Molecular Targets of Prevention, Diagnosis, and Treatment

Goal

Facilitate the expanded exploration of the causes of cancer and the discovery, development, and delivery of agents that specifically "target" these causes to prevent, diagnose, treat, and provide follow-up surveillance of cancer.

Introduction

A new era in biomedical research holds extraordinary potential for new strategies in cancer prevention, diagnosis, and treatment.

• Proteomics, specific biomarkers, and newer nanotechnology assays will provide the basis for a wide range of technologies for early detection and diagnosis.
• Physicians will have specific information on the stage of progression of most cancers.
• Patients will be treated with targeted agents both singly and in combinations uniquely designed to prevent some cancers and control others with minimal or no side effects.

Other potential benefits include the following:

• Targeted delivery of new drugs and real-time monitoring of drug levels through biosensors will ensure ongoing treatment efficacy and minimize the possibility of resistance.
• Cancer patients will more often experience a chronic rather than fatal disease and will be able to enjoy a high quality of life.
• We will be able to apply our knowledge of the molecular signatures of cancer to predict the course of the disease, individual responses to cancer/precancer therapies, and the risk of adverse drug reactions for treating the most fatal cancers. Such approaches will allow for the development and selection of more individualized and effective therapies.

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Progress in Pursuit of Our Goal

An interdisciplinary, collaborative, cooperative approach is needed if we are to realize rapid, efficient translation of basic scientific advances into new tools, reagents, and molecularly targeted lead compounds for use in clinical research. NCI is partnering with various groups as a way to carry out this research agenda. (For more on NCI partnering activities, NCI Partners to Advance Cancer Research.)

Discovery

• Identifying and Validating Molecular Targets for Cancer Intervention
• Identifying Compounds That Hit the Targets

Development

• Providing Resources for Pre-Clinical Development of Promising Compounds
• Developing New Strategies for Cancer Intervention

Delivery

• Moving Developed Agents into Clinical Testing for Safety and Efficacy
• Supporting Clinical Trials of Molecularly Targeted Agents for Cancer Prevention
• Supporting Clinical Trials of Anti-Cancer Vaccines

Discovery

The process of creating an effective, molecularly targeted cancer drug begins with basic research and the search for chemical compounds with potential anti-cancer properties and molecules within cancer cells and their surroundings that might provide targets for cancer interventions.

Identifying and Validating Molecular Targets for Cancer Intervention

Through the Molecular Target Drug Discovery (MTDD) program, investigators are identifying novel molecular targets, validating these as targets for cancer therapy, and developing tests that determine how well potential agents work against these targets.

• One grantee used a computational model to study the site of interaction between a drug and a protein involved in apoptosis.
• Another team discovered a breast cancer-relevant gene that is expressed differently in Caucasian and African American patients. This discovery could help scientists to understand differences among races in susceptibility to breast cancer.

In the NCI Intramural Research Program, investigators are discovering new hereditary cancer syndromes and identifying genes that contribute to disease, such as the gene associated with clear cell renal carcinoma in von Hippel-Lindau disease. The study of inherited mutations is providing new insight into sporadic disease. In addition, the study of pathways for these inherited diseases may spur new developments in future diagnostics and therapeutics.

The Chemical Genetics Institute (formerly the Molecular Targets Laboratory) was first funded in Fiscal Year 2002 to capitalize on the opportunities emerging from advances in genomics, molecular biology, combinatorial chemistry, informatics, and imaging. Through this initiative, scientists are creating a resource of biological assays and chemical probes (compounds used to study molecular targets) to study cancer-related targets. This work facilitates biological studies of cancer, including physiological and biochemical monitoring, and provides a platform for drug discovery.

The Mouse Models of Human Cancers Consortium (MMHCC) is a collaborative program designed to derive and characterize mouse models, and to generate resources, information, and innovative approaches to the application of mouse models in cancer research. Through the MMHCC, groups of academic researchers have created and are making available to other researchers mice with defined genetic alterations that predispose the animals to certain types of cancer. More than 75 strains were available as of 2003. These mouse models could serve as a basis for testing new, molecularly targeted treatment and prevention strategies. The Consortium will develop partnerships with pharmaceutical industry sponsors to facilitate the testing and evaluation of new compounds identified by Consortium members.

Identifying Compounds That Hit the Targets

Through several NCI initiatives, chemists and biologists are collaborating to create libraries of compounds to be either evaluated for their overall therapeutic potential, or screened to identify those that modulate the biological activity of validated targets.

• 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. More than 100 research groups engaged in targeted cancer research have been supplied with these samples.
• The National Cooperative Drug Discovery Groups (NCDDG) program supports innovative, interdisciplinary, multi-project approaches to discover new anti-cancer treatments. Thirteen funded groups are progressing in a variety of areas.
• In Biology and 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. A recent discovery used combinatorial chemistry to uncover a small molecule that disrupts the interaction of two proteins involved in angiogenesis (blood vessel development) to inhibit the growth of skin tumors in an animal model.
• The Rapid Access to NCI Discovery Resources (R*A*N*D) program 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 for use by scientists.

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Development

Translating laboratory discoveries into agents for human use is an exacting task that requires very specific, interrelated activities. For example, investigators must produce sufficient quantities of a drug for formulation, stability, and safety testing. Subsequent studies enable scientists to determine the mode and amount of drug to use in early clinical testing or whether a drug should even be advanced to this stage. NCI is supporting this critical arm of drug development through a variety of initiatives.

Providing Resources for Pre-Clinical Development of Promising Compounds

The Rapid Access to Intervention Development (RAID) program provides preclinical drug development resources to academic institutions.

• One team is developing a steroidal compound that suppresses estrogen-stimulated breast tumor growth through inhibition of a particular enzyme. RAID is providing radiolabeled material, additional efficacy, formulation, and toxicology studies for this compound.
• Another researcher has hypothesized that a treatment regimen involving high-dose chemotherapy, stem cell transplantation, and an Yttrium-labeled antibody will prove effective for relapsed Hodgkin's lymphoma. RAID is producing clinical-grade antibody that will be radiolabeled by the researchers.

Ten interventions developed through RAID were ready to advance to clinical testing by the end of 2002.

The National Cancer Drug Development Group (DDG) supports the development of experimental cancer drugs for which NCI holds the FDA-approved Investigational New Drug (IND) application, regardless of whether the drug was discovered by NCI, industry, academia, or another source. A number of promising agents from this program have progressed to clinical trials.

• One agent developed by DDG-supported researchers is a synthetic improvement on a naturally occurring anti-tumor antibiotic. This agent binds to DNA and is highly active in animal models against ovarian, melanoma, and breast tumors, while exhibiting less toxicity than the parent compound. Clinical trials will be scheduled in both the United Kingdom and the United States.
• Another agent developed through this program is a synthetic compound derived from a marine sponge that has shown anti-cancer activity in animal models representing breast and lung cancers, producing tumor-free animals in both cancers. The compound is currently in Phase I clinical trials in the United States.

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. Groups are targeting angiogenesis, survival and proliferation signals for tumors, new ways to measure the effectiveness of tumor vaccines, and the structure of tumor chromosomes.

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. Through five rounds of competition the program has awarded 50 FLAIR grants, including:

• The development of novel drug delivery systems, imaging technologies, anti-angiogenesis drugs, and anti-metastatic agents.
• The design of small compounds able to mimic the action of proteins.
• The design of agents that sensitize cancer cells to radiation.

Within the Intramural Program, the Molecular Targets Development Program (MTDP) facilitates the discovery of compounds that may serve as bioprobes for functional genomics, proteomics, and molecular target validation research, as well as for candidates for drug development. During the past year the MTDP has focused on biomolecular assay development, drug development, and collaborations with various academic and private pharmaceutical partners.

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Developing New Strategies for Cancer Intervention

Intramural laboratories are currently developing treatment and prevention therapies for a variety of cancers. 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. 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.

Intramural investigators also have shown that "adoptive transfer" is a promising approach to treating patients with refractory metastatic melanoma and has potential applications to other tumor types. Cells of the immune system are harvested from the patient, activated against the tumor antigen, and re-introduced into the patient, where they attack the tumor.

Delivery

Once preclinical testing has been completed, agents that are deemed suitable for human testing enter early-stage clinical trials for safety and efficacy. Compounds that survive early clinical testing proceed to broader clinical testing to determine whether cancer patients or those at risk for cancer will actually benefit from the agents.

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Moving Developed Agents into Clinical Testing for Safety and Efficacy

The RAID and DDG programs have delivered more than 30 new therapies for clinical testing in the past 10 years.

• One therapy that uses a virus modified to deliver a pair of therapeutic suicide genes to prostate tumors entered clinical trials in January 2002. NCI produced the virus, conducted in vivo studies, and assessed initial safety studies.
• Clinical trials have been initiated in the United States and England on a derivative of geldanamycin, a potent growth inhibitor of several pediatric neural tumor cell lines. NCI contractors produced a large quantity of geldanamycin and developed a viable formulation of the derivatives for clinical use.
• An immunotoxin (BL-22), developed intramurally and manufactured by NCI-Frederick, is being tested in patients with Hairy Cell leukemia (HCL) at the NIH Clinical Center. Further studies of this drug in HCL patients will be performed by an industry sponsor. Investigators are also modifying this immunotoxin for testing in patients with chronic lymphocytic leukemia.
• Another compound, a histone deacetylase (HDAC) inhibitor, is highlighted in Turning Genes on to Fight Cancer: The Role of Histone Deacetylase Inhibitors in Cytotoxic T-Cell Lymphoma Therapy, in this chapter.

The Rapid Access to Prevention Intervention Development Program (RAPID) supports the movement of agents for cancer prevention into clinical testing. RAPID helps academic investigators expedite preclinical and early clinical drug development of investigational agents with the potential to prevent, reverse, or delay carcinogenesis. Modeled after the RAID program, RAPID is designed to accomplish the tasks that are rate-limiting in bringing discoveries from the laboratory to the clinic by making the preclinical and early clinical drug development contract resources of NCI available to academic investigators.

Through 20 currently funded RAPID projects, NCI supports early clinical investigation of targeted chemoprevention agents to examine their effects on their molecular targets in the patient. Current projects include:

• A second-generation human papillomavirus (HPV) vaccine that is both economical and stable.
• Mycochemicals with specific efficacy in lung and colon cancer prevention models.
• Modified components of dietary crucifers developed in preclinical prevention models of breast and prostate cancer, as well as HPV replication models.

Supporting Clinical Trials of Molecularly Targeted Agents for Cancer Prevention

NCI supports clinical trials for chemoprevention that measure or identify molecular targets involved in the cancer process.

• The Selenium and Vitamin E Cancer Prevention Trial (SELECT) will assess the molecular genetics of cancer risk and associations between diet and prostate cancer.
• Investigators are studying the estrogen receptor as a key to breast cancer risk in the Breast Cancer Prevention Trial (BCPT) and the Study of Tamoxifen and Raloxifene (STAR). NCI also has begun an initiative that funds investigator-initiated research focused on two key aspects of this problem: validating surrogate biomarkers and identifying potential molecular targets for chemoprevention of human ER-negative breast cancer.
• Epidemiologic studies have suggested that prostate cancer risk may be higher in men who consume only small amounts of fruits and vegetables or high amounts of milk, dairy products, and meat. NCI is fostering investigator-initiated research to identify and characterize molecular targets affected by nutrients, and further, to determine how these targets can affect outcomes in prostate cancer prevention.

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Supporting Clinical Trials of Anti-Cancer Vaccines

NCI has initiated a consortium to develop a new generation of anti-cancer vaccines. This consortium consists of translational research laboratories within the Intramural Program, expert clinicians from numerous institutions throughout the country, and representatives from the biotechnology and pharmaceutical industries.

NCI Clinical Center researchers have initiated two clinical trials examining a vaccine that activates cytotoxic (killer) T-cells to attack tumor cells in patients with advanced colorectal, pancreatic, and lung carcinomas. Another group is conducting a similar trial for prostate cancer patients. In a Phase III randomized trial, investigators are testing an individualized vaccine against B-cell follicular lymphoma. This trial is being conducted through an arrangement with a biotechnology investment group.

Intramural laboratories have been collaborating on early-phase clinical trials of prophylactic HPV 16 vaccine in unaffected volunteers for the prevention of cervical cancer. The vaccine has been found to be safe while producing an immune response. NCI and a pharmaceutical partner will conduct a large-scale trial in Costa Rica. Another intramural laboratory is developing new targeted approaches to replace standard, cytotoxic chemotherapy for the AIDS-related malignancy Kaposi's sarcoma.

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Objectives and Fiscal Year 2005 Milestones and Required Funding Increases

Discovery

Development

Discovery

Development

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The Targeted Therapy Approach

Traditional chemotherapy drugs developed using past paradigms tend to be non-selective - that is, while treating the cancer, they also attack a number of healthy cells. Despite these disadvantages, conventional chemotherapy drugs, when used alone or in combination with surgery or radiation, can cure some cancers and ease symptoms in others.

Our ability to devise treatments selectively targeted against cancer cells is integrally linked to our understanding of the basic biology of cancer, including its molecular basis. This understanding has also begun to provide insights into why conventional agents often prove successful in curing only a fraction of those individuals diagnosed with a specific form of cancer.

Cancer types have traditionally been defined according to the anatomical location of the tumor - for example, breast, lung, or prostate - and the appearance of the cancer cell under the microscope. However, recent analyses of genome-wide expression patterns are beginning to reveal that traditional classifications may encompass a number of molecularly distinct diseases.

Cancer is a complex and varied disease, and the mechanism of action and interconnections of various molecular targets is an area of research that has and will continue to yield opportunities to target and control cancer. Continued discovery of new molecular targets and their mechanisms of action will provide a robust source for numerous innovations in the prevention, detection, and treatment of cancer.

NCI efforts to identify and validate molecular targets are designed to marry the ability to define new, more precisely targeted therapies with the newly emerging ability to identify individual patients who might have a higher likelihood of responding to a given therapy (pharmacogenomics). Molecular target-related discovery and development initiatives will be allied seamlessly with others focused on molecular imaging and molecular diagnostics.

To realize this agenda, we need to create even closer ties between laboratory and clinical research to integrate drug discovery, development, and delivery into the clinical setting. Collaborations between NCI's Extramural and Intramural Programs will be strongly encouraged and supported to facilitate the translation of the findings of molecular targets from the bench to the bedside, and back to the bench for further refinement.

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Turning Genes on to Fight Cancer: The Role of Histone Deacetylase Inhibitors in Cytotoxic T-Cell Lymphoma Therapy

Cellular DNA is efficiently packaged inside a cell's nucleus. To prevent the DNA from becoming tangled like necklaces in a jewelry box, proteins called histones interact with the DNA, acting as spools around which the DNA can wrap itself. However, when the DNA is this tightly wrapped, the genes encoded by the DNA are repressed or silent. The cell uses chemical acetyl groups and a class of proteins known as histone deacetylases (HDACs) to regulate the degree to which DNA is wrapped around the histones. HDACs remove acetyl groups from histone protein, turning off gene expression and silencing the gene.

Scientists have found that, in many types of cancer, some genes that would normally restrain cell growth are repressed by the activity of HDACs. Researchers hypothesized that expression of these cell cycle-halting genes could be induced if cellular HDACs could be inhibited.

Some HDAC inhibitors (HDACi) are currently being studied in clinical trials:

• Investigators funded through an NCI extramural contract award developed one such HDACi, depsipeptide. After encountering cardiac toxicity during the initial development, investigators varied the depsipeptide dose for safety. NCI intramural researchers are now studying depsipeptide in Phase I clinical trials, where it has been shown to be an effective therapy for cytotoxic T-cell lymphoma.
• Researchers are also examining mechanisms of resistance to depsipeptide.
• Clinical trials of other HDACi compounds, for other tumor types, are in progress.

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