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Scientific Priorities for Cancer Research: NCI's Extraordinary Opportunities |
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Molecular Targets of Prevention and Treatment
Goal
The Opportunity
Progress in Pursuit of Our Goal
2003 Plan and Budget Increase Request
Goal
Accelerate discovery, development, and testing of prevention and treatment agents that target the molecular changes of cancer.
The Opportunity
We are entering an era in cancer research that holds the potential for an exciting new approach to drug development for cancer prevention and treatment. These drugs will be designed to target specific molecular features of cancer cells, such as small but critical errors in genes or proteins that lead to tumor growth.
By selectively attacking cancer cells, these revolutionary agents promise to be less toxic and more effective than current drugs. This extraordinary opportunity of molecular targeting has been generated by knowledge gained through recent advances in multiple research disciplines from basic cancer biology to synthetic and biosynthetic chemistry.
Our ability to treat cancer is integrally linked to our understanding of cancer. Historically, using available technology scientists could tell by features such as the shape or size of the cell whether it was cancerous, but not why it was cancerous nor how its inner workings might differ from normal cells. Yet investigators applied what they could see to produce the drugs now in use that, alone or with surgery or radiation, can cure some cancers and ease symptoms in others.
However, these drugs tend to be non-selective - while treating the cancer they also attack a number of healthy cells. Consequently, cancer chemotherapy is often accompanied by a variety of sometimes devastating short- or long-term side effects. It has also been hard to pinpoint why many tumors do not respond well to available drugs.
Scientists are now harnessing recent advances in technology to learn more about the nature of cancer and to identify ways that cancer cells differ from healthy cells at the molecular level. This knowledge creates the potential for cancer drugs that target these differences to more effectively attack the cancer while sparing healthy tissues.
To harness this potential we need to create better ties between laboratory and clinical research to integrate drug discovery, development, and clinical testing. In this cooperative setting researchers can effectively:
- Identify molecular targets in the cell
- Find drugs that will "hit" the targets
- Test these drugs for safety and efficacy in the laboratory and in animal studies
- Test the use of successful candidate drugs in clinical trials
Ultimately these drugs will be used by health care providers to more effectively prevent and treat cancer, with far fewer side effects.
Progress in Pursuit of Our Goal
Our ever increasing knowledge of the molecular changes that cause a normal cell to become a cancer cell has paved the way to a whole new approach to cancer drug discovery. Researchers are developing a new generation of cancer drugs that target these molecular changes to delay, stop, or reverse cancer growth.
The development of such "smart" drugs involves a multi-step process that begins as scientists search for molecular targets in cancer cells.
Scientists then validate these targets to detemine whether they might be able to find a drug that will interact with, or "hit" the molecular target to prevent or treat the cancer.
Next, they generate and test the function of a repertoire of potential anti-cancer agents against these targets.
Finally, they take the steps needed to test candidate drugs in the clinic.
The NCI is advancing this molecular targeting approach to drug discovery through a number of exciting initiatives:
Identifying and Validating Molecular Targets for Drug Discovery
Providing resources for Exploiting Molecular Targets for Drug Discovery
Identifying Compounds That Hit the Targets
Turning Promising Target-Directed Compounds into Drugs for Human Use
Developing Clinical Trials Programs To Study New Molecular Target Agents
Identifying and Validating Molecular Targets for Drug Discovery
Through the Molecular Target Drug Discovery (MTDD) program investigators are:
- Identifying novel molecular targets
- Validating these targets as sites that can be exploited for cancer therapy
- Developing tests that determine how well potential agents work on these targets
The 41 research groups currently supported are studying a number of molecular targets.
- One group of scientists is investigating Bcl-xL, an aberrant protein that enables cancer cells to evade apoptosis, or programmed cell death - a process that normally eliminates damaged cells from the body.
- Another group is investigating Heat Shock Protein (HSP) 90, a "stress response" protein that is overexpressed in tumors and may play an important role in cancer growth.
- Still another team is studying how DNA methylation can lead to cancer. Methylation is a specific type of chemical alteration that can prevent or reduce the expression of affected genes. Researchers have found that in some cancers DNA repair genes and tumor suppressor genes are silenced by this mechanism and unable to do their job in preventing cancer.
Resources for Exploiting Molecular Targets for Drug Discovery
The Molecular Targets Laboratories (MTLs) were first funded in FY 2002 to capitalize on the opportunities emerging from advances in genomics, molecular biology, combinatorial chemistry, informatics, and imaging. Through this initiative scientists are applying advances to create a resource of biological assays and chemical probes (compounds used to study molecular targets) to study cancer-related targets. This work enables biological studies of cancer, including physiological and biochemical monitoring, and provides a platform for drug discovery.
Through the Mouse Models of Human Cancers Consortium groups of academic researchers have created and are making available to researchers mice with defined genetic alterations that predispose the animals to certain types of cancer. Six strains were available as of 2001, and up to 30 more may be added annually.
These models could serve as a basis for testing new molecular targeting treatment and prevention strategies. As more models are added, it will be possible to create subsequent generations of mice with more than one genetically defined alteration to resemble human tumors even more closely. Academic members of the consortium are developing ties to pharmaceutical industry sponsors to facilitate the testing and evaluation of new compounds in these mouse strains.
We are working with the National Institute for General Medical Sciences on the National Beam Program to provide:
- Technology to quickly identify the structure of important molecular targets in cancer cells
- Efficient computer modeling to identify potential anti-cancer agents suited to "hit" the targets based on these structures
Partners are constructing "the x-ray beamline" at the Argonne National Laboratories. This cutting-edge technology will greatly improve scientists' ability to determine the complex structure of proteins and larger multi-molecular complexes.
Identifying Compounds That Hit the Targets
Through several NCI initiatives, chemists and biologists are collaborating to create libraries of synthetic, biological, and natural compounds that will be tested for therapeutic potential against validated molecular targets. These scientists are developing "smart" assays, or tests used to screen the compounds to identify those that "hit" defined target molecules.
- The National Cooperative Drug Discovery Groups program supports innovative, multidisciplinary, multi-project approaches to discover new anticancer treatments. Thirteen funded groups are progressing in a variety of areas, including an innovative effort to design and evaluate novel anti-cancer drugs that inhibit the enzyme geranylgeranyltransferase I (GGTase I).
GGTase I is involved in activating a cellular pathway involving the Ras oncogene, which has been implicated in a number of human cancers. Researchers hope to identify an agent that will selectively suppress GGTase I and the cancer-promoting activity of the Ras pathway. This research is an excellent example of how a basic discovery generated through an NCI grant can be expanded into clinical development with support from special NCI initiatives.
- In Biology-Chemistry Centers, multidisciplinary teams of scientists use a combination of chemical and biological techniques to create libraries of chemically diverse structures with potential anti-cancer effects. Using "smart" assays, scientists screen the compounds to identify those that will interact with cancer-specific molecular targets.
The six teams funded through this initiative have screened hundreds of thousands of compounds for anti-cancer activity. Promising compounds include the newly designed GFB-111 molecule. This novel molecule binds to growth factors - proteins that help to regulate new tissue growth - and has been shown to significantly inhibit new blood vessel formation (angiogenesis), and thereby growth of human tumors studied in mice.
- NCI supports
. Using high-throughput screening, scientists are testing these extracts for use either as targeted cancer drugs or as probes to study targets in the cell. One chemical, Halichondrin B, which occurs naturally in a Pacific Ocean sponge, has been found to have considerable anti-tumor activity. Because of the scarcity of Halichondrin B in its natural form, researchers have started designing promising synthetic analogs. Two such analogs have shown significant anti-tumor activity against human breast, colon, melanoma, and ovarian tumors grown in laboratory animals and will next be studied for clinical usefulness.
- The Rapid Access to NCI Discovery Resources (R*A*N*D) is a new program that expedites the development of drug research capabilities in academic institutions. R*A*N*D focuses on laboratory-based studies that are the starting points for new drug development, supporting early formulation, pharmacokinetic, pharmacology, and toxicology studies. R*A*N*D assists in the development of high-throughput laboratory assays to screen large numbers of promising chemicals.
The program supports the development of libraries of chemicals that scientists can draw upon for study. One of the five initial R*A*N*D projects uses microarray technology to study molecular profiles of leukemia cells and to identify more targets. Another exciting project is creating a library based on a compound that targets an important cellular protein involved in angiogenesis, or generation of new blood vessels -an integral component of tumor growth.
- NCI provides, at no cost, samples of synthetic chemicals, collected natural products, and biological materials to investigators who want to screen them against molecular targets. NCI has made available more than 140,000 synthetic chemicals, 80,000 natural products extracted from plants and marine organisms, and a variety of biological agents for use in studying the compounds.
Turning Promising Target-Directed Compounds into Drugs for Human Use
Translating laboratory discoveries into agents for human use is an exacting task that requires very specific, interrelated activities. For example, sufficient quantities of the drug must be made for formulation, stability, and safety testing. Drug optimization and development studies enable scientists to determine the manner and amount of drug to be delivered based on a drug's overall effect on an animal. NCI is supporting this critical arm of drug development through a variety of initiatives.
- The Rapid Access to Intervention Development (RAID) program provides preclinical drug development resources to academic institutions in 50 current projects. Two interventions developed through RAID are now being tested in clinical trials. One intervention is a novel gene therapy approach that delivers a pair of therapeutic "suicide genes" to prostate tumors, thereby rendering malignant cells sensitive to specific drugs and radiation. The other is the anti-cancer agent 6-Diazo-5-Oxo-l-Norleucine (DON), which selectively inhibits growth of neuroendocrine tumor cells. As many as nine additional agents will be in clinical trials testing by the end of FY 2001.
- The Rapid Access to Preventive Intervention Development (RAPID) program provides preclinical and early clinical drug development resources to academic investigators who are developing novel agents to prevent, reverse, or delay cancer development. The seven projects currently funded through RAPID include studies to develop certain marine-derived products as chemopreventive agents, a human papillomavirus vaccine, and work to determine the preventive effects of certain proteins.
- The Drug Development Group provides support for academic and corporate-derived compounds when NCI is responsible for conducting and monitoring the drug's clinical development. A number of promising agents have been developed through this program. PS-341, a novel compound presented to NCI by Millennium Pharmaceuticals, is the first in a new class of agents that take aim at a new cellular target - the proteasome enzymes. These enzymes play an important role in the breakdown of proteins that regulate the cell cycle. PS-341 inhibits the breakdown of these proteins and leads to cancer cell suicide. In preliminary clinical trials, PS-341 produced promising effects in both multiple myeloma and prostate cancer patients. NCI and Millenium are pursuing further clinical testing.
Certain cancer-causing genes induce cancer when they block the normal expression of healthy genes. Histone deacetylase (HCAC) inhibitors relieve this suppression. In cooperation with extramural organizations, NCI has studied the anti-tumor effects of several such inhibitors, including pyroxamide, an inhibitor identified by an NCI-supported Cancer Center as a candidate for cancer drug development. Pyroxamide considerably reduced tumor growth in animal models of breast, lung, and prostate cancer without causing toxicity. Preliminary clinical trials are now underway at the Cancer Center.
- The Flexible System to Advance Innovative Research (FLAIR) provides funds to small businesses to develop cancer therapeutic and prevention agents from basic discovery to clinical trials. There are currently 20 active FLAIR grants, including an investigation of a potential anti-cancer agent, PX-12. This agent targets thioredoxin, a cellular protein that is overexpressed in a number of human cancers and associated with aggressive tumor growth and poor patient prognosis. PX-12, which inhibits the growth-promoting activities of thioredoxin, has shown potent anti-tumor activity against leukemia, breast, and lung cancers in animal models. Phase 1 clinical trials supported by the FLAIR program are now under way.
- The Radiation Modifier Evaluation Module (RAMEM) program will serve individual investigators and industry in the design and development of treatment programs for the use of novel molecular, biologic, and cytotoxic agents in conjunction with radiation therapy. Integration of molecular imaging, molecular signatures, and molecular therapeutics with radiation therapy is a high priority of NCI's Intramural Program because new anti-cancer agents may ultimately be used in combination with radiation therapy.
Developing Clinical Trials Programs To Study New Molecular Target Agents
The Interdisciplinary Research Teams for Molecular Target Assessment (IRTMTA) is a new program that enables interdisciplinary teams of scientists to develop molecular assays, molecular and cellular imaging probes, and other tools to assess the effects of targeted interventions in preclinical models and in early clinical trials. The teams will study critical biological processes to uncover high-priority targets for cancer prevention or treatment and drug discovery. The first set of applications for this program was funded in early FY 2001.
The Plan - Molecular Targets of Prevention and Treatment
Goal
Facilitate the expanded exploration of the causes of cancer and the discovery and development of agents that specifically "target" these causes to treat and prevent cancer.
Fiscal Year 2003 Objectives, Milestones, and Funding Increases Needed
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| Objective 1: Identify, characterize, and validate the combinations of deregulated cellular proteins and pathways that cause cancer in precancerous and cancerous cells. |
- Through the Molecular Target Drug Discovery Grants (MTDD), increase support for research to identify cellular targets and discover related anti-cancer agents. Continue support for the MTDD Grants and previously awarded Biology-Chemistry P01s. Provide screening assistance and informatics management.
|
$6.00 M |
| TOTAL |
$6.00 M |
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| Objective 2: Determine the cancer-causing deregulated pathways that can be targeted by prevention or treatment agents. |
- Amplify support for the Molecular Target Laboratories to bolster the systematic search for new preventive and therapeutic agents.
- Develop assays to identify possible treatments for cancer and
- acquire large libraries of natural and synthetic compounds.
|
$5.00 M |
- Support the Mouse Models of Human Cancers Consortium to accelerate the pace of making available accurate, reproducible mouse models of human cancers.
|
$1.00 M |
| TOTAL |
$6.0 M |
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| Objective 3: Provide the infrastructure for researchers to develop assays to test large numbers of potential drugs against validated "drugable" deregulated proteins and pathways. |
- Expand support for the National Cooperative Drug Discovery Groups.
|
$5.00 M |
- Expand the availability of NCI discovery resources to academic laboratories through the Rapid Access to NCI Discovery Resources program (RAPID).
|
$1.00 M |
- Expand efforts to collect, inventory, and distribute diverse compounds - synthetic chemicals, natural products, and biological materials, and provide informatics support for anti-cancer research.
|
$3.00 M |
- Develop a translational research program to closely link molecular imaging, cancer signatures and molecular targets. This would allow serial imaging and serial biopsies used to assess genomics and proteomics, to be coupled with therapeutic interventions which use systemic agents, radiation therapy, immunologic treatment and chemopreventive agents. The ability to conduct multiple studies will provide a robust data set to understand the biology behind the image needed to credential new molecular targets.
|
$3.00 M |
- Support an intramural Molecular Targets Drug Discovery Program to develop screening assays for biomolecules that interact with molecular targets, conduct screens to test candidates for probes and inhibitors of molecular targets, characterize and validate compounds that hit the targets, and facilitate development of needed research chemicals as well as promising molecular target compounds. Support the isolation, purification and characterization of individual components of natural products extracts.
|
$1.00 M |
- Develop a clinical proteomics initiative to use laser capture microdissection of human tissue specimens and to develop new laboratory tools, including a new protein array, 2D-PAGE (a technique used to characterize proteins), signal pathway profiling, and SELDI-TOF (a sophisticated technique used to analyze protein patterns) protein pattern fingerprinting for clinical proteomic applications in human cancer and drug toxicity detection.
|
$2.00 M |
| TOTAL |
$15.0 M |
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| Objective 4: Facilitate the steps necessary to turn a target-specific lead compound into a clinical agent. |
- Expand support for the Rapid Access to Intervention Development program.
|
$3.0 M |
- Increase funding to RAPID to develop prevention agents from the laboratory through clinical trials of efficacy.
|
$1.0 M |
- Expand assistance to small businesses through Flexible System to Advance Innovative Research.
|
$3.0 M |
| TOTAL |
$7.0 M |
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| Objective 5: Investigate the use of novel combinations of radiation therapy with molecular therapeutics. |
- Support individual investigators and industry to develop treatment programs using new agents with radiation therapy. Facilitate collaboration with industry and individual investigators and establish a system for alerting clinical investigators when agents are ready for clinical trials.
|
$ 0.50 M |
| TOTAL |
$ 0.50 M |
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| Objective 6: Fund Clinical Trials Networks that will take drug candidates into human trials designed to test whether or not the drug is working against the intended target and is affecting the progression of the cancer in the intended manner. |
- Widen support for the Interdisciplinary Research Teams for Molecular Target Assessment program.
|
$2.0 M |
| TOTAL |
$2.0 M |
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