Advancing Discovery and Its Application |
Email this page |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Molecular Targets of Prevention and Treatment
The OpportunityRecent advances in deciphering the human genome have launched an exciting new era in biomedical research with tremendous potential for cancer prevention, diagnosis, and treatment. New drugs are now being designed to target specific molecular features characteristic of cancer cells, including genetic mutations, factors causing changes in gene expression, structural changes in the proteins that are products of mutated genes, and alterations in signaling pathways. Molecularly targeted interventions result from the integration of multiple research disciplines and can be classified into five general molecularly targeted strategies that will guide future research. Research Avenues for Molecular Targeting
Drugs developed using past paradigms attack both cancerous and healthy cells, often causing devastating short- and long-term side effects. Moreover, individual patient responses to conventional agents vary, even in cases where cancers appear to be identical. Molecularly targeted therapies hold the promise of being more highly selective, drastically reducing the incidence of side effects in patients. These advances provide us with new diagnostic tools that will permit clinicians to more precisely identify those patients who are most likely to benefit from a given therapeutic agent. Drugs developed to target one type of cancer are often found to be effective against other cancers as well. We foresee a day when the treatment for each patient's cancer will be individualized based on the unique set of molecular targets expressed by his or her particular tumor. Progress in Pursuit of Our GoalNCI is advancing the molecular targeting approach to drug discovery through a number of exciting initiatives, from target identification through testing in clinical trials. A number of these efforts address needs identified by Progress Review Groups, expert panels who assess research requirements for specific types of cancer. The identification and validation of molecular targets is being facilitated through the Molecular Target Drug Discovery (MTDD) program. After target identification, investigators are validating these targets as sites that can be exploited for cancer prevention and therapy, and developing tests to determine how effectively potential agents work on these targets. NCI is supporting the development of resources for exploiting molecular targets through the Molecular Targets Laboratory (MTL) and the Mouse Models of Human Cancers Consortium (MMHCC). The MTL was first funded in FY 2002 to capitalize on the opportunities emerging from advances in genomics, molecular biology, combinatorial chemistry, informatics, and imaging, to create a resource of biological assays and compounds used to study molecular targets. The MMHCC is a collaborative program designed to derive and characterize mouse models of human cancers, and to generate resources, information, and methodologies to apply in cancer research. The Consortium expects to make available to researchers up to 30 new mouse models each year, and it is developing partnerships with pharmaceutical industry sponsors to facilitate the testing and evaluation of new compounds identified by consortium members. Through several NCI initiatives, chemists and biologists are collaborating to create libraries of synthetic, biological, and natural compounds to identify compounds that hit targets. The next step is to evaluate their therapeutic potential in molecular target assays.
To expedite drug discovery, NCI is providing sample sets of more than 140,000 synthetic chemicals; 80,000 natural products extracted from plants and marine organisms; and other biological materials to investigators who might have discovered potential targets. In order to speed up the rate of discovery, NCI has made available small "diverse" sets of compounds taken from the full repository. The sets include the "structural" diversity set of 1,990 compounds that vary by chemical structure and the "mechanistic" diversity set of 879 compounds that attack cancer cells via different pathways or aberrant proteins. More than 60 research groups engaged in targeted cancer research have been supplied with these sets. One discovery includes a small molecule capable of inhibiting the growth of cancer cells by restoring the normal tumor-suppression function to the mutated p53 gene. Sample sets from the repository are helping NCI's Chemistry and Biology Group with research on a novel cell cycle inhibitor. Translating promising target-directed compounds into drugs for human use is an exacting task that requires very specific, interrelated activities. NCI is supporting this critical arm of drug development through a variety of initiatives including the Rapid Access to Intervention Development (RAID) program. RAID provides preclinical drug development resources to academic institutions in 62 current projects. Three 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, rendering malignant cells sensitive to specific drugs and radiation. Another intervention is the anti cancer agent 6 Diazo 5 Oxo l Norleucine (DON), which selectively inhibits growth of neuroendocrine tumor cells. The third is a novel stabilizer of microtubule assembly that may prove useful against paclitaxel resistant solid tumors. As many as six additional agents, targeting pediatric neuroblastoma, pancreatic cancer, and tumors expressing a variant epidermal growth factor (EGF) receptor, will be in clinical trials by the end of FY 2002. NCI's Drug Development Group provides support for academic and corporate-derived compounds when NCI is responsible for conducting and monitoring the drug's clinical development. For more than 15 years, researchers have attempted to design cancer therapies to avoid toxicities associated with standard chemotherapeutic agents. BL22, one such targeted toxin, originated in an intramural NCI laboratory and was developed through NCI's biologicals production facility. It is now showing promising results in a Phase I trial: 11 of 16 patients with chemotherapy resistant hairy cell leukemia have shown complete remission, lasting up to 18 months, mostly without major side effects. Certain cancers occur when the normal expression of healthy genes is blocked. Histone deacetylase (HDAC) inhibitors relieve this suppression. In cooperation with extramural organizations, NCI has studied the anti tumor effects of several such inhibitors, including depsipeptide. Depsipeptide reduced tumor growth in a variety of animal models and had an acceptable toxicity profile. Based on favorable Phase I clinical results it is proceeding to Phase II trials. MS-275 is another HDAC inhibitor also brought to the United States under NCI leadership and is also in early clinical trials. 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. One FLAIR grant supported development of an immune modulating agent called A-007, already in Phase I clinical trials. This agent has been approved for Phase II trials to test its efficacy in treating cervical cancer. FLAIR support enabled another researcher to define the x-ray crystal structure of topoisomerase I, an enzyme involved in DNA transcription and replication. Other efforts, being supported through this program, include novel drug delivery systems, imaging, anti-angiogenesis, the design of small compounds able to mimic the action of proteins, newly designed agents that sensitize cancer cells to radiation, and anti-metastatic agents. The Radiation Modifier Evaluation Module (RAMEM) program will serve individual investigators and industry in the design and development of treatment programs using novel molecular, biologic, and cytotoxic agents in conjunction with radiation therapy. This integration is a high priority of NCI's Intramural Program because new anti-cancer agents may ultimately be used in combination with radiation therapy. To assist in developing clinical trials programs to study new molecular target agents the NCI is fostering teams of interdisciplinary scientists through the Interdisciplinary Research Teams for Molecular Target Assessment (IRTMTA). These teams study critical biological processes to uncover high priority targets for cancer prevention or treatment and drug discovery. The first set of applications, focusing on angiogenesis, tumor proliferation, tumor vaccines, and structure of tumor chromosomes, was funded last year. The NCI is supporting ongoing research in the molecular targets of prevention through the Rapid Access to Prevention Intervention Development Program (RAPID). This program avails the preclinical and early clinical drug development contract resources of NCI to academic investigators to expedite preclinical and early clinical drug development of investigational agents with the potential to prevent, reverse, or delay carcinogenesis. Through 17 currently funded projects, NCI supports clinical trials of mechanistically targeted agents to examine the effects of various chemopreventive agents on molecular targets. As part of the large-scale prevention trials, NCI supports supplemental studies and specimen repositories aimed at answering a variety of mechanistic and molecular questions. For example:
NCI's Center for Cancer Research (CCR), which coordinates all basic and clinical intramural research, is uniquely positioned to expedite rapid and efficient translation of basic scientific advances into new tools, reagents, and molecularly targeted leads. Major priorities of the CCR include fostering interdisciplinary collaborations between basic researchers and clinical investigators and training postdoctoral fellows to function in this new research environment. To this end, the CCR has formed the Molecular Targets Faculty composed of scientists from diverse laboratories and branches working together cooperatively as part of the intramural Molecular Targets Drug Discovery Program (MTDDP). The MTDDP also promotes collaborations with various academic and pharmaceutical partners and is designed to facilitate the discovery of compounds that can serve as probes for functional genomics, proteomics, and molecular target validation or candidates for drug development. Recognizing the importance of anti-cancer vaccines in prevention and treatment, NCI has established the CCR Vaccine Initiative, a consortium of multidisciplinary scientists, consisting of expert clinicians and industrial representatives. These consortium components work together as follows: the laboratories in the intramural program at NCI conduct basic and translational research in immunology and molecular biology to develop new vaccines and vaccine strategies that can be translated efficiently to the clinic. The clinical components, both at cancer centers nationwide and at the NIH, carry out clinical trials for a range of human tumors, with these new vaccines and vaccine strategies, and interact with the NCI intramural laboratories to monitor patients' immune responses. Components of industry interact with the intramural laboratories through a CRADA mechanism and provide clinical-grade vaccine for the clinical trials. The NCI Cancer Therapy and Evaluation Program (CTEP) and the FDA monitor various regulatory aspects of these programs, along with other regulatory bodies and committees. This consortium has spearheaded the development of new, more sophisticated recombinant vaccines that are now in the clinic and others that will enter the clinic shortly. The potential of proteomics to further cancer research is being exploited by two CCR programs. The Biomedical Proteomics Program (BPP) provides NCI investigators with the most powerful analytical approaches available to further the understanding of the molecular mechanisms underlying carcinogenesis and tumor progression. The BPP works hand-in-hand with the NCI Clinical Proteomics Program to identify proteins and pathways important in human cancers. The Plan - Molecular Targets of Prevention and TreatmentGoalFacilitate 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. Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004
|
A gene is said to be "expressed" when the cell uses its genetic information to produce protein. Back
"Signaling pathways" are complex molecular interactions that begin when a cell receives a signal, like a protein binding to a receptor, from outside of itself. Back