Empowering Innovation: Maintaining the Nation’s Edge in High-Risk, High-Impact Biomedical Research and Development

Richard Aragon, Ph.D.Center for Strategic Scientific Initiatives,

Office of the Director, NCIJuly 20, 2010

A Representative Program: IMATMission and Goals

Program Mission: To stimulate the development and application of new technologies that transform researchers’ abilities to identify molecular (and cellular) changes that distinguish pre-cancerous and cancerous cells from normal cells.

Program Goals:• To focus innovative technology development efforts from multiple

communities on cancer• To solicit highly innovative technology development projects from the

scientific and medical communities (and other communities!)• To accelerate the maturation and dissemination of meritorious

technologies from feasibility to development and/or commercialization.• To bring those technologies to clinicians, researchers, and ultimately,

the patient

Established in 1998 as a single Program Announcement (PA)

Why The IMAT Program Was Established

• Established to encourage highly innovative cancer technology development projects that: • Address the complexity of cancer, including myriad molecular and

cellular processes• Understand relevant genes and roles of nucleic acids, proteins, and

other cellular factors and modifications• Interrogate cells and tissues at multiple levels (genomic, epigenomic,

proteomic, metabolomic, kinomic)• Provides novel mechanisms, program, and review structures to:

• Support innovative cancer-relevant technology from inception• Support development of novel applications of those technologies that

uniquely enable cancer biology research by R01 investigators• Support and promote the commercialization of innovative and emerging

technology platforms• Ensures that resulting technologies are robust and appropriate for

intended applications in basic, preclinical, and clinical settings

Unique Attributes of IMAT

• Multidisciplinary – technologies solicited and drawn from a variety of disciplines, fields, and institutions/organizations

• Investigator Initiated – utilizes investigator-initiated research project grant mechanisms with the intent of developing better tools and technologies capable of being put back into the hands of the larger research and industrial communities

• Trans-Divisional – comprised of representatives from all NCI divisions having a common purpose of ensuring the development of cutting-edge, high-impact technologies and platforms

• Innovation Focused – solicits and supports the development, maturation, and dissemination of technically innovative, high risk, high impact and potentially high payoff technologies

• Technology Focused – does not support traditional hypothesis driven research but rather supports the development, transfer, and commercialization of tools and platforms to enable more effective and comprehensive R01 research

• Commitment to New or First-Time Investigators – approximately 1/3 of the program’s portfolio is comprised of new or first-time investigators

• Commitment to Diversity – provides novel education and training programs for historically disadvantaged individuals from high school to post-doctoral levels in areas of emerging technology; encourages participation of international institutions, collaborations, and investigators

Unique Attributes of IMAT Special Emphasis Review Panels (SEPs)

• Emphasis on high-risk, high-impact, but also high-payoff multidisciplinary technologies

• Reviewers represent and equal mix of experts from academia and industry

• Reviewers drawn from both domestic and international institutions and organizations

• Emphasis on technology development vs. traditional hypothesis-driven research

• Milestone-based, with performance milestones that quantitatively address improvements in measures such as specificity, sensitivity, speed, and similar performance parameters

• Staged process requiring quantitative evidence of progress or feasibility before advancement to the next stage

• Focus on whether and how a technology represents a demonstrable, quantitative improvement over current state of the art

Life Cycle of an IMAT Technology Development Project

Projects are initiated from:

R21/Phase I R33/Phase II

Mechanism:Exploratory/pilot phase;

requires innovative technology/approach; no preliminary data required

Mechanism:Developmental phase; requires feasibility data

Requirements:• Description of study

• Relevance to cancer

• Quantitative milestones

• Novel research tool, new detection methodology, or treatment technology

• Improvement over state-of-the-art

Requirements:• Plan for developing the

technology

• Description of potential impact

• Description of completed milestones or evidence of technical feasibility

Technology Dissemination via:

• NCI Programs and Initiatives• Collaboration• Publication• Licensing• Commercialization

Technology Tools for Researchers:

• Better, Faster, Cheaper!• Clinical specimen

preservation / analysis• Ultra-high-throughput

molecular and genetic characterization

• Technology-guided interventions

IMAT Funding Mechanisms

Biomedical R&D “Theme” Areas

Innovative Technology Development for Cancer

Research

Innovative and Applied Emerging Technologies for

Biospecimen Science

Application and Use of Transformative Emerging

Technologies for Cancer Research

NCI Biological and Clinical Research Programs, Public/Private

Partnerships, or Commercialization

Technologies, Approaches, and Knowledge to Understand, Prevent, Detect, Diagnose, and Treat Cancer

IMAT

Program Management Team: Encompassing all NCI Divisions

• Office of The NCI Director:Carolyn Compton, M.D., Ph.D.Richard Aragon, Ph.D., DirectorKimberly Myers, Ph.D.

• Division of Cancer Biology: Jennifer Couch, Ph.D. J. Randy Knowlton, Ph.D.Gerry Li, Ph.D.

• Division of Cancer Prevention: Paul Wagner, Ph.D.Lynn Sorbara, Ph.D.

• Division of Cancer Treatment and Diagnosis:Jim Jacobson, Ph.D.Rodrigo Chuaqui, M.D.Avraham Rasooly, Ph.D.

• Division of Cancer Control and Population Sciences:Mukesh Verma, Ph.D.Rao Divi, Ph.D.

IMAT Funded Awards: 1998 - 2009

Fiscal Year Number of Awards‡

1998 501999 572000 322001 632002 362003 212004 02005 47 2006 482007 512008 50

2009 48

Total: 503

IMAT

• Utilizes multiple investigator-initiated mechanisms to provide maximal flexibility to the investigator

• Solicits a wide array of technologies under the premise of finding the “diamond in the rough”

• Does not restrict technologies only to those that are “mission oriented” or to only those from academia or industry

• Has demonstrated progress in technology development and dissemination in a fraction of the time quoted in Projects Hindsight and Comroe-Dripps• IMAT has only been in existence for 9 years (and in its present

programmatic form for only 4 years)!!!

Where’s The “Beef”?: Examples of Historical IMAT Blockbusters

IMAT “Blockbusters”: Example 1Gene Expression ArraysJonathan D. Oliner, Ph.D., Affymetrix

• IMAT Award: Reverse-Engineering Signal Transduction Networks (1998)

• Impact: Gene expression arrays allow researchers to follow the downstream effects of perturbations to biochemical pathways or networks by highlighting changes in gene expression.

• Fredriksson S, Baner J, Dahl F, Chu A, Ji H, Welch K, Davis RW. Multiplex amplification of all coding sequences within 10 cancer genes by Gene-Collector. Nucleic Acids Res. 2007;35(7):e47.

GeneChip® CustomSeq® Resequencing Arrays

IMAT “Blockbusters”: Example 2RNA Later

Gary Latham, Ph.D., Ambion, Inc.

• IMAT Award: Enzymatic Tools for Degrading Tissue and Preserving RNA (2001); SBIR Phase II Awardee (2005-2007)

• Impact: Researchers can store tissue samples without significant loss of RNA integrity

• Patented (application serial number 60/514,313)• Commercially released by Ambion in February, 2005

IMAT “Blockbusters”: Example 3MudPit

John R. Yates, Ph.D., University of Washington/Scripps

• IMAT Award: Direct MS Analysis of Complex Protein Mixtures (1999)

• Impact: The MudPit (multi-dimensional protein identification technology) platform marks the transition from traditional 2-D gel electrophoresis to 2-D liquid chromatography; PubMed lists 97 abstracts on MudPIT, including 6 focused on cancer.

IMAT “Blockbusters”: Example 4Illumina Bead Technologies

Mark Chee, Ph.D., Illumina, Inc.

• IMAT Awards:• Gene Expression Analysis on Randomly Ordered DNA Arrays (1998)• Parallel Array Processor (1998)• Protein Profiling Arrays (1999)

• Impact: The ultra-high-throughput Illumina bead platform allows researchers to simultaneously assay over 100,000 points for gene expression, alternative splice detection, and protein expression; at least 35 publications listed in PubMed relating to this technology, 6 of which directly relate to cancer.

IMAT “Blockbusters”: Example 5Proteomic Arrays

Dave Krizman, Ph.D., Expression Pathology

• IMAT Award: Protein Arrays for Molecular Analysis of Cancer Tissue (2002)

• Impact: New technology that permits effective, high-throughput discovery and analysis of protein biomarkers in formalin fixed paraffin embedded (FFPE) tissue

IMAT “Blockbusters”: Example 6Quantum Dot Technology

Robert H. Daniels, Ph.D., Quantum Dot Corp. (Invitrogen)

• IMAT Award: Sensitive, Multiplexed Analysis of Breast Cancer Markers (1999)

• Impact: Quantum dots (semi-conductor nanocrystals) are photostable labels that emit extremely bright light in a range of colors enabling researchers to monitor complex interactions within living cells or in situ on tissue microarrays; PubMed lists 38 publications on quantum dot or Qdot conjugation with streptavidin. Of these, 6 focus on the use of these conjugates in cancer research.

IMAT “Blockbusters”: Example 7ICAT

Rudolf Aebersold, Ph.D. , Institute for Systems Biology

• IMAT Award: Isotope Coded Affinity Tags (ICAT) for Quantitative Proteomics (2000)

• Impact: Large-scale analysis of complex samples, including whole proteomes and small-scale analysis of subproteomes; 218 publications in Pubmed on ICAT technology, 34 focusing on cancer.

• 7 patent applications filed or already granted (Methods for Isolation and Labeling of Sample Molecules, Patent 7,183,116)

• Patents Filed or Granted: Methods for Isolating and Labeling Sample Molecules (20020168644, 20040265810, and 20040110186), Methods for High Throughput and Quantitative Proteome Analysis (20040033625), two with the title Methods for Rapid and Quantitative Proteome Analysis (20020119490 and 20060008851) and Androgen-Regulated Genes and Uses for Diagnosis, Prognosis and Treatment of Prostate Neoplastic Conditions (20040121413).

New or First-Time Investigators

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FY05 FY06 FY07 FY08

Fiscal Year

Num

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Total Applications

New or First-TimeInvestigators

Specific Patent Approvals (2007 through 8/2008)Source: USPTO (information provided below has not been altered in any way)

SingaporeE. Liu (R33 CA126966-01)

B. Guillaume

IsraelS. Frankenburg (R21 CA114160-01A1)

SwedenU. Landgeren (R21 CA126727-01)

O. EriccsonK. Pardali

CanadaS. Kelley (R21 CA114135-01)S. Tanner (R21 CA137694-01)

Principal Investigator Supported Junior Investigator

IMAT Globally

IMAT Contributions to the NCI Technology Development Portfolio (FY 2005-2008)

IMAT applications reviewed in FY 2005 through FY 2007 as a percentage of all technology development applications reviewed by the NCI ( based on DEA 2007 Annual Report).

IMAT Impact: Number of Articles in Peer-Reviewed Journals Citing IMAT Grants

IMAT Impact: Publications Between 2007 and May, 2010 That Specifically Cite IMAT Awards

2008 – 2010 Publications Include: 12 Nature publications, 7 Proceedings of Nat’l Academy of Sciences publications, and 3 Cell publications

IMAT Impact: Number of Patent Applications Filed and Received (Source: USPTO)

*As of August, 2008

IMAT Impact: Number of Patents and Patent Applications Citing an IMAT Award Between 2008 and May, 2010 (Source: USPTO/STPI)

71 new patent submissions, 27 approved patents

IMAT Impact: Invention Count and Institutions Represented

172 Inventions with patents / patent applications based on IMAT grant awards!

IMAT Feeds Into Other Programs and Initiatives

Interrogating Epigenetic Changes in Cancer Genomes(ICBP Program)

High Throughput Methylation Analysis in Cancer (R33 CA084701)Novel Tool for Analysis of Promoter Hypermethylation (R33 CA094441)

Ohio State University;

University of Missouri

Huang, Tim

Assessment of serum peptide profiling to detect cancer-specific patterns(Clinical Proteomics Program)

Peptide Profiling Techniques to Detect Thyroid Carcinoma (R21CA111942)Peptide Profiling Techniques to Detect Thyroid Carcinoma (R33CA111942)

Memorial Sloan-Kettering Cancer Center

Tempst, Paul

A Proteomics Platform for Quantitative, Ultra-High Throughput, and Ultra-Sensitive

(Clinical Proteomics Program)

Ultra-Sensitive Approach for Monitoring Gene Production (R33 CA081654)High Throughput FTICR for Molecular Analysis of Cancer (R33 CA086340)

Battelle Pacific Northwest

Laboratories

Smith, Richard

Proteomic Phosphopeptide Chip Technology for Protein Profiling

(Clinical Proteomics Program)

Parallel Synthesis of RNA Oligonucleotide Microarrays (R21 CA084708)

University of Houston

Gao, Xiaolian

Nanotechnology Platform for Targeting Solid Tumors

(NCI Cancer Nanotech Alliance)

Technology/Map Endothelial Targets/Human Renal Tumors (R33 CA118602)Technology to Unmask Accessible Tumor Vascular Targets (R33 CA097528)

Sidney Kimmel Cancer Center

Schnitzer, Jan

DNA-linked Dendrimer Nanoparticle Systems for Cancer Diagnosis and

Treatment(NCI Cancer Nanotech Alliance)

Photonic Crystal Fiber Probe Fluorescence Biosensing (R33CA112141)

University of Michigan

Baker, James

IMPACTIMAT AwardAffiliationPI Name

Recent NIH Roadmap Transformative-R01 Award Acquisitions (2008 – 2009)

Anticipated 2010 Funding Opportunity Structure: First-Year Awards ONLY

Innovative Technology Development for Cancer Research

Anticipated funding $4 million

Anticipated awards ~ 15

Objective To serve as the discovery tool of the larger program by soliciting and funding highly innovative, high risk and cancer relevant technology development projects

Mechanisms Exploratory/Developmental Research Grants R21

Application and Use of Emerging Transformative Technologies in Cancer Research

Anticipated funding $4 million

Anticipated awards ~ 15

Objective To develop emerging technologies related to cancer research in an appropriate biological or clinical context

Mechanisms Exploratory/Developmental Research Grants R21, Developmental Grants R33

Innovative and Applied Emerging Technologies in Biospecimen Science

Anticipated funding $2.5 million + 1.5 million contract (RFP)

Anticipated awards ~ 6 + awards from contracts/RFP

Objective To develop sample preparation techniques and methodologies that are essential for effective research and technology development and validation towards clinical application

Mechanisms Exploratory/Developmental Research Grants R21, Developmental Grants R33

New Education and Training Initiatives (in collaboration with CRCHD)

New Networking Initiatives: IMAT-CPTC Joint Programs Meeting (October 2008, 2009)

2009 Theme: Striking Meaningful Collaborations and Maximizing Synergies

Science: November, 2008 and January, 2009

RECENT IMAT Blockbusters 2008 - 2010

Example 1: MGA Technology, 2008 “Innovation of the Year

MGA Lab-On-A-Chip For T-Cell Lymphoma Diagnosis: An IMAT-Funded Technology

James Landers, Ph.D.. University of Virginia

• A microminiaturized analytical system with sample-in/answer-out capability – a complete “diagnostic lab on a chip” technology

• Impact: Highly integrated system capable of detecting infectious agents present in complex biofluids in less than 30 minutes

Diagnosis of certain blood cancers in under 1 hour

Example 2: Raindance Technologies, Inc. (Boston Globe, August 31, 2008)

Lexington Company has New Analytic DeviceBy Davis Bushnell, Globe CorrespondentThe Boston Globe, August 31, 2008

LEXINGTON - RainDance Technologies Inc. has come up with arevolutionary technology, the company says, that will change the waylaboratory samples are analyzed for medical research and drug preparation.

“What we’re essentially doing is replacing the test tube with a platform that produces[tiny] droplets at a rate of 10 million per hour,” said Stephen E. Becker, 44, vice president ofcommercial operations. “Each droplet, the equivalent of an individual test tube, might containa single molecule, reaction, or cell.”

“We recognize that this new technology platform will change the way science is done,”chief executive Christopher D. McNary, 53, said during a recent interview in the company’s27,000-square-foot facility off Hartwell Avenue, where there are 52 employees. Thirteenothers will be hired by year’s end, he said.

McNary, who previously had been a vice president and general manager of Waltham-based Thermo Fisher Scientific, said he’s “unaware of any other [company or institution]using our patented technology.”

RainDance’s first instruments are expected to be delivered to laboratories in November,McNary said, adding that prices have yet to be announced. The instruments will be used forDNA resequencing, a major step “in detecting mutations associated with various congenitaldiseases,” he said. “This is a $1 billion market.”

Much of the technology was developed in a Harvard University laboratory run by DavidA. Weitz, 57, a professor of physics and applied physics. He is also a founder of the four-year-old firm along with Darren R. Link, 40, RainDance’s vice president of research, andAndrew Griffiths, 44, a British scientist who is currently conducting research in Strasbourg,France.

The technology has been five years in the making.“We took droplets of water in oil and used fluid devices to manipulate the droplets with

enormous precision,” Weitz said.Besides its technology, the company has another distinction, according to McNary. “We

were the first to relocate to Massachusetts in May of this year, to take advantage of “ a billpassed by the Legislature that will provide $1 billion worth of grants and tax incentives overa 10-year period to the life sciences industry.

RainDance received some tax incentives and assistance from state officials in findingmodern office and laboratory space, said McNary, noting that the Hartwell Avenue buildinghad been home to MGI Pharmaceutical, which is now across the street.

The first offices of RainDance in Guilford, Conn., he said, were shared with The

Rothberg Institute for Childhood Diseases. Jonathan Rothberg, 45, was one of RainDance’sfirst investors and is now the Lexington company’s chairman.

In the first half of 2007, the company received ‘a little more than $30 million fromventure capital firms,’ McNary said. The lead firms are Mohr Davidow Ventures and AlloyVentures, both based in Menlo Park, Calif.

Susan Siegel, a Mohr Davidow partner, said, “RainDance is enabling experiments onhow the human genome can be played out.” Once the stock market gyrations are over,RainDance will have an initial public offering, Siegel said. “But if the economy doesn’timprove in due course, there could be another round of funding.”

The Lexington firm also receives about $1 million a year from grants andcollaborations, McNary said. Last month, for example, RainDance began a nonfundedcollaborative effort on aging and disease with Scripps Translational Science Institute of SanDiego.

“We’ll explore the genetic makeup of older individuals to try to determine whatpredisposes some to good health and others to poor health,” said Becker, the RainDance vicepresident.

Richard J. Roberts, 64, one of three Nobel Prize winners on RainDance’s scientificadvisory board, said the company’s technology shows particular promise “for pushingmedical diagnostics research.” Roberts, who won a Nobel in 1993 for physiology ormedicine, is chief scientific officer of New England Biolabs of Beverly.

Christopher D. McNary,president of RainDanceTechnologies, with a fluidiccircuit chip used in theDNA sequence enrichmentprocess.

RainDance Technologies RDT-1000 Microfluidic Platform (Commercialized 2009)

“Non-Traditional” Investigators Supported by IMAT

• David Beebe, Ph.D. (Engineering)“Microfluidic Channels for High Density, High Performance Culture Assays” R21 CA122672-01A1

• Gregory Farris, Ph.D. (Applied Physics) “Signatures for Functional Optical Imaging of Cancer” R21 CA090532-01

• Stuart Lindsay, Ph.D. (Biophysics) “Mapping Epigenetic Modifications at the Nanoscale: Aptamers for Microscopy” R21 CA125510-01A1

• David Nolte, Ph.D. (Physics) “Highly Multiplexed Assays on the BioCD for Acute Lymphocytic Leukemia” R21 CA125336-01A2

“Non-Traditional” Investigators Supported By IMAT

• Scott Manalis, Ph.D. (Applied Physics)“Developing a single cell growth monitor for classifying therapeutic response” R21 CA137695-01

• Bartosz Grzybowski, Ph.D. (Chemical and Biological Engineering)“Microassay Systems for Diagnosis of Cancer Cell Motility and Metastasis” R21 CA137707-01

• David Beebe, Ph.D. (Mechanical & Biomed. Engineering)“Microchannel cell-based assays to enable cancer research”

R33 CA137673-01

Transgenomic Licenses Exclusive Rights to Cold PCROctober 09, 2009

Byline: a GenomeWeb staff reporterNewsletter: GenomeWeb Daily NewsGenomeWeb Daily News - October 9, 2009

NEW YORK (GenomeWeb News) – Transgenomic has licensed exclusive rights to Cold-PCR technology from the Dana Farber Cancer Institute, the firm said Thursday.

The Omaha, Neb.-based pharmacogenomics firm said that it has exclusive rights to commercialize the technology for combined use with Sanger sequencing as well as for mitochondrial DNA analysis. Financial and further terms of the license were not disclosed.

Cold-PCR is a variation on standard PCR and "enriches mutations in DNA samples and is a much more sensitive technique for finding low level mutations in tissue and body fluids that are involved with a variety of diseases," said Transgenomic. The firm believes the technology will be able to detect cancer-related mutations that are present at a low level compared to normal DNA.

"We have long wanted a technology that would permit us to screen patients earlier in their development of cancer and we hope that Cold-PCR provides us the sensitivity and analytical accuracy to achieve this goal," Transgenomic CEO Craig Tuttle said in a statement.

Transgenomic had licensed an option on the Cold-PCR technology earlier this year. The firm said it used that option period to test the feasibility of the technology and developed laboratory improvements for its use.

Example 3: COLD-PCR TechnologyExcerpt from Genome Web October 9, 2009

IMAT “Blockbusters”: COLD-PCR

Mike Makrigiorgos, Ph.D., COLD-PCR Technology

• IMAT Award: Genome Amplification Tolerant to Sample Degradation (2005 - 2007)Technology for sensitive and reliable mutational profiling in pancreatic cancer (2008)

• Impact: New technology that allows detection of DNA mutations when present in very low copy number ratios, including applications for:

Blood--based cancer mutation testingDefinitive genotyping of tumor samples with low percentage malignant cellsMutation detection in circulating tumor cellsIdentification of resistance clones in primary tumorsVery low heteroplasmy detection in mitochondrial DNAViral resistance mutation monitoring

• Promises to provide the enhanced sensitivity and analytical accuracy necessary to screen cancer patients earlier in their individual development of the disease

• Licensed by TransGenomic Corporation in late 2009/early 2010

COLD-PCR Licensed by TransGenomic and Marketed January, 2010

Thank You

http://innovation.cancer.gov

raragon@mail.nih.gov