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Archive for the ‘Genomic Expression’ Category


Pharmacotyping Pancreatic Cancer Patients in the Future: Two Approaches – ORGANOIDS by David Tuveson and Hans Clevers and/or MICRODOSING Devices by Robert Langer

Curator: Aviva Lev-Ari, PhD, RN

 

This curation provides the resources for edification on Pharmacotyping Pancreatic Cancer Patients in the Future

 

  • Professor Hans Clevers at Clevers Group, Hubrecht University

https://www.hubrecht.eu/onderzoekers/clevers-group/

  • Prof. Robert Langer, MIT

http://web.mit.edu/langerlab/langer.html

Langer’s articles on Drug Delivery

https://scholar.google.com/scholar?q=Langer+on+Drug+Delivery&hl=en&as_sdt=0&as_vis=1&oi=scholart&sa=X&ved=0ahUKEwixsd2w88TTAhVG4iYKHRaIAvEQgQMIJDAA

organoids, which I know you’re pretty involved in with Hans Clevers. What are your plans for organoids of pancreatic cancer?

Organoids are a really terrific model of a patient’s tumour that you generate from tissue that is either removed at the time of surgery or when they get a small needle biopsy. Culturing the tissue and observing an outgrowth of it is usually successful and when you have the cells, you can perform molecular diagnostics of any type. With a patient-derived organoid, you can sequence the exome and the RNA, and you can perform drug testing, which I call ‘pharmacotyping’, where you’re evaluating compounds that by themselves or in combination show potency against the cells. A major goal of our lab is to work towards being able to use organoids to choose therapies that will work for an individual patient – personalized medicine.

Organoids could be made moot by implantable microdevices for drug delivery into tumors, developed by Bob Langer. These devices are the size of a pencil lead and contain reservoirs that release microdoses of different drugs; the device can be injected into the tumor to deliver drugs, and can then be carefully dissected out and analyzed to gain insight into the sensitivity of cancer cells to different anticancer agents. Bob and I are kind of engaged in a friendly contest to see whether organoids or microdosing devices are going to come out on top. I suspect that both approaches will be important for pharmacotyping cancer patients in the future.

From the science side, we use organoids to discover things about pancreatic cancer. They’re great models, probably the best that I know of to rapidly discover new things about cancer because you can grow normal tissue as well as malignant tissue. So, from the same patient you can do a comparison easily to find out what’s different in the tumor. Organoids are crazy interesting, and when I see other people in the pancreatic cancer field I tell them, you should stop what you’re doing and work on these because it’s the faster way of studying this disease.

SOURCE

Other related articles on Pancreatic Cancer and Drug Delivery published in this Open Access Online Scientific Journal include the following:

 

Pancreatic Cancer: Articles of Note @PharmaceuticalIntelligence.com

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/05/26/pancreatic-cancer-articles-of-note-pharmaceuticalintelligence-com/

Keyword Search: “Pancreatic Cancer” – 275 Article Titles

https://pharmaceuticalintelligence.wordpress.com/wp-admin/edit.php?s=Pancreatic+Cancer&post_status=all&post_type=post&action=-1&m=0&cat=0&paged=1&action2=-1

Keyword Search: Drug Delivery: 542 Articles Titles

https://pharmaceuticalintelligence.wordpress.com/wp-admin/edit.php?s=Drug+Delivery&post_status=all&post_type=post&action=-1&m=0&cat=0&paged=1&action2=-1

Keyword Search: Personalized Medicine: 597 Article Titles

https://pharmaceuticalintelligence.wordpress.com/wp-admin/edit.php?s=Personalized+Medicine&post_status=all&post_type=post&action=-1&m=0&cat=0&paged=1&action2=-1

  • Cancer Biology & Genomics for Disease Diagnosis, on Amazon since 8/11/2015

http://www.amazon.com/dp/B013RVYR2K

 

 

VOLUME TWO WILL BE AVAILABLE ON AMAZON.COM ON MAY 1, 2017

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A novel 5-gene pancreatic adenocarcinoma classifier: Meta-analysis of transcriptome data – Clinical Genomics Research @BIDMC

Curator: Tilda Barliya, PhD

Analysis of  Bhasin et al paper and Literature search

Table 1: 5-genes classifiers as biomarkers for PDAC:

Gene symbol Gene name Subcellular localization
ECT2 Epithelial cell transforming sequence 2 oncogene Nucleus, cytoplasm
AHNAK2 AHNAKE nucleoprotein 2 Plasma membrane, cytoplasm
POSTN Periostin, osteoblast specific factor Extracellular space
TMPRSS4 Transmembrane protease, serine 4 Plasma membrane

 

SERPINB5 Serpin peptidase inhibitor, clade B (ovalbumin) member 5 Extracellular space


Introduction
:

  • Bhasin et al, conducted a beautiful study using a powerful meta-analysis from different sources to identify the “important/classifier” genes associated with Pancreatic Cancer (PDAC).
  • The authors identified 5 genes that were considered as good classifiers (table 1).
  • It is important to note that the meta-analysis was performed on tissue and microdissection samples.
  • In their summary, the authors aim to validate these genes in blood/urine samples.
  • While these genes might be over expressed in tissue samples it may not be true to their existence in blood and careful examination and validation is required.
  • Liquid biopsies are emerging as the go-to use tools for disease detection, mostly aimed for early diagnosis.
  • Liquid biopsies are non-invasive biopsies of blood, urine (potentially saliva) and their “exotic” components, i.e miRNA, exosomes etc.
  • Since Liquid biopsies are non-invasive, they are painless and patients are more complied.
  • It is important to note that there is a gap between the expression of a gene or a protein in tissue section and their expression in the blood and may not necessarily correlate.
  • It will be very interesting to follow their research and future outcomes.

Additional References:

  • TMPRSS4: an emerging potential therapeutic target in cancer.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453593/

  • The tumour trail left in blood

http://www.nature.com/nature/journal/v532/n7598/full/532269a.html

Aashir Awan, PhD, wrote on 12/28/2016

I was wondering if these same 5 genes were upregulated in the pancreatic ductal adenocarcinoma cell lines that are available out there.  In doing cell biology work, there is always a dilemma whether cancer cell lines correctly re-capitulate in vivo tumors or not.  Personally, I prefer primary cell lines to do analysis but this finding can be used to test primary vs cell line.  In addition, I’ve attached the gene network for Ect2.  If you look carefully, the two big proteins that jump out are RACGAP1 and KIF23.  I think in designing therapies, combinatorial targets can yield the best outcomes.  Drugs directed towards two or more targets would seem ideal in my opinion.

ect2

Gene Network for Ect2

Original Research
Oncotarget. 2016 Apr 26;7(17):23263-81. doi: 10.18632/oncotarget.8139.

Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier.

Abstract

PURPOSE:

Pancreatic ductal adenocarcinoma (PDAC) is largely incurable due to late diagnosis. Superior early detection biomarkers are critical to improving PDAC survival and risk stratification.

EXPERIMENTAL DESIGN:

Optimized meta-analysis of PDAC transcriptome datasets identified and validated key PDAC biomarkers. PDAC-specific expression of a 5-gene biomarker panel was measured by qRT-PCR in microdissected patient-derived FFPE tissues. Cell-based assays assessed impact of two of these biomarkers, TMPRSS4 and ECT2, on PDAC cells.

RESULTS:

A 5-gene PDAC classifier (TMPRSS4, AHNAK2, POSTN, ECT2, SERPINB5) achieved on average 95% sensitivity and 89% specificity in discriminating PDAC from non-tumor samples in four training sets and similar performance (sensitivity = 94%, specificity = 89.6%) in five independent validation datasets. This classifier accurately discriminated PDAC from chronic pancreatitis (AUC = 0.83), other cancers (AUC = 0.89), and non-tumor from PDAC precursors (AUC = 0.92) in three independent datasets. Importantly, the classifier distinguished PanIN from healthy pancreas in the PDX1-Cre;LSL-KrasG12D PDAC mouse model. Discriminatory expression of the PDAC classifier genes was confirmed in microdissected FFPE samples of PDAC and matched surrounding non-tumor pancreas or pancreatitis. Notably, knock-down of TMPRSS4 and ECT2 reduced PDAC soft agar growth and cell viability and TMPRSS4 knockdown also blocked PDAC migration and invasion.

CONCLUSIONS:

This study identified and validated a highly accurate 5-gene PDAC classifier for discriminating PDAC and early precursor lesions from non-malignant tissue that may facilitate early diagnosis and risk stratification upon validation in prospective clinical trials. Cell-based experiments of two overexpressed proteins encoded by the panel, TMPRSS4 and ECT2, suggest a causal link to PDAC development and progression, confirming them as potential therapeutic targets.

KEYWORDS:

bioinformatics; biomarkers; meta-analysis; pancreatic cancer; transcriptome

PMID:
26993610
PMCID:
PMC5029625
DOI:
10.18632/oncotarget.8139

SOURCE

Oncotarget, Vol. 7, No. 17 – Referred as PDF, above

 

BIDMC Researchers Discover Early Indicators of Pancreatic Cancer

LibermannBhasin_PancreasCancerStudy

Markers may help doctors detect pancreatic cancer before it becomes deadly

In photo: First author Manoj Bhasin, PhD, and co-senior author Towia Libermann, PhD, Co-Director and Director of BIDMC’s Genomics, Proteomics, Bioinformatics and Systems Biology Center.

SOURCE

http://www.bidmc.org/News/PRLandingPage/2016/March/Libermann-Pancreatic-Cancer-Research-2016.aspx

BOSTON – Pancreatic cancer, the fourth leading cause of cancer death in the United States, is often diagnosed at a late stage, when curative treatment is no longer possible. A team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has now identified and validated an accurate 5-gene classifier for discriminating early pancreatic cancer from non-malignant tissue. Described online in the journal Oncotarget, the finding is a promising advance in the fight against this typically fatal disease.

“Pancreatic cancer is a devastating disease with a death rate close to the incidence rate,” said co-senior author Towia Libermann, PhD, Director of the Genomics, Proteomics, Bioinformatics and Systems Biology Center at BIDMC and Associate Professor of Medicine at Harvard Medical School (HMS). “Because more than 90 percent of pancreatic cancer cases are diagnosed at the metastatic stage, when there are only limited therapeutic options, earlier diagnosis is anticipated to have a major impact on extending life expectancy for patients. There has been a lack of reliable markers, early indicators and risk factors associated with pancreatic cancer, but this new way of differentiating between healthy and malignant tissue offers hope for earlier diagnosis and treatment.”

The investigators used a number of publicly available gene expression datasets for pancreatic cancer and developed a strategy to reanalyze these datasets together, applying rigorous statistical criteria to compare different datasets from different laboratories and different platforms with each other. The team then selected a subset of data for developing a panel for differentiating between pancreatic cancer and healthy pancreas tissue and thereafter applied this “Pancreatic Cancer Predictor” to the remaining datasets for independent validation to confirm the accuracy of the markers.

After demonstrating and independently validating that a 5-gene pancreatic cancer predictor discriminated between cancerous and healthy tissue, the researchers applied the predictor to datasets that also included benign lesions of the pancreas, including pancreatitis and early stage cancer. The predictor accurately differentiated pancreatic cancer, benign pancreatic lesions, early stage pancreatic cancer and healthy tissue. The predictor achieved on average 95 percent sensitivity and 89 percent specificity in discriminating pancreatic cancer from non-tumor samples in four training sets and similar performance (94 percent sensitivity, 90 percent specificity) in five independent validation datasets.

“Using innovative data normalization and gene selection approaches, we combined the statistical power of multiple genomic studies and masked their variability and batch effects to identify robust early diagnostic biomarkers of pancreatic cancer,” said first author Manoj Bhasin, PhD, Co-Director of BIDMC’s Genomics, Proteomics, Bioinformatics and Systems Biology Center and Assistant Professor of Medicine at HMS.

“The identification and initial validation of a highly accurate 5-gene pancreatic cancer biomarker panel that can discriminate late and early stages of pancreatic cancer from normal pancreas and benign pancreatic lesions could facilitate early diagnosis of pancreatic cancer,” said co-senior author Roya Khosravi-Far, PhD, Associate Professor of Pathology at BIDMC. “Our findings may open a window of opportunity for earlier diagnosis and, consequently, earlier intervention and more effective treatment of this deadly cancer, leading to higher survival rates.”

The first diagnostic application of the panel may be for analyses of fine needle biopsies routinely used for diagnosing pancreatic cancer and for determining the malignant potential of mostly benign pancreatic cysts that can sometimes be precursors of pancreatic cancer. In addition to providing a new tool for diagnoses, the research may also lead to new insights into how pancreatic cancer arises.

“Because these five genes are ‘turned on’ so early in the development of pancreatic cancer, they may play roles as drivers of this disease and may be exciting targets for therapies,” said Libermann. Most of the five genes—named TMPRSS4, AHNAK2, POSTN, ECT2 and SERPINB5—have been linked to migration, invasion, adhesion, and metastasis of pancreatic or other cancers.

The scientists next plan to evaluate the precise roles of the five genes and to validate the accuracy of their diagnostic assay in a prospective clinical study. “Moving forward, we will explore the potential to convert this tissue-based diagnostic into a noninvasive blood or urine test,” Libermann said.

“To further enhance the diagnostic power of this biomarker, we plan to expand it by including non-coding RNAs, proteins, metabolites and mutations associated with pancreatic cancer. This will result in development of the first of its kind biomarker that gauges pancreatic cancer alterations from multiple genomic angles for making highly accurate diagnoses,” added Bhasin. Such an inexpensive and simple test could help transform the landscape of pancreatic cancer and help prevent many of the estimated 330,000 deaths that it causes worldwide each year.

Study coauthors include BIDMC investigators Kenneth Ndebele, Octavian Bucur, Eric Yee, Jessica Plati, Andrea Bullock, Xuesong Gu, Eduardo Castan, Peng Zhang, Robert Najarian, Maria Muraru and Rebecca Miksad, and the University of Nebraska-Lincoln’s Hasan H. Otu. The work was supported by the National Institutes of Health, National Cancer Institute and Ben and Rose Cole Charitable Pria Foundation.

SOURCE

http://www.bidmc.org/News/PRLandingPage/2016/March/Libermann-Pancreatic-Cancer-Research-2016.aspx

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Reduction in Mortality in Breast Cancer Patients: Outcome of Drug Interactions

 Reporter: Aviva Lev-Ari, PhD, RN

Drug interactions using gene-expression data: common molecular pathways that might account for drug pairs with apparent synergistic effects, searching for drug-protein interactions in the twoXAR company’s database.
“This is a holistic look at the data — EHR, gene expression, protein targets of drugs — all in one analysis,”

Study reveals drug interactions that may reduce mortality in breast cancer patients

Stanford researchers found that certain drug combinations were associated with lower mortality rates among breast cancer patients, pointing to potential drug targets and new ways of thinking about known diseases.

DEC 9 2016

Nigam Shah

Nigam Shah

Patient health records revealed two drug combinations that may reduce mortality rates in breast cancer patients, according to a study led by researchers at the Stanford University School of Medicine.

The drugs involved were commonly used noncancer drugs that turned out to be associated with a longer average survival rate in breast cancer patients.

The study was published online Dec. 9 in the Journal of the American Medical Informatics Association. The lead author is Stanford postdoctoral scholar Yen Low, PhD. The senior author is Nigam Shah, MBBS, PhD, associate professor of medicine and of biomedical data science.

“So we ran the analysis, and we found a few drug combinations that seemed to associate with better survival,” said Shah.

‘How do we know it’s true?’

Specifically, there were three pairs of drug types. The two combinations in Red are impplicated with improved survivability.

  • anti-inflammatory drugs, such as aspirin or naproxen, and blood-lipid modifiers, such as statins;
  • lipid modifiers and drugs such as fluticasone used to treat asthma like conditions; and
  • anti-inflammatories and anti cancer hormone antagonists — typically, drugs that suppress the synthesis of estrogen.

SOURCE

http://med.stanford.edu/news/all-news/2016/12/study-reveals-drug-interactions-that-may-reduce-mortality.html

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The Parker Institute in SF – A Collaboration of 6 centers, over 40 labs, and over 300 of the nation’s top researchers, all working together to cure Cancer

Reporter: Aviva Lev-Ari, PhD, RN

 

The Parker Institute an unprecedented collaboration between the country’s leading immunologists and cancer centers:  Memorial Sloan Kettering Cancer Center, Stanford University, University of California, Los Angeles, University of California, San Francisco, the University of Pennsylvania, and the University of Texas MD Anderson Cancer Center

Our network brings together the world’s best. We are 6 centers, over 40 labs, and over 300 of the nation’s top researchers, all working together to cure cancer.

Stanford Cancer Institute funding opportunity webpage: http://med.stanford.edu/cancer/research/funding.html

More information about the Parker Institute for Cancer Immunotherapy can be found at: http://www.parkerici.org

Memorial Sloan Kettering Cancer Center: A world-renowned center for cancer treatment and research, pioneering immunotherapy research since the 19th century.

Stanford Medicine: A world class leader in research and information technologies empowering the development of the next generation of immunotherapies.

University of California, Los Angeles: Renowned for cancer research treatment & prevention.

University of California, San Francisco: A basic-research powerhouse – the genetic drivers of cancer were discovered here – and home to one of the world’s top medical centers.

University of Pennsylvania: One of America’s foremost academic medical centers, and the world leader in T cell-based cancer immunotherapy.

The University of Texas MD Anderson Cancer Center:One of the world’s most respected cancer centers, instrumental in the development of cancer immunotherapy based on checkpoints, blockades.

SOURCE

http://www.parkerici.org/institute/overview

Parker Institute for Cancer Immunotherapy and Cancer Research Institute Launch Collaboration on Cancer Neoantigens

Researchers at 30 organizations to test algorithms that predict tumor markers from DNA in hunt for new personalized cancer treatments

Parker Institute and CRI Launch a Neoantigen Alliance

 

SAN FRANCISCO AND NEW YORK – Dec. 1, 2016 – The Parker Institute for Cancer Immunotherapy and the Cancer Research Institute (CRI) today announced a major collaboration focused on neoantigens. The search for these unique cancer markers has become a robust area of research as scientists believe they may hold the key to developing a new generation of personalized, targeted cancer immunotherapies.

This new collaboration, the Tumor neoantigEn SeLection Alliance (TESLA), includes 30 of the world’s leading cancer neoantigen research groups from both academia and industry. Because these tumor markers are both specific to each individual and unlikely to be present on normal healthy cells, neoantigens represent an optimal target for the immune system and make possible a new class of highly personalized vaccines with the potential for significant efficacy with reduced side effects.

“Bringing together the world’s best neoantigen research organizations to accelerate the discovery of personalized cancer immunotherapies is exactly the type of bold research collaboration that I envisioned when launching the Parker Institute,” said Sean Parker, Silicon Valley entrepreneur and founder of the Parker Institute for Cancer Immunotherapy. “This alliance will not only leverage the immense talents of each of the researchers but will also harness the power of bioinformatics, which I believe will be critical to driving breakthroughs.”

The goal of the initiative is to help participating groups test and continually improve the mathematical algorithms they use to analyze tumor DNA and RNA sequences in order to predict the neoantigens that are likely to be present on each patient’s cancer and most visible to the immune system. In support of this, Parker Institute and CRI have partnered with renowned open science nonprofit, Sage Bionetworks, to manage the bioinformatics and data analysis.

Initially, the project is expected to focus on cancers such as advanced melanoma, colorectal cancer and non-small cell lung cancer that tend to have larger numbers of mutations and thus more neoantigens. Over time, the initiative will seek to broaden the relevance of neoantigen vaccines to a wide range of cancers.

Participants come from universities, biotech, the pharmaceutical industry and scientific nonprofits. The researchers represent a wide swath of scientific fields, including immunology, data science, genomics, molecular biology, and physics and engineering.

“This project embodies the spirit of collaboration and partnership between academia, industry and nonprofits that the Parker Institute strives to foster,” said Jeffrey Bluestone, Ph.D., president and CEO of the Parker Institute for Cancer Immunotherapy. “It is a great example of how we are breaking down traditional barriers to conduct groundbreaking, multidisciplinary science to get cancer treatments to patients faster.”

“The Cancer Research Institute and the Parker Institute share a belief that the immune system is a platform technology that can be harnessed to turn all cancers into a curable disease,” said Adam Kolom, Parker Institute vice president of business development and strategic partnerships and CRI’s Clinical Accelerator program director. “We believe that by bringing together the top laboratories in the world that are developing neoantigen prediction software, we will be able to unlock the promise of this next generation of personalized cancer immunotherapies sooner.”

This marks the first major collaboration between the San Francisco-based Parker Institute for Cancer Immunotherapy, launched in April 2016, and the Cancer Research Institute, founded in 1953 in New York City.

“We’re proud to join the Parker Institute in this collaboration, which demonstrates the vital role that nonprofits can play in bringing together stakeholders from across sectors to work alongside one another to advance the field of cancer immunotherapy,” said Jill O’Donnell-Tormey, Ph.D., Cancer Research Institute CEO and director of scientific affairs.

Participating researchers said they looked forward to working collaboratively through the alliance to solve one of immunotherapy’s most complex problems.

“This experiment is truly remarkable because of its potential to help us more precisely identify abnormal proteins in an individual’s tumor that can be used as targets for personalized cancer immunotherapy,” said professor Robert D. Schreiber, Ph.D., director of the Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs at Washington University School of Medicine in St. Louis. “We believe that this type of precision medicine, used alone or with other forms of immunotherapy, will significantly improve our capacity to treat cancer patients more effectively and with fewer side effects than current treatments.”

About Neoantigens

Neoantigens are markers present on the surface of cancer cells but absent on normal tissue, making them attractive drug target candidates. They commonly arise from mutations that occur as tumor cells rapidly divide and multiply. The immune system can recognize these markers as “foreign,” and as a result, target the cancer cell for destruction. In order to predict which neoantigens will be present on a patient’s tumor, researchers have developed software programs to analyze tumor DNA and output the unique set of markers that the immune system is most likely to recognize.

What the Alliance Will Do

Participating research groups will receive genetic sequences from both normal and cancerous tissues. Using each laboratory’s own algorithms, each group will output a set of predicted neoantigens that are anticipated to be present on the tumor cells and recognizable by the immune system. The predictions will then be validated through a series of tests to assess which predictions are most likely to be correct and recognizable by T-cells. Through this effort, each participant will be provided with data to inform and to further improve their algorithms and therefore the potential effectiveness of personalized neoantigen vaccines for cancer.

Participating Organizations

Currently, the research institutions taking part include the Broad Institute of MIT and Harvard, Caltech, the Dana-Farber Cancer Institute, the La Jolla Institute for Allergy and Immunology, the Ludwig Institute for Cancer Research, Roswell Park Cancer Institute, The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, the University of California, Santa Cruz, The Carole and Ray Neag Comprehensive Cancer Center at UConn Health and Washington University School of Medicine. Internationally, scientists from the Fondazione Network Italiano per la Bioterapia dei Tumori, National Cancer Centre Singapore, the National Center for Tumor Diseases at Heidelberg University Hospital and the Netherlands Cancer Institute have also stepped forward to join the project.

Participants from industry include Advaxis; Agenus; Amgen; BioNTech; Bristol-Myers Squibb; Genentech, a member of the Roche Group; ISA Pharmaceuticals; MedImmune, the global biologics research and development arm of AstraZeneca; Neon Therapeutics and Personalis, Inc.

The six academic research centers that make up the core of the Parker Institute are also expected to participate, including: Memorial Sloan Kettering Cancer Center, Stanford Medicine, the University of California, Los Angeles (UCLA), the University of California, San Francisco, the University of Pennsylvania and The University of Texas MDAnderson Cancer Center. Initial tissue samples are expected to be provided by Memorial Sloan Kettering Cancer Center, National Cancer Centre Singapore, Roswell Park Cancer Institute, UCLA, the University Hospital of Siena in Italy and the John Theurer Cancer Center at Hackensack University Medical Center, a member of Hackensack Meridian Health. As the project progresses, the alliance will add to its growing roster of participants.

About the Parker Institute for Cancer Immunotherapy

The Parker Institute for Cancer Immunotherapy brings together the best scientists, clinicians, and industry partners to build a smarter and more coordinated cancer immunotherapy research effort.

The Parker Institute is an unprecedented collaboration between the country’s leading immunologists and cancer centers: Memorial Sloan Kettering Cancer Center, Stanford Medicine, the University of California, Los Angeles, the University of California, San Francisco, the University of Pennsylvania and The University of Texas MD Anderson Cancer Center. The Parker Institute was created through a $250 million grant from The Parker Foundation.

The Parker Institute’s goal is to accelerate the development of breakthrough immune therapies capable of turning cancer into a curable disease by ensuring the coordination and collaboration of the field’s top researchers, and quickly turning their findings into patient treatments. The Parker Institute network brings together six centers, more than 40 industry and nonprofit partners, more than 63 labs and more than 300 of the nation’s top researchers focused on treating the deadliest cancers.

About the Cancer Research Institute

The Cancer Research Institute (CRI), established in 1953, is the world’s leading nonprofit organization dedicated exclusively to transforming cancer patient care by advancing scientific efforts to develop new and effective immune system-based strategies to prevent, diagnose, treat, and eventually cure all cancers. Guided by a world-renowned Scientific Advisory Council that includes three Nobel laureates and 26 members of the National Academy of Sciences, CRI has invested $336 million in support of research conducted by immunologists and tumor immunologists at the world’s leading medical centers and universities, and has contributed to many of the key scientific advances that demonstrate the potential for immunotherapy to change the face of cancer treatment. To learn more, go to cancerresearch.org.

Contact Information:

Shirley Dang
Science Communications Manager
Parker Institute for Cancer Immunotherapy
sdang@parkerici.org
415-930-4385

Brian Brewer
Director of Marketing and Communications
Cancer Research Institute
bbrewer@cancerresearch.org
212-688-7515 x242

SOURCE

http://www.parkerici.org/media/2016/parker-institute-for-cancer-immunotherapy-cri-neoantigen-alliance

 

Parker Institute for Cancer Immunotherapy (PICI) @ Stanford Medicine Bedside to Bench Grant Program Call for Proposals 

The Parker Institute for Cancer Immunotherapy (PICI) @ Stanford Medicine Bedside to Bench Grant Program supports early stage projects that will enhance interdisciplinary basic and translational research among the Stanford scientific community in Cancer Immunotherapy.

The PICI Bedside to Bench Grant will support collaborations between basic scientists and clinical researchers that lead to fundamental discoveries and advance the field of cancer immunotherapy. These awards are targeted to faculty with early-stage, high-risk ideas that would not be funded by traditional sources.  We are particularly interested in the following areas of study:  

  • T-Cell Therapies,
  • Checkpoint Non-Responders,
  • Antigen Discovery and
  • the Tumor Microenvironment.

All proposals must involve at least one basic science and one clinical investigator.    We encourage applications from scientists across a broad array of disciplines whose combined perspectives will help to accelerate the pace of discovery.

We are particularly interested in proposals that seek to identify correlative biomarkers of response to immunotherapy or that will enable discovery of new targets or pathways that could be leveraged for therapeutic gain using immune based therapies.

SOURCE

http://www.parkerici.org

 

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Pioneers of Cancer Cell Therapy:  Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors

Curator: Aviva Lev-Ari, PhD, RN

Chimeric Antigen Receptor T-Cell Therapy: Players in Basic & Translational Research and Biotech/Pharma

The companies are teamed with academic pioneers:

  • Novartis with University of Pennsylvania;
  • Kite Pharma with the National Cancer Institute; 
  • Juno Therapeutics with Sloan Kettering,
  • the Fred Hutchinson Cancer Research Center in Seattle and Seattle Children’s Hospital.

cancer33

IMAGE SOURCE: National Cancer Institute

 

 “CAR-T cell immunotherapy” –  genetically modified T cells that are engineered to target specific tumor antigens and/or genes that are involved in survival, proliferation, and the enhancement of effector functions have been under intense research.

 

CAR technology was originally reported by Zelig Eshhar in 1993.

https://www.weizmann.ac.il/immunology/sci/EshharPage.html

Prof. Zelig Eshhar, Ph.D., served as Chairman of the Department of Immunology at the Weizmann Institute. Prof. Eshhar has been Chair of Scientific Advisory Board at TxCell S.A. since April 2016. Prof. Eshhar has been a Member of Scientific Advisory Board at Kite Pharma, Inc. since August 8, 2013. Prof. Eshhar served as a Member of Scientific Advisory Board at Intellect Neurosciences, Inc. since April 2006.

Prof. Eshhar pioneered the CAR approach (or T-Body as he termed it) to redirect T cells to recognize, engage and kill patient’s tumor cells by engineering them with a construct that combines the anti-target specificity of an antibody with T cell activation domains. Prof. Eshhar serves on several editorial boards, including Cancer Gene Therapy, Human Gene Therapy, Gene Therapy, Expert Opinion on Therapeutics, European Journal of Immunology and the Journal of Gene Medicine. He was a Research Fellow in the Department of Pathology at Harvard Medical School and in the Department of Chemical Immunology at the Weizmann Institute in Israel. His achievements were recognized by several international awards, most recently the CAR Pioneering award by the ATTACK European Consortium. Prof. Eshhar obtained his B.Sc. in Biochemistry and Microbiology and his M.Sc. in Biochemistry from the Hebrew University, and his Ph.D. in the Department of Immunology from the Weizmann Institute of Science.

http://www.bloomberg.com/research/stocks/people/person.asp?personId=32720993&privcapId=32390485

 

Zelig Eshhar and Carl H. June honored for research on T cell engineering for cancer immunotherapy

New Rochelle, NY, November 11, 2014–Zelig Eshhar, PhD, The Weizmann Institute of Science and Sourasky Medical Center, and Carl H. June, MD, PhD, Perelman School of Medicine, University of Pennsylvania, are co-recipients of the Pioneer Award, recognized for lentiviral gene therapy clinical trials and for their leadership and contributions in engineering T-cells capable of targeting tumors with antibody-like specificity through the development of chimeric antigen receptors (CARs). Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers, is commemorating its 25th anniversary by bestowing this honor on the leading Pioneers in the field of cell and gene therapy selected by a blue ribbon panel* and publishing a Pioneer Perspective by the award recipients. The Perspectives by Dr. Eshhar and Dr. June are available free on the Human Gene Therapy website at http://www.liebertpub.com/hgt until December 11, 2014.

In his Pioneer Perspective entitled “From the Mouse Cage to Human Therapy: A Personal Perspective of the Emergence of T-bodies/Chimeric Antigen Receptor T Cells” Professor Eshhar chronicles his team’s groundbreaking contributions to the development of the CAR T-cell immunotherapeutic approach to treating cancer. He describes the method’s conceptual development including initial proof-of-concept, and the years of experimentation in mouse models of cancer. They first tested the CAR T-cells on tumors transplanted into mice then progressed to spontaneously developing cancers in immune-competent mice, which Dr. Eshhar describes as “a more suitable model that faithfully mimics cancer patients.” He recounts successful antitumor effects in mice with CAR modified T-cells injected directly into tumors, with effects seen at the injection site and at sites of metastasis, and even the potential of the CAR T-cells to prevent tumor development.

Dr. Carl H. June has led one of the clinical groups that has taken the CAR therapeutic strategy from the laboratory to the patients’ bedside, pioneering the use of CD19-specific CAR T-cells to treat patients with leukemia. In his Pioneer Perspective, “Toward Synthetic Biology with Engineered T Cells: A Long Journey Just Begun” Dr. June looks back on his long, multi-faceted career and describes how he combined his knowledge and research on immunology, cancer, and HIV to develop successful T-cell based immunotherapies. Among the lessons Dr. June has embraced throughout his career are to follow one’s passions. He also says that “accidents can be good: embrace the unexpected results and follow up on these as they are often times more scientifically interesting than predictable responses from less imaginative experiments.”

“These two extraordinary scientists made seminal contributions at key steps of the journey from bench to bedside for CAR T-cells,” says James M. Wilson, MD, PhD, Editor-in-Chief of Human Gene Therapy, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.

SOURCE

http://www.eurekalert.org/pub_releases/2014-11/mali-ze111114.php

The General procedure of CAR-T cell therapy involves the follwoing steps:

1) Separate T cells from patient;

2) Engineer these T cells to express an artificial receptor, which is called “CAR” that usually targets tumor-specific antigen;

3) Expand the CAR T cells to a sufficient amount;

4) Re-introduce the CAR T cells to patient.

There are two major components that are critical to the CAR-T cell immunotherapy:

  • the design of CAR itself and
  • the choice of the targeted tumor specific antigen.

SOURCE

http://www.ochis.org/node/209

 

First publication on Adoptive transfer of genetically modified T cells is an attractive approach for generating antitumor immune responses

Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19

James N. Kochenderfer, Wyndham H. Wilson, John E. Janik, Mark E. Dudley, Maryalice Stetler-Stevenson, Steven A. Feldman, Irina Maric, Mark Raffeld, Debbie-Ann N. Nathan, Brock J. Lanier, Richard A. Morgan, Steven A. Rosenberg

Abstract

Adoptive transfer of genetically modified T cells is an attractive approach for generating antitumor immune responses. We treated a patient with advanced follicular lymphoma by administering a preparative chemotherapy regimen followed by autologous T cells genetically engineered to express a chimeric antigen receptor (CAR) that recognized the B-cell antigen CD19. The patient’s lymphoma underwent a dramatic regression, and B-cell precursors were selectively eliminated from the patient’s bone marrow after infusion of anti–CD19-CAR-transduced T cells. Blood B cells were absent for at least 39 weeks after anti–CD19-CAR-transduced T-cell infusion despite prompt recovery of other blood cell counts. Consistent with eradication of B-lineage cells, serum immunoglobulins decreased to very low levels after treatment. The prolonged and selective elimination of B-lineage cells could not be attributed to the chemotherapy that the patient received and indicated antigen-specific eradication of B-lineage cells. Adoptive transfer of anti–CD19-CAR-expressing T cells is a promising new approach for treating B-cell malignancies. This study is registered at www.clinicaltrials.gov as #NCT00924326.

SOURCE

According to Setting the Body’s ‘Serial Killers’ Loose on Cancer

After a long, intense pursuit, researchers are close to bringing to market a daring new treatment: cell therapy that turbocharges the immune system to fight cancer.

By ANDREW POLLACK  AUG. 1, 2016

http://www.nytimes.com/2016/08/02/health/cancer-cell-therapy-immune-system.html?_r=0

Dr. June’s 2011 publications did not cite Dr. Rosenberg’s paper [Blood, 2010] from the previous year, prompting Dr. Rosenberg to write a letter to The New England Journal of Medicine. Dr. June’s publications also did not acknowledge that the genetic construct he had used was the one he had obtained from Dr. Campana of St. Jude.

From the Lab to the bedside to the Out Patient Clinic

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Topical Solution for Combination Oncology Drug Therapy: Patch that delivers Drug, Gene, and Light-based Therapy to Tumor

Reporter: Aviva Lev-Ari, PhD, RN

 

Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment

Affiliations

  1. Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Harvard-MIT Division for Health Sciences and Technology, Cambridge, Massachusetts 02139, USA
    • João Conde,
    • Nuria Oliva,
    • Mariana Atilano,
    • Hyun Seok Song &
    • Natalie Artzi
  2. School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK
    • João Conde
  3. Grup dEnginyeria de Materials, Institut Químic de Sarrià-Universitat Ramon Llull, Barcelona 08017, Spain
    • Mariana Atilano
  4. Division of Bioconvergence Analysis, Korea Basic Science Institute, Yuseong, Daejeon 169-148, Republic of Korea
    • Hyun Seok Song
  5. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    • Natalie Artzi
  6. Department of Medicine, Biomedical Engineering Division, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    • Natalie Artzi

Contributions

J.C. and N.A. conceived the project and designed the experiments. J.C., N.O., H.S.S. and M.A. performed the experiments, collected and analysed the data. J.C. and N.A. co-wrote the manuscript. All authors discussed the results and reviewed the manuscript.

Nature Materials
15,
353–363
(2016)
doi:10.1038/nmat4497
Received
22 April 2015
Accepted
26 October 2015
Published online
07 December 2015

The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA-triple-helix structure comprising two miRNAs—a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)—provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple-helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer.

SOURCE

http://www.nature.com/nmat/journal/v15/n3/abs/nmat4497.html#author-information

 

 

Patch that delivers drug, gene, and light-based therapy to tumor sites shows promising results

In mice, device destroyed colorectal tumors and prevented remission after surgery.

Helen Knight | MIT News Office
July 25, 2016

Approximately one in 20 people will develop colorectal cancer in their lifetime, making it the third-most prevalent form of the disease in the U.S. In Europe, it is the second-most common form of cancer.

The most widely used first line of treatment is surgery, but this can result in incomplete removal of the tumor. Cancer cells can be left behind, potentially leading to recurrence and increased risk of metastasis. Indeed, while many patients remain cancer-free for months or even years after surgery, tumors are known to recur in up to 50 percent of cases.

Conventional therapies used to prevent tumors recurring after surgery do not sufficiently differentiate between healthy and cancerous cells, leading to serious side effects.

In a paper published today in the journal Nature Materials, researchers at MIT describe an adhesive patch that can stick to the tumor site, either before or after surgery, to deliver a triple-combination of drug, gene, and photo (light-based) therapy.

Releasing this triple combination therapy locally, at the tumor site, may increase the efficacy of the treatment, according to Natalie Artzi, a principal research scientist at MIT’s Institute for Medical Engineering and Science (IMES) and an assistant professor of medicine at Brigham and Women’s Hospital, who led the research.

The general approach to cancer treatment today is the use of systemic, or whole-body, therapies such as chemotherapy drugs. But the lack of specificity of anticancer drugs means they produce undesired side effects when systemically administered.

What’s more, only a small portion of the drug reaches the tumor site itself, meaning the primary tumor is not treated as effectively as it should be.

Indeed, recent research in mice has found that only 0.7 percent of nanoparticles administered systemically actually found their way to the target tumor.

“This means that we are treating both the source of the cancer — the tumor — and the metastases resulting from that source, in a suboptimal manner,” Artzi says. “That is what prompted us to think a little bit differently, to look at how we can leverage advancements in materials science, and in particular nanotechnology, to treat the primary tumor in a local and sustained manner.”

The researchers have developed a triple-therapy hydrogel patch, which can be used to treat tumors locally. This is particularly effective as it can treat not only the tumor itself but any cells left at the site after surgery, preventing the cancer from recurring or metastasizing in the future.

Firstly, the patch contains gold nanorods, which heat up when near-infrared radiation is applied to the local area. This is used to thermally ablate, or destroy, the tumor.

These nanorods are also equipped with a chemotherapy drug, which is released when they are heated, to target the tumor and its surrounding cells.

Finally, gold nanospheres that do not heat up in response to the near-infrared radiation are used to deliver RNA, or gene therapy to the site, in order to silence an important oncogene in colorectal cancer. Oncogenes are genes that can cause healthy cells to transform into tumor cells.

The researchers envision that a clinician could remove the tumor, and then apply the patch to the inner surface of the colon, to ensure that no cells that are likely to cause cancer recurrence remain at the site. As the patch degrades, it will gradually release the various therapies.

The patch can also serve as a neoadjuvant, a therapy designed to shrink tumors prior to their resection, Artzi says.

When the researchers tested the treatment in mice, they found that in 40 percent of cases where the patch was not applied after tumor removal, the cancer returned.

But when the patch was applied after surgery, the treatment resulted in complete remission.

Indeed, even when the tumor was not removed, the triple-combination therapy alone was enough to destroy it.

The technology is an extraordinary and unprecedented synergy of three concurrent modalities of treatment, according to Mauro Ferrari, president and CEO of the Houston Methodist Research Institute, who was not involved in the research.

“What is particularly intriguing is that by delivering the treatment locally, multimodal therapy may be better than systemic therapy, at least in certain clinical situations,” Ferrari says.

Unlike existing colorectal cancer surgery, this treatment can also be applied in a minimally invasive manner. In the next phase of their work, the researchers hope to move to experiments in larger models, in order to use colonoscopy equipment not only for cancer diagnosis but also to inject the patch to the site of a tumor, when detected.

“This administration modality would enable, at least in early-stage cancer patients, the avoidance of open field surgery and colon resection,” Artzi says. “Local application of the triple therapy could thus improve patients’ quality of life and therapeutic outcome.”

Artzi is joined on the paper by João Conde, Nuria Oliva, and Yi Zhang, of IMES. Conde is also at Queen Mary University in London.

SOURCE

http://news.mit.edu/2016/patch-delivers-drug-gene-light-based-therapy-tumor-0725

Other related articles published in thie Open Access Online Scientific Journal include the following:

The Development of siRNA-Based Therapies for Cancer

Author: Ziv Raviv, PhD

https://pharmaceuticalintelligence.com/2013/05/09/the-development-of-sirna-based-therapies-for-cancer/

 

Targeted Liposome Based Delivery System to Present HLA Class I Antigens to Tumor Cells: Two papers

Reporter: Stephen J. Williams, Ph.D.

https://pharmaceuticalintelligence.com/2016/07/20/targeted-liposome-based-delivery-system-to-present-hla-class-i-antigens-to-tumor-cells-two-papers/

 

Blast Crisis in Myeloid Leukemia and the Activation of a microRNA-editing Enzyme called ADAR1

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/06/10/blast-crisis-in-myeloid-leukemia-and-the-activation-of-a-microrna-editing-enzyme-called-adar1/

 

First challenge to make use of the new NCI Cloud Pilots – Somatic Mutation Challenge – RNA: Best algorithms for detecting all of the abnormal RNA molecules in a cancer cell

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/17/first-challenge-to-make-use-of-the-new-nci-cloud-pilots-somatic-mutation-challenge-rna-best-algorithms-for-detecting-all-of-the-abnormal-rna-molecules-in-a-cancer-cell/

 

miRNA Therapeutic Promise

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/05/01/mirna-therapeutic-promise/

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CRISPR’s Unwanted off-target effects: Need for safety study designs with Gene-Editing

Reporter: Stephen J. Williams, Ph.D.

From CafePharma at https://www.statnews.com/2016/07/18/crispr-off-target-effects/

Do CRISPR enthusiasts have their head in the sand about the safety of gene editing?

WASHINGTON — At scientific meetings on genome-editing, you’d expect researchers to show pretty slides of the ribbony 3-D structure of the CRISPR-Cas9 molecules neatly snipping out disease-causing genes in order to, everyone hopes, cure illnesses from cancer to muscular dystrophy. Less expected: slides of someone kneeling on a beach with his head in the sand.

Yet that is what Dr. J. Keith Joung of Massachusetts General Hospital showed at the American Society of Hematology’s workshop on genome-editing last week in Washington. While the 150 experts from industry, academia, the National Institutes of Health, and the Food and Drug Administration were upbeat about the possibility of using genome-editing to treat and even cure sickle cell disease, leukemia, HIV/AIDS, and other blood disorders, there was a skunk at the picnic: an emerging concern that some enthusiastic CRISPR-ers are ignoring growing evidence that CRISPR might inadvertently alter regions of the genome other than the intended ones.

“In the early days of this field, algorithms were generated to predict off-target effects and [made] available on the web,” Joung said. Further research has shown, however, that such algorithms, including one from MIT and one calledE-CRISP, “miss a fair number” of off-target effects. “These tools are used in a lot of papers, but they really aren’t very good at predicting where there will be off-target effects,” he said. “We think we can get off-target effects to less than 1 percent, but we need to do better,” especially if genome-editing is to be safely used to treat patients.

Off-target effects occur because of how CRISPR works. It has two parts. RNA makes a beeline for the site in a genome specified by the RNA’s string of nucleotides, and an enzyme cuts the genome there. Trouble is, more than one site in a genome can have the same string of nucleotides. Scientists might address CRISPR to the genome version of 123 Main Street, aiming for 123 Main on chromosome 9, only to find CRISPR has instead gone to 123 Main on chromosome 14.

In one example Joung showed, CRISPR is supposed to edit a gene called VEGFA (which stimulates production of blood vessels, including those used by cancerous tumors) on chromosome 6. But, studies show, this CRISPR can also hit genes on virtually every one of the other 22 human chromosomes. The same is true for CRISPRs aimed at other genes. Although each CRISPR has zero to a dozen or so “known” off-target sites (where “known” means predicted by those web-based algorithms), Joung said, there can be as many as 150 “novel” off-target sites, meaning scientists had no idea those errors were possible.

One reason for concern about off-target effects is that genome-editing might disable a tumor-suppressor gene or activate a cancer-causing one. It might also allow pieces of two different chromosomes to get together, a phenomenon called translocation, which is the cause of chronic myeloid leukemia, among other problems.

Many researchers, including those planning clinical trials, are using web-based algorithms to predict which regions of the genome might get accidentally CRISPR’d. They include the scientists whose proposal to use CRISPR in patients was the first to be approved by an NIH committee. When scientists assure regulators that they looked for off-target effects in CRISPR’d cells growing in lab dishes, what they usually mean is that they looked for CRISPR’ing of genes that the algorithms flagged.

As a result, off-target effects might be occurring but, because scientists are doing the equivalent of the drunk searching for their lost keys only under the lamppost, they’re not being found.

Other articles on CRISPR and Gene Editing on this Open Access Journal Include:

FDA Cellular & Gene Therapy Guidances: Implications for CRSPR/Cas9 Trials

CRISPR/Cas9 Finds Its Way As an Important Tool For Drug Discovery & Development

CRISPR, the Genome Editing Technology is Nearing Human Trials: Human T cells will soon be modified using the CRISPR technique in a clinical trial to attack cancer cells

Use of CRISPR & RNAi for Drug Discovery, CHI’s World PreClinical Congress – Europe, November 14-15, 2016, Lisbon, Portugal

CRISPR: A Podcast from Nature.com on Gene Editing

AND Please See Our Following ebooks available on Amazon containing interviews with Dr. Jennifer Duodna

Volume One: Genomics Orientations for Personalized Medicine

Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology

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