analysis of this patient’s resistant tumor demonstrated upregulation of mTOR and ERK/MEK signals . The latter suggests the possibility that a combination of IGFR/mTOR and MEK inhibitors might warrant investigation in order to reverse resistance. Four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which was controlled while maintaining drug dose. Side effects of this regimen were well controlled with medication and the assistance of an endocrinologist, when necessary

Conclusions: This mechanism-based approach shows evidence of activity for temsirolimus and cixutumumab in EWS family tumors. The majority of best responders developed grade 3 side effects which were well controlled by supportive measures, suggesting that drug dose should not be compromised.

This study was supported by R21CA13763301A1 (Aung Naing), U01CA62461 (Razelle Kurzrock), and U01CA62487 (Patricia LoRusso)

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279575.htm?utm_source=twitterfeed

FDA NEWS RELEASE For Immediate Release: November 10, 2011 Media Inquiries: Shelly Burgess, 301-796-4651, shelly.burgess@fda.hhs.gov Consumer Inquiries: 888-INFO-FDA

FDA approves first cord blood product

The U.S. Food and Drug Administration today approved HEMACORD, the first licensed hematopoietic progenitor cells-cord (HPC-C) cell therapy.

HEMACORD is indicated for use in hematopoietic stem cell transplantation procedures in patients with disorders affecting the hematopoietic (blood forming) system. For example, cord blood transplants have been used to treat patients with certain blood cancers and some inherited metabolic and immune system disorders.

“The use of cord blood hematopoietic progenitor cell therapy offers potentially life-saving treatment options for patients with these types of disorders,” said Karen Midthun, M.D., director, FDA’s Center for Biologics Evaluation and Research.

HEMACORD contains hematopoietic progenitor cells (HPCs) from human cord blood. Cord blood is one of three sources of HPCs used in transplants; the other two are bone marrow and peripheral blood. Once these HPCs are infused into patients, the cells migrate to the bone marrow where they divide and mature. When the mature cells move into the bloodstream they can partially or fully restore the number and function of many blood cells, including immune function.

In an effort to assist manufacturers in applying for licensure for certain cord blood units, FDA issued the 2009 guidance document entitled “Guidance for Industry: Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications.” FDA instituted a two-year phase-in period for HPC-C manufacturers to submit either a license application or an investigational new drug application. That phase-in period ended Oct. 20, 2011, and these manufacturers now must submit such applications.

Approval of HEMACORD was based on reliance on safety and effectiveness data submitted to a public docket and data submitted in the license application demonstrating compliance with other regulatory requirements. This is the first approval of a license application for cord blood.

HEMACORD has a boxed warning regarding the risks of Graft Versus Host Disease (GVHD), engraftment syndrome, graft failure, and infusion reactions, each of which may be fatal. Patients who receive HEMACORD should be monitored carefully. A risk benefit assessment, unit selection and administration of HEMACORD should be done under the direction of a physician experienced in hematopoietic stem cell transplantation.

HEMACORD is manufactured by the New York Blood Center, Inc., based in New York, NY.

For more information:

BLA Guidance

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279575.htm?utm_source=twitterfeed

Product Approval -Hemacord http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/default.htm

http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/default.htm

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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http://www.merck.com/newsroom/news-release-archive/research-and-development/2011_1005.html

FDA Accepts New Drug Application Filing for
Ridaforolimus, Investigational mTOR Inhibitor

WHITEHOUSE STATION, N.J. & CAMBRIDGE, Mass., Oct. 5, 2011 — Merck (NYSE:MRK),
known outside the United States and Canada as MSD, and ARIAD Pharmaceuticals,
Inc., (NASDAQ:ARIA), today announced that the U.S. Food and Drug Administration
(FDA) has accepted for filing and review the New Drug Application (NDA) for
ridaforolimus, an investigational oral mTOR inhibitor under development for the
treatment of metastatic soft-tissue or bone sarcomas in patients who had a
favorable response to chemotherapy. The FDA assigned a Standard review
classification to this application.

Merck and ARIAD previously announced that the European Medicines Agency had
accepted the marketing authorization application for ridaforolimus. As part of
an exclusive license agreement with ARIAD, Merck is responsible for the
development and worldwide commercialization of ridaforolimus in oncology. ARIAD
intends to co-promote ridaforolimus in the United States.

About Sarcoma
Sarcomas are a group of cancers of connective tissue of the body for which there
are currently limited treatment options. Sarcomas can arise anywhere in the body
and are divided into two main groups – bone tumors and soft-tissue sarcomas.

About Ridaforolimus
Ridaforolimus is an investigational targeted and potent small-molecule inhibitor
of the protein mTOR, a protein that acts as a central regulator of protein
synthesis, cell proliferation, cell cycle progression and cell survival,
integrating signals from proteins, such as PI3K, AKT and PTEN, known to be
important to malignancy.

Merck's Commitment to Oncology
Merck is committed to advancing all aspects of cancer care – prevention,
treatment and supportive care. Through strong internal research capabilities,
selective alliances and acquisitions, and enabling technologies, Merck is
looking to lead in the discovery, development and delivery of anticancer
therapies.

About Merck
Today's Merck is a global healthcare leader working to help the world be well.
Merck is known as MSD outside the United States and Canada. Through our
prescription medicines, vaccines, biologic therapies, and consumer care and
animal health products, we work with customers and operate in more than 140
countries to deliver innovative health solutions. We also demonstrate our
commitment to increasing access to healthcare through far-reaching policies,
programs and partnerships. For more information, visit
www.merck.com and connect
with us on Twitter, Facebook and YouTube.

About ARIAD
ARIAD Pharmaceuticals, Inc. is an emerging global oncology company focused on
the discovery, development and commercialization of medicines to transform the
lives of cancer patients. ARIAD's approach to structure-based drug design has
led to three internally discovered, molecularly targeted product candidates for
drug-resistant and difficult-to-treat cancers, including certain forms of
chronic myeloid leukemia, soft tissue and bone sarcomas and non-small cell lung
cancer. For additional information, visit
http://www.ariad.com.

Merck Forward-Looking Statement
This news release includes “forward-looking statements” within the meaning of
the safe harbor provisions of the United States Private Securities Litigation
Reform Act of 1995. Such statements may include, but are not limited to,
statements about the benefits of the merger between Merck and Schering-Plough,
including future financial and operating results, the combined company's plans,
objectives, expectations and intentions and other statements that are not
historical facts. Such statements are based upon the current beliefs and
expectations of Merck's management and are subject to significant risks and
uncertainties. Actual results may differ from those set forth in the
forward-looking statements.

The following factors, among others, could cause actual results to differ
from those set forth in the forward-looking statements: the possibility that the
expected synergies from the merger of Merck and Schering-Plough will not be
realized, or will not be realized within the expected time period; the impact of
pharmaceutical industry regulation and health care legislation; the risk that
the businesses will not be integrated successfully; disruption from the merger
making it more difficult to maintain business and operational relationships;
Merck's ability to accurately predict future market conditions; dependence on
the effectiveness of Merck's patents and other protections for innovative
products; the risk of new and changing regulation and health policies in the
United States and internationally and the exposure to litigation and/or
regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking
statement, whether as a result of new information, future events or otherwise.
Additional factors that could cause results to differ materially from those
described in the forward-looking statements can be found in Merck's 2010 Annual
Report on Form 10-K and the company's other filings with the Securities and
Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

ARIAD Forward-Looking Statement
This press release contains “forward-looking statements” including, but not
limited to, statements relating to clinical data for ridaforolimus in the
treatment of metastatic soft-tissue and bone sarcomas. Forward-looking
statements are based on management's expectations and are subject to certain
factors, risks and uncertainties that may cause actual results, outcome of
events, timing and performance to differ materially from those expressed or
implied by such statements. These risks and uncertainties include, but are not
limited to, results of clinical studies of the Company's product candidates,
timing and acceptance of regulatory filings for drug approval, and other factors
detailed in the Company's public filings with the U.S. Securities and Exchange
Commission. The information contained in this press release is believed to be
current as of the date of original issue. The Company does not intend to update
any of the forward-looking statements after the date of this document to conform
these statements to actual results or to changes in the Company's expectations,
except as required by law.

# # #

http://www.jci.org/articles/view/42874?search[article_text]=arsenic&search[authors_text]=

Arsenic
trioxide inhibits human cancer

cell growth and tumor development in

mice by
blocking Hedgehog/GLI

pathway

Elspeth M.
Beauchamp¹,
Lymor Ringer¹,
Gülay Bulut¹,
Kamal P. Sajwan¹,
Michael D. Hall¹,
Yi-Chien Lee¹,
Daniel Peaceman¹,
Metin Özdemirli¹,
Olga Rodriguez¹,
Tobey J. Macdonald²,
Chris Albanese¹,
Jeffrey A. Toretsky¹
and Aykut Üren¹

¹Lombardi
Comprehensive Cancer Center, Georgetown University Medical Center, Washington,
DC, USA.
²Department
of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.

Address correspondence to: Aykut Üren, 3970
Reservoir Rd. NW, NRB, Room E312, Washington, DC 20057, USA. Phone:
202.687.9504; Fax: 202.687.1434; E-mail:
au26@georgetown.edu.

First published December 22, 2010
Received for publication March 4, 2010, and accepted in revised form October 13,
2010.