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Cancer

Cancer

Cancer

Description
Cancer is a disease caused by damage to DNA, the genetic material that carries hereditary instructions. Cancer can be caused by heredity or external factors that can cause uncontrolled abnormal cell growth. Risk factors include exposure to certain agricultural/industrial chemicals, lifestyle choices, family history and the presence of another disease or medical problem.

Who is at Risk?
Risk of developing cancer can be increased or decreased by the lifestyle choices you make or the kind of environment you live and work in. But even a person at low risk may get cancer, just as a person at high risk may not. Some factors appear to increase the risk of developing cancer. There are some factors that you cannot change, for example, age or family history of cancer. There are some risk factors related to everyday choices that you can change. You can choose to be a non-smoker and avoid tobacco smoke, eat a healthy diet, be physically active every day, stay at a healthy weight, limit alcohol use, reduce your exposure to ultraviolet rays from the sun or tanning beds, know your body and report any changes to your doctor or dentist, and follow safety instructions when using hazardous materials at home and at work.

Sources: Evita Natural Medical Centers of America, Canadian Cancer Society

Creating Zinc Finger Transcription Factors - A New Way to Approach Medical Problems
Carlos F. Barbas III, Ph.D., Janet and W. Keith Kellogg II Chair in Molecular Biology, and his colleagues have created new types of zinc finger proteins, commonly occurring proteins that bind to DNA. Barbas has strung his novel proteins together to not only bind to specific genes, but more intriguingly, to actually turn any gene in the human genome on or off. This type of directed protein evolution can accelerate the development of therapeutics for a variety of diseases, including cancer and AIDS, two areas where Barbas" attention is currently focused.

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TSRI Collaborates on New Technology to Determine Cancer Risks
In a unique multidisciplinary project involving physicians, physicists, and engineers from Scripps Research, PARC, Scripps Cancer Center and Scripps Clinic, TSRI researchers have helped to develop a new device and method that potentially can determine which patients with cancer are at risk of developing metastases. Micrometastases are cancer cells that leave the tumor and potentially form life-threatening tumors in other organs. Up to now, no tools have been available to measure these cells reliably.

The Rare Cell Detection Project involves TSRI collaborators Jorge Nieva, M.D. and Peter Kuhn, Ph.D. as well as Richard Bruce, Ph.D. from the Palo Alto Research Center and Joan Kroner, M.D. from Scripps Clinic. Together, the team has developed the FAST Cytometer that is capable of scanning 50,000,000 blood cells in two minutes, in order to discover the estimated 10-20 cancer cells circulating in a teaspoon of blood. The initial research will focus on using the technology in breast cancer to determine which patients are at risk for cancer to spread throughout the body.

Promising New Anticancer Drugs from Rare Corals Synthesized in TSRI Laboratory
TSRI scientists have performed the first total chemical synthesis of a number of promising new anticancer compounds, first isolated from rare species of corals and related marine organisms near Australia. The team, headed by Professor K.C. Nicolaou, Ph.D., succeeded in assembling these compounds in the laboratory by designing a multistep strategy using simple chemical building blocks such as carvone, an oil readily available from caraway or dill seeds, frequently used as a commodity chemical in perfumes and foods. Eleutherobin, one of the novel compounds synthesized, appears similar to the anticancer drug, Taxol, in its mechanism of preventing cells from dividing.

The synthesis could ultimately lead to more effective and safer therapeutic agents that kill cancer cells very powerfully. Nicolaou is the winner of numerous prizes, including the Tetrahedron Prize for Creativity in Organic Chemistry for "his creative and productive investigations in natural products synthesis, which through his remarkable ingenuity and ability to develop novel synthetic technologies, have enabled him to extend the frontiers of the field into challenging new areas."

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Structure Shows How One Human Protein Reduces the Potency of Chemotherapy
 A team of research scientists at TSRI have solved the structure of a human protein called AGT that is known to interfere with the action of certain chemotherapy drugs. AGT repairs damaged DNA inside human cells. Cancer cells can use it to repair DNA that has been damaged in the course of chemotherapy - thus rendering the chemotherapy ineffective. The structure of AGT was solved in the laboratory of TSRI Professor John Tainer, Ph.D. by Research Associate Douglas Daniels.

The fine details of this x-ray structure may help scientists find ways to fight certain cancers, such as brain tumors, which express high levels of AGT making them resistant to chemotherapy. Inhibitors to interfere with AGT"s actions are currently being tested in clinical trials. The idea is that these inhibitors could be administered at the same time as chemotherapy to make chemotherapy more effective. In 2001, 553,768 people in the U.S. died of some form of cancer.

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Programmable Antibodies - A Hybrid Cancer Therapy Described By TSRI Scientists
 A team of TSRI scientists has designed a "hybrid" anticancer compound that physically combines the potent punch of a cancer cell-targeting agent with the long-lasting dose of an antibody. The hybrid compound is a cross between two molecules. One is a traditional anticancer drug, a small molecule that targets cancer tumors. The other is a type of antibody, which is a protein produced in great abundance by the body"s immune system and found naturally in the bloodstream. The hybrid of the two was found to have a profound effect on the size of tumors in mouse models - shrinking tumors of both Kaposi"s sarcoma and colon cancers in these preclinical studies. Moreover, this approach is general enough that it could be used to design hybrids against any number of cancers.

TSRI Professor Carlos F. Barbas III, Ph.D., and several other TSRI scientists collaborated in the interdisciplinary research. The beauty of the hybrid is that while the antibody portion keeps the hybrids circulating, the small-molecule portion guides them towards cancer cells. Once there, the antibody part of the hybrid would activate other parts of the immune system that recognize the antibody and destroy the cells to which they are attached.

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Tissue Factor in the Fight Against Tumors
 One new cancer is diagnosed every 30 seconds in the United States, and every 90 seconds another American dies of cancer. A novel approach to detection and treatment is to block the flow of blood to a tumor and asphyxiate and/or starve the tumor. TSRI Professor Thomas S. Edgington, M.D. has been working on a strategy within this paradigm by seeking to initiate thrombotic occlusion of the blood vessels in tumors, effectively blocking the local flow of blood. This produces a "gangrene" effect in the tumors. Starved of oxygen, the tumor cells undergo immediate asphyxiation and tumor cell death on a massive scale. Edgington"s technique involves delivering molecules of tissue factor (TF) to tumor vascular endothelium cells, which line the blood vessels that carry the blood to the tumors. TF has the ability to initiate the formation of blood clots within the vessels - a process known as thrombosis. If released in the blood vessels of tumors, the clots interrupt the tumor"s blood supply and lead to an "avalanche" of tumor cell death.

The tissue factor receptor has to land on the precisely correct part of the tumor blood vessel cell surface. Edgington and his colleagues have found a way to deliver molecules such as TF to specifically target only those vessels that are supplying blood to tumors and leave the rest of the vasculature alone. They used a truncated 24-amino acid stretch of the binding domain of a vascular growth factor and showed that when injected into the blood stream it can find and anchor a viral phage particle to the blood vessels only of a tumor. This ability to target tumors may be used as the basis of a diagnostic to image the tumor vasculature - a technology that could help surgeons see the exact size and locations of tumors that could then be surgically removed.

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Group Designs DNA Vaccine that Inhibits Growth of Cancerous Tumors
 A group of TSRI researchers have developed a novel DNA vaccine that helps the body resist the growth of cancerous tumors by choking off the tumors" blood supply. Not yet tested in humans and still in preliminary development, their vaccine has the potential to treat many types of cancer, and it may provide a new strategy for the rational design of cancer therapies. The researchers, led by Professor Ralph Reisfeld, Ph.D., stimulated the immune system to recognize proliferating blood vessels in the tumor vasculature and to recruit killer T cells to destroy these vessels. Deprived of its blood supply, the tumor eventually dies.

The solution that the researchers employed was to target not the tumor cells themselves but the endothelial cells that proliferate to form new blood vessels. Unlike the tumor cells, which readily mutate to resist treatment, the endothelial cells are not prone to mutations and therefore represent a more stationary target. And targeting the endothelial cells proved effective because these cells are absolutely necessary for tumor growth, since they provide the blood that the tumor cells need to grow. The researchers hope that their study establishes a proof of concept that may eventually contribute to the development of novel cancer therapies.

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Making the Most of Lymphopenia - Study at TSRI Suggests Powerful New Ways to Treat Cancer
 A study undertaken by investigators at TSRI suggests a new, potentially more effective way to battle cancer - hit the immune system with cancer vaccines or cancer cells when it"s down and it will bounce back swinging harder than ever against those cancer cells. The technique involves administering an injection of fresh immune cells to replace the ones that die immediately after chemotherapy or irradiation. An injection of cancer cells at the same time serves as a form of "immunotherapy," which induces a person"s immune system to attack existing colonies of those cancer cells. In the technique, the fresh immune cells immediately begin to multiply and, because they see the cancer cells, they are rapidly activated to kill them. The study was led by TSRI Professor Argyrios N. Theofilopoulos, M.D.

For years, the main treatment of various sorts of cancers has been systemic chemotherapeutics - drugs that have a cytotoxic effect on rapidly dividing cancer cells - or irradiation, the use of x-rays or some other sort of ionizing radiation that is also lethal to cancer cells. However, they both cause collateral damage, killing non-cancerous cells as well. Like innocent bystanders, T cells and other cells of the immune system are killed along with the tumor cells during chemotherapy and irradiation - a state referred to as "lymphopenia." Immunotherapy, another approach to cancer therapy, involves helping the T lymphocytes and other cells of the immune system to attack and kill cancer cells. It is best at killing small colonies of cancer cells before they grow into tumors. The study by Theorfilopoulos and his colleagues suggests the anti-tumor effect of immunotherapy could be increased if it were coupled with injection of fresh T cells after chemotherapy or irradiation. In in vivo studies with murine models, Theofilopoulos and his colleagues were able to establish protection against tumor formation and strong regression of existing tumors.

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TSRI Team Solves Structure of Important Tumor Growth Protein - A Target for Cancer Therapy
 A team of scientists at TSRI have solved a structure of a protein that is crucial for cancer tumor growth. Blocking this protein has already proven to be an effective way of stopping tumor growth in animal models, and the unforeseen molecular details revealed by the structure are like a roadmap for the development of future anti-cancer therapeutics. Peter Wright, Ph.D., Cecil H. and Ida M. Green Investigator in Medical Research, and Jane Dyson, Ph.D. solved the structure of the important domain of an activator protein called hypoxia inducing factor (HIF-1) in complex with its "coactivator" protein called CBP. HIF-1 is a potential target for drugs that will stop tumor growth because it is extremely important for angiogenesis.

Angiogenesis, the process where blood vessels are formed and differentiated, is the body"s way of responding to hypoxia, a deficiency of oxygen reaching the body"s tissues. Blocking angiogenesis can regress tumors, and scientists are particularly interested in finding ways of accomplishing this, with the goal of identifying specific drugs that might produce milder side effects than general chemotherapy. And one of the best starting points for designing specific drugs is to thoroughly understand the structures and mechanisms of the important molecular players involved. This information provides a starting point for the design of antitumor agents. These agents would block the effect of HIF-1 in cancerous cells. And, lacking oxygen, the cancerous cells would not be able to continue dividing and tumor growth would stop.

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Crucial Genetic Diversity Enzyme Long Sought by Biologists Discovered by TSRI Scientists
 Simultaneous reports by two teams, led by TSRI Professor Paul Russell, Ph.D. and Associate Professor Clare H. McGowan, Ph.D. have identified a "resolvase" enzyme that may be responsible for generating genetic diversity during sexual reproduction. The discovery of this enzyme could lead to improved cancer chemotherapy. Resolvase is essential for a crucial step in DNA recombination because it is the molecule that allows two chromosomes to cross over. It is one of the most important enzymes involved in genetic recombination. Resolvase is the molecule that allows children to inherit a unique mixture of traits from mother and father; without it, we wouldn"t have the infinite range of genetic combinations that makes us all different.

The identification of a human resolvase may have a profound effect on cancer therapy because the enzyme also has an important role in cell replication. Cancer cells are often defective in the mechanisms that sense damaged DNA. Russell and McGowan envision that treatment of tumors with chemotherapeutics that damage DNA, combined with rational targeting of resolvase activity, could be a highly potent cancer treatment.

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Possible Therapeutic Targets for Metastatic Cancer
 TSRI Professor James Quigley, Ph.D. is involved in identifying the molecules that determine why a human tumor cell migrates to and survives in a different organ - a different environment with different growth factors, adhesion molecules, hormones, and glandular products nearby. Identifying these molecules would yield information about both the basic biology of metastatic cancer and possible therapeutic targets. Quigley"s approach involves first generating many monoclonal antibodies raised against "crude" tumor cell antigen populations - whole cells and cell membranes - and then screening for those that block the metastatic ability of the cell. Quigley reasons that any antibody that arrests the metastasis must have as its target some antigen involved in the process. The antigens of those antibodies that do block metastasis can be isolated and sequenced. These antigens should be cell molecules that are essential components for metastasis and, perhaps, eventual targets for therapeutics.

Quigley uses an assay of chicken eggs with their shells removed that are placed in an incubator to develop for a few days. Because the eggs are only a few days old, they are immunoligically naïve and will tolerate human tumor cells. After ten days, a tumor is placed on the soft chorioallantoic membrane on the inside of the shell and an antibody against the tumor cells is injected into the egg. Quigley uses an aggressive tumor cell that will grow and form metastases in under a week. An antibody of interest can be injected into the egg and tested for the ability to block metastasis. After a week with the tumor, metastatic cells can be detected by looking for evidence of human tumor DNA in a part of the egg that is distinct from where the tumor was implanted a week before. Occasionally a protein (antigen) is found that, when blocked, reduces or stops metastasis. Quigley"s group has found several of these thus far. The blocking antibodies are also tested in a mouse metastasis model to insure that inhibition of human tumor cell spreading is not confined to the chick egg system. In addition to metastasis, Quigley"s laboratory studies normal and tumor-induced angiogenesis, the process where new blood vessels are formed and differentiated. The goal of both the metastasis and the angiogenesis work is to identify molecules that could become targets for intervention.

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A Vaccine Factory Inside Each Cell
TSRI Associate Professor Bruce Torbett, Ph.D. is developing and testing a gene delivery technique that may someday be used to deliver genes into cells, providing a high level of protection against HIV or cancer. The technique involves treating hematopoietic stem cells (HSC). These are the pluripotent granddaddy of all blood cells, located in the bone marrow, that develop into lymphocytes, platelets, erythrocytes, and red blood cells. The basic idea is to give these cells genes that will allow them to resist an HIV infection, then implant them into tissue where they can freely grow, develop, and resist HIV infection. The same approach may be used to inhibit cells from becoming cancerous.

Using a crippled version of HIV as a gene delivery vector/vehicle that can no longer spread in human cells and cause disease, Torbett"s group has shown that human stem cells can be given the gene for green fluorescent protein from jelly fish, and all cells developed from these stem cells express the protein. One vector would take out the patient"s bone marrow, remove the stem cells and infect them with the intrabody gene using the HIV vector, then return the cells to the patient. The stem cells would then develop into dendritic cells and blood cells, including cells that HIV infects, such as macrophages and T-cells. These progeny cells, then, would be effectively resistant to HIV. Having a selective advantage over the wild type cells, they would repopulate the body. The intrabodies would then do what antiretroviral drugs have done for years: keep the virus in check. The idea is to keep the viral level low, protect the T-cells, and allow the immune system to do its job and control the infection. This approach could one day be used as a vaccine to protect people from being infected. Inserting HIV intrabody genes is only one of several applications of Torbett"s work to control cellular function. Another promising application is the treatment of certain types of cancer called acute myeloid leukemia (AML), a common form of acute leukemia in adults.

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Addressing Chemotherapy Drug Resistance
TSRI Assistant Professor Geoffrey Chang, Ph.D. is pursuing the structures of several types of membrane transporters. One of these, the drug efflux pumps, may be an important system for deterring the threat of antibiotic-resistant bacteria and addressing the related problem of the sometimes low efficacy of chemotherapy. Efflux pumps are broad-based defense mechanisms that bacterial and cancerous cells use to resist pharmaceuticals, transporting the drugs out of the cell.

Very good drugs exist to fight cancer and to kill bacteria, but they can"t always get in the cells to work. One of the eventual goals is the development of a new class of drugs that patients would take in conjunction with antibiotic or chemotherapeutic agents to keep those drugs in the cells and increase their efficacy. Chang is hoping to solve a novel structure of a membrane complex involved in antibiotic and chemotherapy drug resistance.

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Working Toward Better Leukemia Treatment
TSRI Associate Professor Dong-Er Zhang, Ph.D. is investigating blood cells that go wrong and eventually cause acute myeloid leukemia, a rapidly progressing disease characterized by the accumulation of immature, functionless cells in the bone marrow and blood. Acute myeloid leukemia begins with an accumulation of blast cells, the earliest marrow cells that can be identified, which block normal blood cell development. As a result, red cells, white cells and platelets are not produced in sufficient numbers. Zhang"s lab is studying the regulation of gene expression. Particular genes are expressed in blood cells. Their hypothesis is if they can understand the regulation of this gene expression, they can learn how cell differentiation happens.

A gene called AML1 is involved in the regulation of myeloid-lineage specific genes, and other labs" work has indicated that AML1 is involved in chromosome translocations identified in leukemia patients. Zhang focused on AML1 as an important transcription factor that might provide some valuable clues as to how myeloid cells form. Another research team has found that, in 12 percent of acute myeloid patients, AML1 was fused to a gene called ETO to encode a protein called ALM1-ETO. Zhang used mice to see if this fusion protein might be involved in the development of leukemia cells. The results were dramatic: normal blood cell development was blocked, and the embryos were unable to survive. Ultimately, Zhang"s understanding of how human leukemia develops will lead to better treatment of this disease.

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Tackling the Problem of Carbohydrate Recognition
 In the cellular world, sugars are responsible for jump-starting some of the most destructive human diseases. Cancer, virus and bacterial cells all have unique sugar structures called receptors on their surfaces; until recently, very few people knew what they did or even why they were there in the first place. A significant portion of TSRI Professor Chi-Huey Wong, Ph.D."s research life has been spent trying to understand the role of sugars with the added goal of developing small molecules to affect their function. Viral and bacterial cells are like uninvited guests. During infections, even metastatic cancers, these cells spread throughout the body, searching for a place to light. When they land on the surface of a host cell, they immediately try to insinuate their way inside - and the host cell always recognizes its sugar receptors first. Wong"s goal is to better understand the way sugar receptors work in order to better develop a new strategy of therapy.

Wong and his colleagues are researching ways to stop sugar structures from working. To create a vaccine, they can attach a unique sugar receptor to a carrier protein and inject this joined compound into the body. The immune system produces an antibody that recognizes the sugar receptor. When these new antibodies discover a cancer cell with the same sugar receptor, the antibodies block the receptor, and prevent the cancer cells from attaching to an endothelial or host cell. As a result, the cancer can be stopped. The goal is the same in developing a new drug therapy, but with a slight variation. Rather than tricking the body into producing an antibody, Wong hopes to design small molecules that will activate the immune system to produce weapons to kill cancer cells, or that will inhibit the formation of the sugar receptors - in other words, small molecules that will wreck the machinery that produces the sugars in the first place. Various cells have unique sugars but some cancer shells share the same structures, especially metastatic cancer cells. But to proliferate, the metastatic cancer cell still has to attach itself to the host cell, and that attachment is often through the sugar receptors. A very small molecule can be designed that mimics the cancer cell surface receptors, so they both have to compete for the host cell attachment - but the small molecule wins.

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Small Molecule Shuts Off Gene Expression and Keeps Cancer in Check
 A team of scientists from TSRI and Caltech, led by TSRI Professor Joel Gottesfeld, Ph.D. with his collaborator Professor Peter Dervan of Caltech, have reported that a small molecule they have created blocks the replication of a wide variety of cancer cells, including cancer cells derived from leukemia, prostate, pancreatic, cervical, colon, and bone cancers. Evidence suggests that the compound works by shutting down one member of the human gene family that encodes the protein histone H4, an essential building block of chromosomes. This is significant because histone H4 has never before been considered a target for anti-cancer therapy. Although there are fourteen genes in the human genome that encode the same histone H4 protein, one of these genes is highly expressed in cancer cells. The active molecule selectively down-regulates this particular histone gene. Furthermore, the scientists report the compound can block the growth of tumors in mice without obvious toxicity. The compound is actually a hybrid molecule made by combining a DNA-binding molecule, called a hairpin polyamide, with the anti-cancer drug chlorambucil. Chlorambucil is a widely used chemotherapeutic drug, which targets DNA relatively nonspecifically. The scientists wanted to design a molecule that would silence genes that are upregulated, or highly expressed in cancer cells but not in normal cells. To do this, Gottesfeld and his colleagues synthesized a library of his pyrrole-imidazole polyamides with a variety of specificities and attached to them the anticancer compound, chlorambucil. The scientists screened the library of polyamide-chlorambucil molecules looking for those that could affect the growth of cancer cells. They identified one molecule that caused the cancer cells to stop growing and to undergo profound morphological changes - the cells grew very large. The cells were also unable to divide, arresting in the stage of cell division before they are able to separate their chromosomes.

These molecules have been silencing some genes that were necessary for the cancer cell"s growth and division. Histone proteins are important in cancer. Since cancer cells are rapidly dividing, they need to overexpress histone proteins so that they can assemble their replicated DNA into chromosomes for cell division. Not having enough histones is anathema to cancer cells, as the scientists found when they tested their compound on cancer cells in the lab. The compound blocked the replication of cells, and the cells ballooned because they could not wrap their DNA around histones and keep it compact. The scientists injected laboratory rodents with live cancer cells from metastatic colon carcinoma cells, which were previously treated with the small molecule. A control group was injected with the untreated cancer cells. At the end of the experiment, all the rodents in the control group had developed large tumors, while none of the animals in the experimental group showed tumor growth. In a second experiment, the researchers injected cancer cells into the laboratory animals once again, but this time they waited for tumors to develop prior to injecting the active compound. Those animals that were not treated with the compound developed very large tumors, but the tumors in the animals that received the compound did not develop further. These results suggest that the gene encoding the histone H4 protein might be a new target for drugs designed to treat human cancers. Current work in Gottefeld"s lab will extend these findings to other forms of cancers and will define the mechanism of action of the active molecule further.

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Uncovering New Proteins to Serve as Novel Targets for Anticancer Drugs
 The cause of lung cancer in nonsmokers is not known; it is probably a combination of environmental and genetic factors. Cancer is the result of uncontrolled growth and replication of body cells. Normally, this growth is regulated by finely tuned signals that the cells receive from the environment. These signals are transmitted by specific interactions of cellular proteins. One of these signaling proteins that control cell growth and survival is Akt. In lung cancer cells it is abnormally activated. This enhancement of Akt makes lung cancer cells resistant to treatment with anticancer drugs; it also causes them to replicate rapidly.

The lab of TSRI Professor Peter Vogt, Ph.D. has been studying Akt and its role in cell growth and survival. This work is uncovering new proteins that interact with Akt and that can serve as novel targets for anticancer drugs. Vogt and his colleagues are searching for small molecules that inhibit the Akt signal, and have pioneered new techniques that have resulted in the synthesis of several thousand new drug-like compounds. They are evaluating these compounds using high throughput automated equipment. Inhibitors of Akt signaling identified in this way could be developed into effective lung cancer drugs.

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Better Understanding of Role of Chronophin Holds Promise for Development of Cancer Drugs
 TSRI Professor Gary Bokoch, Ph.D. and his colleagues have identified an enzyme called chronophin that is involved in regulating the dynamics of the actin cytoskeleton in cells. Actin dynamics play important roles in fundamental processes that include cell division, growth, and motility. These processes contribute to such diverse physiological situations as wound healing, angiogenesis, innate immunity, metastasis in cancer, and neuronal development.

An abnormal division of cells was seen when chronophin function was altered. This is significant as cell division defects are a hallmark of cancer. The data from Bokoch and his associates suggests the possibility that chronophin may be involved in the pathogenesis of malignant cancers such as neuroblastomas and germ cell seminomas, which are the most common form of solid tumors in children. A better understanding of the role of chronophin in aneuploid cancers holds promise for the development of cancer drugs targeting this unique type of phosphotase.

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Brain Tumor Angiogenesis
Gioblastoma multiforme (GBM) is an incurable malignant brain tumor, usually fatal within one year of diagnosis. Using a syngenic rat 9L gliosarcoma model, TSRI Professor Martin Friedlander, M.D., Ph.D., and his colleagues have developed a novel drug delivery method in which naked plasmid DNA is selectively targeted to brain tumors via intra-arterial injection.

Administration of a plasmid encoding an angiostatic peptide, endostatin, resulted in an 80% tumor volume reduction one week after treatment and enhanced survival time by up to 47%. Treated tumors exhibited a 40% decrease in tumor vessel density accompanied by alterations in tumor vessel ultrastructure. Friedlander and his colleagues conclude that intra-arterial injection of plasmids can selectively target therapeutic genes to CNS neoplasms. This method of gene therapy holds promise for the treatment of these highly malignant brain tumors.

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Studying Skin Lymphoma
Anaplastic T cell lymphoma is a type of skin lymphoma caused by a break in the normal chromosomes that causes two genes, ALK and NPM, to be situated right next to each other. It is a highly aggressive systemic disease. It can occur at any time from childhood to old age, but is more commonly diagnosed among children and young adults. High-risk patients do not respond well to available therapies. The abnormal positioning of NPM next to ALK causes the ALK gene to become abnormally active and causes the leukemia. It affects multiple cellular survival pathways, shifting the balance towards uncontrolled cell proliferation.

TSRI Professor Peter Vogt, Ph.D., is studying why ALK activation causes the lymphoma by better understanding the changes in the ALK protein associated with the disease. He is also working on determining whether drugs that impact other members of the protein family to which ALK belongs might be useful in treating lymphomas caused by ALK.

New Study May Help Improve Treatment Of Cancer
 Scientists at Scripps Research have shown that injections of a certain cytokine together with the right monoclonal antibody increases white blood cells that coordinate immune responses to tumor and infected cells. These results may point the way to an improved cancer therapy that helps patients boost their own immune response to the disease. The findings could also be significant for developing new ways to help patients with autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, or juvenile diabetes. The study showed that these injections caused a massive selective increase in the immune system"s two main types of T cells. It showed that different cytokine-antibody complexes such as IL-2/IL-2 mAb could be clinically useful to selectively boost or inhibit the immune response in vivo. Onur Boyman, M.D., a member of the Scripps Research Department of Immunology, led the study. The type of monoclonal antibody that was injected was specific to interleukin-2 (IL-2), a naturally occurring protein and a known immunotherapy for metastatic melanoma and renal cancer. The researchers showed that the anti-IL-2 monoclonal antibody (IL-2 mAb) expands the proliferation of specific T cells in vivo by increasing the biological activity of naturally occurring IL-2 through the formation of immune complexes. When combined with recombinant IL-2, some IL-2/IL-2 mAb complexes cause more than a 100-fold proliferation in CD8+ T cells, which can target virally infected cells or tumor cells. Interleukin-2 increases the number of a subset of CD8+ T cells (referred to as antigen-experienced or memory T cells) in circulation and is often used for tumor immunotherapy and vaccination. However, IL-2 also stimulates CD4+ T regulatory cells, which can suppress those same memory T cells. Therefore, the prevailing view was that administration of IL-2 mAb removes the IL-2-dependent CD4+ T regulatory cells, which in turn leads to an expansion of CD8+ T cells.

In the study, however, Boyman noticed that the enhancing effect of IL-2 mAb correlated with naturally occurring levels of IL-2. He concluded that, despite its reported neutralizing effect, IL-2 mAb actually expanded the proliferation of CD8+ T cells simply by increasing the biological activity of pre-existing IL-2 through the formation of antibody-cytokine immune complexes in vivo. He next combined recombinant IL-2 with IL-2 mAb, which led to an even more dramatic expansion. This expansion effect also extended to other types of antibody-cytokine complexes, such as IL-4/IL-4 mAb and IL-7/IL-7 mAb. Despite these findings, no one yet knows why these antibody-cytokine complexes are such potent immune response boosters in vivo. A few studies have suggested that injecting a cytokine together with the right antibody increases the half-life of the cytokine in vivo, accompanied by a very mild immune activation. But Boyman"s study suggests a different mechanism and that joining a cytokine to its specific antibody opens the way for selective and vigorous stimulation of T cell subsets. With some types of antibodies, injecting IL-2/IL-2 mAb complexes might be clinically useful for tumor immunotherapy and for expanding T cell numbers after bone marrow transplantation. On the other hand, expansion of CD4+ T regulatory cells by IL-2 combined with another type of IL-2 mAb might provide a basis for treating autoimmune disease.

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Scripps Research Study Reveals New Function Of Protein Kinase Pathway In Tumor Suppression
Scientists at The Scripps Research Institute have discovered a surprising new function of a well-known signaling pathway that, when activated, can inhibit tumor development. This finding may lead to the development of drugs that can serve as an effective cancer therapy by artificially activating this pathway in cancer cells. The study was led by Associate Professor Peiqing Sun, Ph.D. and Professor Jiahuai Han, Ph.D.

The research focused on signaling pathways that mediate an anti-tumor defense response called senescence, or cellular aging. The research, which was conducted in both human cell culture and rodent models with skin cancer or lymphoma, identified one essential element of this anti-tumor response, namely, p38-regulated/activated protein kinase (PRAK). Previous to this research, PRAK's physiological functions had been poorly understood. In uncovering this basic mechanism, the scientists advanced our knowledge in terms of how cancers develop. More importantly, they have identified a pathway in normal cells that, when activated, can inhibit tumor development. This lays the groundwork for new cancer therapy - for future drug development to artificially activate this pathway in cancer cells.

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Scripps Research And St. Jude"s Team Finds A Widely Used Anti-Malarial Drug Prevents Cancer Development
Scientists at The Scripps Research Institute and St. Jude"s Children"s Research Hospital have found that a commonly prescribed anti-malarial drug effectively prevents the development of certain types of human cancer in mouse models. The drug, chloroquine, which has been in use since 1946, prevented development of cancer in models of two distinct human cancer syndromes, Burkitt lymphoma, a cancer of the lymphatic system, and ataxia telangiectasia (A-T), a rare and progressive immunodeficiency disease that predisposes patients to cancer, especially lymphoma and leukemia. The study showed that chloroquine inhibits the final steps of a pathway that is required for tumor cell survival and effectively eliminates cancer cells in mouse models that replicate human tumors. John Cleveland, Ph.D., a Scripps Research scientist who is chair of the Department of Cancer Biology at the institute's Jupiter, Florida, campus, led the study. The fact that the drug attacks premalignant cells, and cells that overexpress transcription factor MYC, a notorious contributor to tumorigenesis that is implicated in more than 70 percent of all cancers, makes the use of this drug very attractive for chemoprevention and cancer treatment. In the study, chloroquine was very effective in delaying the onset of spontaneous tumors in mice lacking ATM. The ATMgene is a key arbiter of the DNA damage response pathway and is mutated in patients with the cancer-inducing disorder ataxia telangiectasia. These malignancies are particularly difficult to treat because of the acute sensitivities of A-T patients to cytotoxic agents. Chloroquine now offers a potentially novel treatment for these patients because the drug preferentially eliminates cancer cells and is relatively well tolerated.

In addition, the scientists found that treating mouse models of human Burkitt lymphoma just once every five days also dramatically reduced lymphoma development. Interestingly, an epidemiologic study completed in the 1980s supports the potential of this treatment in humans. While this study was designed to investigate the link between malaria and the high incidence of Burkitt lymphoma in equatorial Africa, researchers found that chloroquine treatment decreased the incidence of lymphoma in the region by about 75 percent. Exploring the mechanism of the drug"s cancer-preventing action provided some intriguing insights. At the doses used in the new study, which were similar to those needed to prevent malaria, chloroquine triggered the death of premalignant cells. This suggests that within the context of MYCoverexpression, the drug induces apoptotic cell death-programmed cell death-in response to ineffective autophagic protein degradation and lysosomal changes in the cell. (Lysosomes are cellular recycling centers that degrade old and unwanted material in the cell and recycle building blocks that are used for cell growth.) The p53 protein can induce apoptosis in response to DNA damage or stress, and the study's results suggest that alterations in lysosomal function trigger a p53-dependent cell death response. The most important fact is that the study provides proof of principle for developing antitumor therapies based on the modulation of autophagic pathways, and this offers multiple opportunities for novel drug discovery, whether based on chloroquine or targeting other steps in the autophagy pathway.

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Researchers Develop New Method For Spotting Critical Cancer Drivers
Rapidly improving technologies for sequencing the human genome and the commercial availability of genetic tests for signs of predisposition to disease are just two indicators that an age of personalized medicine is rapidly approaching. In the relatively near future, doctors likely will be able to sequence targeted genes of a patient suffering from a disease and then order a highly effective drug tailored to treat the mutations that caused the person's illness. Of course, such a future will depend on the ability to identify those specific gene mutations, known as drivers, that are responsible for a disease. To that end, Ali Torkamani, a Scripps Research Institute scientist, along with Nicholas Schork, Ph.D., a professor in the Department of Molecular and Experimental Medicine at Scripps Research and the director of research for genomic medicine at Scripps Health discovered a promising new method for identifying these driver mutations. The team's work may help move the concept of personalized medicine forward, and should also enable identification of new targets for more generalized cancer drugs. Finding mutations associated with a disease such as a particular cancer is relatively straightforward using current technologies. The problem is that, in addition to driver mutations, cancer cells usually contain countless other mutations, known as passengers, that are not responsible for the disease. Only a small subset of those mutations actually cause the cancer by giving it some growth advantage, and there's no really good way to tell which ones they are.


Existing methods for pinpointing driver mutations, which have not proven as accurate as doctors and researchers would like, have relied on two basic strategies. The first is the sequence conservation approach. One of the ways cancer progresses is through mutations in genes that code for essential proteins, causing one or more changes in the amino acids used to construct the protein and leading to malfunctions. Sequence conservation methods involve analyzing the amino acids found in critical groups of proteins, because amino acids common to many key proteins are themselves assumed to be key to proper functioning. Mutations that lead to the substitution of one of these key amino acids are then assumed to be driver mutations, because they would likely have significant impacts. The second approach involves statistical analyses of the actual structures of critical proteins. Here, mutations that have already been tied to disease are studied to determine the impacts they have on the proteins they code for, such as specific alterations to the way the protein folds. If troublesome mutations are found to commonly affect a particular aspect of folding, for instance, then other mutations that have similar impacts can be assumed important and likely drivers. The work by Torkamani and Schork involved elements of both these strategies, but the researchers intentionally narrowed their focus to an important group of enzymes known as protein kinases, which modify other proteins and regulate many cellular functions. Mutated protein kinases are known to play important roles in causing certain cancers, and a number of successful drugs on the market for lung, breast, and other forms of cancer are tied to these kinases.

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