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Division of Cancer Treatment and Diagnosis

Description:

The Division of Cancer Treatment and Diagnosis funds research into the development of tools, methodologies and therapeutic agents that will better diagnose, assess, cure and effectively treat cancer. We support a spectrum of research projects from preclinical exploratory research and development through clinical trials.

A. Cancer Diagnosis. The Cancer Diagnosis Program (CDP) supports the development of technologies, reagents, instrumentation, and methodologies to improve cancer diagnosis or prognosis or to predict or assess response to therapy. This does not include technologies for imaging of patients. CDP also supports the adaptation or improvement of basic research technologies for use as clinical tools. Technologies supported by CDP may be designed to work with tissues, blood, serum, urine, or other biological fluids. Technologies supported by CDP include but are not limited to the following:

1. Technologies for comprehensive and/or high throughput analysis of molecular alterations at the level of DNA, RNA, or protein. Includes for example, mutation detection systems, gene expression arrays, systems for monitoring epigenetic changes (alternative splicing or methylation), high throughput proteomics (including post-translational modification and protein-protein interactions and methods for protein quantitation).

2. Micro-electro mechanical systems (MEMs) and other nanotechnologies for the analysis of DNA, RNA, or protein (e.g., micro-capillary systems, lab on a chip applications, micro-separation technologies).

3. Mass spectrometry for the analysis of nucleic acids or proteins.

4. Discovery and development of new or improved diagnostic markers or probes targeting changes in DNA, RNA, or proteins, including the generation of molecular diversity libraries by phage display and other combinatorial techniques, and affinity-based screening methods.

5. cDNA library technologies, including improved methods for generating high quality cDNA clones and libraries and methods for generating high quality cDNA from tissues (including archived specimens).

6. Resources for clinical research.

a. Instruments, technologies or reagents for improved collection, preparation, and storage of human tissue specimens and biological fluids.

b. Improved methods for isolation and storage of DNA, RNA, or proteins.

c. Tissue and reagent standards: development of standard reagents such as representational DNA, RNA, and proteins and standard tissue preparations to improve the quality of or facilitate the validation of clinical laboratory assays.

d. Methodologies for directed micro-sampling of human tissue specimens, including for example, new or improved methodologies for tissue microarrays.

7. Tissue preservation: fixatives and embedding materials or stabilizers that preserves tissue integrity and cellular architecture and simultaneously allows molecular analysis of DNA, RNA, or proteins.

8. Bioinformatics.

a. Methods for acquisition and analysis of data associated with molecular profiling and other comprehensive molecular analysis technologies, including for example, analysis of microarray images and data as well as methods to combine, store and analyze molecular data produced by different techniques (e.g., combined analysis of proteomics and gene expression data).

b. Methods for collecting, categorizing or analyzing large data sets containing pathology data or histological images and associated clinical or experimental data, including for example, tumor marker measurements, tissue microarray data, and other relevant biological information.

c. Software/algorithms to interpret and analyze clinical and pathology data including methods that relate data from clinical databases to external data sources. Includes for example, neural networks, artificial intelligence, data-mining, data-trend analysis, patient record encryption protocols, and automatic diagnostic coding using standard nomeclatures.

d. Informatics tools to support tissue procurement and tissue banking activities.

9. Statistical methods and packages designed for data analysis including correlation of clinical and experimental data.

10. Automated Cytology.

a. High resolution image analysis for use with specimens (e.g., blood, tissues, cells) and tissue microarrays.

b. Instrumentation including microscopy and flow cytometry.

c. CGH, FISH, immunohistochemical staining and other hybridization assays using probes with fluorescent or other novel tags.

d. Methods for single cell isolation and sorting.

e. Methods for single cell classification and analysis.

11. Instrumentation for the detection and diagnosis of tumors, including endoscopy and magnetic resonance spectroscopy (MRS).

12. Immunoassays using monoclonal, polyclonal, or modified antibodies. Affinity-based binding assays using libraries of aptamers including chemical ligands, small peptides or modified antibodies.

For additional information about areas of interest to the CDP Technology Development Branch, visit our home page at: http://cancerdiagnosis.nci.nih.gov.

B. Biochemistry and Pharmacology. Preclinical and Exploratory Investigational New Drug (IND) studies designed to improve cancer treatment. General areas of interest: Discovery of new drugs or drug combinations and treatment strategies, selective targeting, development of clinically relevant preclinical models, pharmaceutical development, ADME (absorption, distribution, metabolism and excretion) studies and toxicologic evaluations, understanding mechanisms of drug actions (responses to therapies), and preventing and overcoming drug resistance. Areas of current emphasis: Molecular targeted approaches, including application of safety and efficacy biomarkers to the discovery and development of drugs; application of advanced technologies, such as nanotechnology and imaging technologies, to improved assays for quantitation of safety and efficacy biomarkers; approaches that reduce costs and increase speed of preclinical drug development; and approaches that will lead to ?personalized medicine,? including better predictions of drug response and adverse reactions, drug-drug interactions, and drug efficacy monitoring. For additional information, please visit our home page at http://dtp.nci.nih.gov and select ?Grants/Contracts.?

1. Drug Discovery.

a. Design and synthesize novel compounds for evaluation as potential anticancer agents. Synthesize simpler analogs of complex antitumor structures that retain antitumor activity.

b. Develop computer modeling and biophysical techniques such as x-ray crystallography and NMR spectroscopy.

c. Design prodrugs of anticancer agents that are selectively activated in cancer cells.

d. Discover new anticancer agents that exploit unique properties of tumors, that induce or modulate apoptosis, or that induce or modulate differentiation.

e. Design and synthesize anticancer prodrugs, latent drugs, or modifiers of cancer drug metabolism or excretion.

f. Develop ways to produce adequate quantities of promising natural products or natural product derivatives through total synthesis.

g. Develop scale-up and manufacturing technology for the synthesis of materials with promising anticancer potential.

h. Develop chemical libraries for anticancer drug screening programs. The generation of small molecular weight libraries (<700 MW, e.g., non-polymeric organic molecules, transition-state analogs, cyclic peptides, peptidomimetics) is encouraged.

i. Develop and apply technologies in genetics, genomics, proteomics, glycomics, lipidomics, metabolomics, and systems biology to the discovery of potential drug targets associated with multiple pathways or networks. Design and optimize agents that block or activate targets/pathways that are likely to control, re-program, retard or kill cancer cells, especially cancer initiating cells (often called cancer stem cells).

2. Drug Evaluation.

a. Develop and evaluate anti-metastatic and/or anti-angiogenesis agents or strategies, including combination therapies, in appropriate model systems.

b. Develop and evaluate anticancer gene therapy in appropriate model systems. The development of new gene delivery approaches is encouraged.

c. Develop novel or improved in vitro and in vivo test systems. There is a special need for new types of in vivo tumor models, such as orthotopic tumor models, models using transgenic or gene knockout animals, and models to evaluate agents that induce differentiation or apoptosis or that target cancer initiating cells (often called cancer stem cells).

d. Develop strategies to detect, prevent, or overcome drug resistance.

e. Develop novel treatment strategies such as extra corporeal treatment.

f. Develop new assays based on molecular targets, especially those that may be amplified or altered in cancer cells. For example, develop assays for agents that interact with oncogenes, suppressor genes, signal transduction pathways, transcription factors, or promoters. Assays based on molecular targets that can be adapted for high volume screening of chemical libraries are especially encouraged as well as in vivo models, which can be used for ?proof of concept? (i.e., validating selectivity of the agent for the target and confirming that modulation of the target results in antitumor activity).

g. Develop cost-effective and useful techniques to improve in vitro cell culture methodology, such as the development of automated systems, serum-free media, or carbon dioxide-free buffering systems to stabilize cell culture performance.

h. Identify and employ novel targets for antitumor drug discovery utilizing non-mammalian genetically defined organisms, such as fruit flies, worms, zebrafish and yeast.

i. Develop and apply technologies such as microarrays, proteomics or RNAi to improve the efficiency of drug discovery.

j. Develop cell lines that contain bioluminescent reporter genes, such as luciferase, that can be controlled by activating specific promoters.

3. Pharmaceutical Development.

a. Develop new methods to improve drug solubility for administration of promising antitumor compounds, such as water miscible nontoxic water solubility enhancing agents.

b. Develop bioavailable alternatives to the intravenous delivery of cytotoxic chemotherapy. For example, develop new excipients to enhance oral bioavailability of anticancer agents.

c. Develop biocompatible additives and excipients for highly concentrated proteins and peptide formulations to enhance bioavailability and stability suitable for subcutaneous delivery of agents.

d. Develop improved methods to reduce thrombophlebitis and other related side effects observed following intravenous injection of some anticancer drugs.

e. Develop new and innovative techniques for sterilization of parenteral dosage forms.

f. Develop in vitro and in vivo models to predict human oral bioavailability of anticancer drugs.

g. Develop practical delivery systems involving nanotechnology (dendrimers, nanoparticles, nanoshells, etc.) or other strategies to deliver anticancer drugs to specific target sites.

h. Develop new technology to manufacture liposomal and intravenous emulsions in an environmentally friendly manner and in accordance with OSHA standards.

i. Develop additives and/or processes to eliminate cold chain storage of biotherapeutic agents, especially vaccines.

4. Toxicology and Pharmacology.

a. Develop biochemical or molecular (genomic, proteomic, or metabolomic) response profiles of specific target organs (e.g., bone marrow, gastrointestinal tract, liver, kidney, heart, lung) to permit rapid identification of toxic effects resulting from anticancer drug administration.

b. Develop clinically relevant in vitro and/or in vivo tests for estimation and prediction of gastrointestinal toxicity, neurotoxicity (central and peripheral), cardiotoxicity, hepatotoxicity, nephrotoxicity and pulmonary toxicity.

c. Correlate in vivo and in vitro models for organ toxicity as described above in 4b. Validate for various anticancer drugs.

d. Develop drug metabolism (Phase I and Phase II) profiles for anticancer agents in human, mouse, rat and dog liver S-9, microsomes and slices.

e. Develop systems to identify toxic effects of drugs by characterizing reactions with biomolecules or receptors.

f. Develop in vitro tests to detect, qualify and quantify toxic effects of antineoplastic drugs. Develop techniques for determining individual variations in drug responses due to genetic polymorphisms or other factors. Develop pharmacodynamic endpoints and surrogate endpoints using appropriate biomarkers to aid in the selection of doses and schedules and the monitoring of responses and toxicity.

g. Develop personal computer programs for pharmacokinetics models capable of predicting drug behavior in humans from preclinical pharmacokinetics data in mice, rats, dogs, and non-human primates.

h. Investigate and develop techniques for relating specific enzyme activities (both catabolic and anabolic) to body sizes of different species.

i. Investigate techniques that would allow parameters, e.g., Km and Vmax for enzymes, to be scaled from preclinical to clinical models.

j. Develop analytical strategies applicable to the quantitation of potent anticancer drugs in biological fluids at the pg/ml level, e.g., Bryostatin.

k. Develop non-invasive techniques to determine drug distribution in various animal models.

l. Evaluate interspecies transporter distribution and its impact on pharmacokinetic parameters, e.g., the impact of pharmacogenetic variation in biodistribution.

m. Determine optimal pharmacokinetic sampling schedules for use in dose titration/pharmacodynamic assessment by integrating information such as pre-clinical pharmacokinetic data, physico-chemical drug properties and mechanism of action.

n. Develop an in vitro/in situ system for high throughput drug screens for oral bioavailability.

o. Develop and deliver organ specific chemo-protective agents.

p. Develop and evaluate rapid, cost-effective methods, including biochemical, functional multiplexed, imaging, nanotechnology-based, and microfluidics-based assays, to quantitate surrogate endpoints for determination of doses, dosing schedules, safety, and efficacy of drugs.

q. Identify and develop biomarkers to evaluate drug activities and toxicities.

r. Develop assays in support of Exploratory Investigational New Drug Studies using biomarkers or other appropriate endpoints.

s. Develop, standardize, and validate cost-effective tools for obtaining comprehensive ADME and toxicology profiles that may better predict the performance of drugs in humans.

t. Develop and analytically validate assays or tools for measuring safety, efficacy, and dosing biomarkers.

5. Animal Production and Genetics.

a. Investigate alternatives to expensive barrier systems for exclusion of pathogens from rodent colonies, e.g., by use of micro-isolator cages, and evaluate their performance.

b. Develop and evaluate specialized shipping containers for pathogen-free animals.

6. Natural Product Discoveries. Note that execution of projects in most of these topic areas will require collaboration and signed agreements with countries where the source organism was originally collected.

a. Develop techniques for the study of non-culturable organisms in order to identify antitumor agents.

b. Develop techniques for the genetic and biochemical characterization and the manipulation of biosynthetic pathways to create leads. Use combinatorial biosynthesis to generate libraries of un-natural natural products as drug leads.

c. Use genetic techniques for the identification of microbial consortia, and for the identification and isolation of genes controlling the biosynthetic pathways producing potential antitumor agents.

d. Express biosynthetic pathways from microbes or microbial consortia that are known to produce antitumor agents, but in organisms amenable to standard fermentation techniques.

e. Investigate new biological methods, such as tissue culture, aquaculture, hydroponics, etc., for the production of natural products as potential anticancer agents.

f. Develop new systems of large-scale production using biotransformation, tissue or cell culture, biotechnology, modification of the chemical ecology of producing organisms, etc., in order to produce the large quantities of anticancer drugs needed for preclinical or clinical development.

g. Develop methods for the isolation, purification, identification, cultivation, and extraction of microorganisms from unusual marine or terrestrial habitats for antitumor screening. Examples are gliding bacteria, barophilic, endophytic, thermophilic, and tropical canopy organisms.

h. Investigate newer methods of isolation and purification, such as super-critical fluid extraction and chromatography, centrifugal countercurrent chromatography or affinity-based separations, in the isolation and purification of natural products with anticancer activity.

i. Develop simple immunoassays that can be used to monitor the levels of natural products of interest in simple extracts of the relevant raw material. These assays should be capable of being developed for use ?in the field? and also in developing countries.

j. Develop analytical and biological methods for isolation, purification and validation of active constituents identified from alternative medicine and complementary studies; use of these purified constituents alone or in combination with conventional anticancer agents.

7. Data Management Systems.

a. Develop data support systems for chemical library programs.

b. Develop bioinformatics tools to accelerate the identification, functional understanding and validation of drug targets.

c. Develop bioinformatics tools to predict ADME and toxicology characteristics of drug candidates.

d. Develop ?data mining? strategies such as neural networks.

e. Develop algorithms for determining optimal drug combinations and for prediction of optimal effectiveness of individual agents.

f. Develop bioinformatics tools to support a systems biology approach to drug discovery and development.

g. Develop bioinformatics tools to support genomic/proteomic and other "omics" profiling experiments in support of drug discovery and development.

C. Cancer and Nutrition. Research to improve the methodology of nutritional assessment in a cancer population. Innovative approaches to evaluate the contribution of nutritional status to response to cancer treatment.

1. Research to improve the methodology of nutritional assessment in a cancer population.

2. Develop means to evaluate the contribution of nutritional status to response to cancer treatment.

D. Clinical Treatment Research. Clinical research studies designed to improve cancer treatment. Emphasis is on clinical trials for the evaluation of new therapeutic agents, development of assay systems to measure patient response to chemotherapy, development of prognostic assays, and development of methods of analysis and management of clinical trials data. Studies designed to improve human subject protections for patient access to clinical cancer trials.

1. Evaluation of New Cancer Therapies.

a. Conduct clinical trials for the evaluation of new therapeutic agents or modalities of treatment employing drugs, biologics or surgery.

b. Clinical trials using ?unconventional therapies,? including, but not limited to, behavioral and psychological approaches, dietary, herbal, pharmacologic and biologic treatments, and immuno-augmentative therapies.

c. Development and evaluation of new clinical approaches using gene transfer or gene therapy technologies.

d. Development and evaluation of new clinical approaches using tumor associated antigens or vaccines in order to enhance immunogenicity.

e. Develop and characterize novel chemical compounds that may be useful anticancer agents, either alone or in combination with other modalities such as radiotherapy.

f. Develop techniques to lessen the toxicity of existing anticancer treatments.

g. Develop new techniques for the delivery of anticancer agents that will maximize therapeutic effects and minimize toxicity.

h. Develop new surgical techniques or tools or improve existing techniques that are/may be utilized in cancer treatment.

i. Characterize and produce clinical grade monoclonal antibodies to detect and treat malignancies.

2. Development of Prognostic Assays to Monitor Patient Response to Therapies.

a. Develop assay systems to measure the response of human tumors to chemotherapy or biologics.

b. Characterize drug resistance mechanisms and design methods to overcome clinical drug resistance.

c. Develop assays for prognostic factors to identify patient subsets who may benefit from specific cancer treatment therapies.

d. Development of assays to assess effects of agents on specific molecular targets in clinical studies.

e. Develop new techniques for relating past preclinical information to past clinical results for prediction of future useful clinical agents from future preclinical data (both in vitro and in vivo).

3. Clinical Trials Informatics.

a. Develop new tools and methodologies for the analysis of clinical trials results.

b. Develop new informatics tools to facilitate clinical trials data entry from the bedside and coordination of data entry and transmission throughout the institution and to other collaborating institutions or organizations.

c. Development of novel web-based approaches to clinical trials informatics for transmission of data to NCI or other organizations. Topics include point of treatment data capture and reporting, electronic protocols, OLAP (On-line Analytical Processing), support for the Common Toxicity Criteria, and drug accountability support.

d. Develop new interchange standards, based on technologies such as XML, for sharing data among heterogeneous systems. Specific applications areas include, Adverse Even Reporting, Case Report Forms.

e. Develop new tools for support of Common Data Elements.

f. Develop new approaches for interface with electronic medical records, with intent to streamline data reporting, registration, and toxicity reporting of Clinical Trial information.

E. Cancer Imaging Program. The mission of this program is to promote and support: Cancer-related basic, translational and clinical research in imaging sciences and technology, and integration and application of these imaging discoveries and developments to the understanding of cancer biology and to the clinical management of cancer and cancer risk.

Toward this effort, CIP 1) funds research in the development of tools, methodologies and imaging agents/probes that will better diagnose, assess, and effectively treat cancer, and 2) supports a spectrum of research projects from preclinical exploratory research and development through clinical trials. Areas of interest include but are not limited to:

1. Development of medical imaging systems for early cancer detection, screening, response to therapy and interventions including image-guided therapy.

2. Development of preclinical and clinical in vivo imaging systems, methods, imaging probes and contrast agents and related image reconstruction, image processing, image display and image-based information as required to detect, classify, monitor and guide therapeutics to cancer and precancerous conditions.

3. Development of methods to assess the value of imaging procedures for the above goals.

4. Development of systems and methods for improved production and distribution of radioactive materials for cancer imaging and/or treatment.

5. Development of systems, methods and their optimization for studying the adverse reactions/effects of image-guided and other diagnostic and therapeutic interventions.

6. Any other investigator-initiated research idea that is relevant to cancer biomedical imaging.

7. Development of systems, methods and their optimization to advance the role of imaging in assessment of response to therapy through increased application of quantitative anatomic, functional, and molecular imaging endpoints in clinical therapeutic trials and dissemination of these systems and methods with appropriate scientific communities.

F. Radiation Research. The Radiation Research Program (RRP) supports basic, developmental and applied research (including clinical) related to cancer treatment utilizing ionizing and non-ionizing radiations. Therapeutic modalities include photon therapy, particle therapy, photodynamic therapy (PDT), hyperthermia, radioimmunotherapy (RIT), systemic targeted radionuclide therapy (STaRT), and boron neutron capture therapy (BNCT). Radiation research encompasses a range of scientific disciplines including basic biology, chemistry, physics and clinical radiation oncology. Topics of interest include, but are not limited to, the following areas:

1. Development of devices for planning, measuring, and delivering radiation therapy or related therapies, including devices for patient positioning and quality assurance for the following: (a) ionizing radiation, particularly 3-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT); (b) PDT; (c) hyperthermia; (d) RIT; (e) STaRT; and (f) particle therapy.

2. Development of devices for dosimetry for (a) ionizing radiation; (b) PDT, particularly those capable of measuring light doses at depth in tissues; (c) thermometry for hyperthermia, particularly non-invasive thermometry; and (d) RIT.

Devices may include chemical, solid state, film, biological or ionization systems to detect or read out exposures. Accuracy, precision and linear response are essential over the range of doses and temperatures employed in the research laboratory and/or in the clinic, depending on their intended use. Devices for thermometry during hyperthermia treatment must give accurate readings with the heating device(s) with which they are to be used.

3. Development and evaluation of computer hardware and software for radiation therapy, such as computation algorithms, computer workstations, image guidance techniques, and informatics methods for treatment planning, delivery and outcomes analysis.

4. Development of novel drugs to increase the effectiveness of radiation therapy or related therapies: (a) chemical modifiers of radiation response, particularly small molecules directed at molecular targets involved in tumor radioresistance; (b) photosensitizers for PDT; (c) sensitizers for use with hyperthermia; and (d) prodrugs that are selectively activated within the tumor.

5. Development of drugs to prevent, reduce or reverse normal tissue response, especially the late effects that develop months or years after therapy.

Compounds that are based on a rationale for achieving a therapeutic gain (an improved differential response between tumor and normal tissue) are of greatest interest. Enhancement of response must be achieved at radiation doses and treatment schedules employed clinically.

6. Development of predictive assays and monitors of response to radiotherapy, PDT, hyperthermia, STaRT, or RIT. Tools are needed to identify patients that would benefit from specific therapeutic approaches.

G. Biological Response Modifiers (BRM). Research on agents or approaches that alter the relationship between tumor and host by modifying the host's biological response to tumor cells with resultant therapeutic benefits. Both preclinical and clinical investigations are conducted on the utility of a wide variety of natural and synthetic agents and on biological manipulations of immunological and non-immunological host mediated, tumor-growth controlling mechanisms in cancer therapy.

Studies are encouraged which utilize in vitro assays and/or animal model systems to investigate mechanisms of BRMs. Examples of innovative research include but are not limited to:

1. Evaluation of molecular genetic approaches to discovery of new therapeutic agents, delivery of BRMs or development of gene therapy.

2. Development of improved techniques to synthesize, screen and develop new oligonucleotides including iRNA sequences for therapeutic purposes, such as signal modulation, anti-oncogene or anti-viral effects.

3. Improvement in cell-culturing techniques, e.g., by developing automated cell culture systems, specialized media, or improved methods to induce activation, proliferation or differentiation.

4. Development of new procedures or reagents for the modulation of the suppressor arm of the immune system in experimental models, directed towards successful immunotherapy.

5. Improvement of tumor-associated antigens or vaccines in an attempt to enhance immunogenicity.

6. Evaluating autoimmunity in the context of anti-tumor response in vivo to vaccines.

7. Development of novel in vitro assays for the primary screening of BRMs.

8. Application of observations describing shared receptors and mediators between the neuroendocrine and immune systems in studying immunobiology and immunotherapy of cancer.

9. Development and optimization of viral oncolytic agents.

10. Development of novel or improved methods for process development and manufacture of biotherapeutics, including but not limited to antibodies, recombinant proteins, peptides, oligonucleotides, and products based on viral or bacterial vectors, per executive order (E.O. 13329) mandating federal agencies assist the private sector in manufacturing innovation efforts.

11. Development of innovative methods for monitoring the manufacturing process for biotherapeutics using in-line or on-line process analyzers to improve the efficiency of process controls and determination of production end-points (see Guidance for Industry, PAT-A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance, www.FDA.gov).

12. Development of methods to more efficiently assess factors related to the ultimate product quality, safety and efficacy of biologics.

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