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  #1  
Old 03-24-2012, 12:44 AM
gdpawel gdpawel is offline
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Default Tumor-Cell Death, Autophagy, and Immunity

A new finding in basic science should trigger a "change in thinking" about how cancer drugs might be developed and tested for maximum effectiveness, says Louis M. Weiner, M.D., director of the Georgetown Lombardi Comprehensive Cancer Center, in a "Clinical Implications of Basic Research" article titled Tumor-Cell Death, Autophagy, and Immunity published in the March 22, 2012 issue of the New England Journal of Medicine (NEJM).

An internationally known expert in immunotherapy research, Weiner was invited, along with Michael T. Lotze, M.D. from the University of Pittsburgh Cancer Institute, by NEJM editors to write an analysis of anticancer immune responses based on a recent report published in the journal Cell (Dec.16, 2011.)

The emerging science described in the cell report reveals how some dying cancer cells may trigger a lasting anti-cancer immune response that can prevent cancer relapses and improve the benefits of treatments. "This is a really exciting development, because we know that manipulating the body's immune system has proven to be the most powerful way to cure advanced cancer that cannot be cured by surgery or radiation treatments," Weiner says. "We now know that how cancer cells die matters, and so we should strive to manipulate that death in a way that primes the body to destroy any cancer that returns," he says. "This might vastly improve cancer care."

The recent Cell study, conducted primarily by researchers in France, focused on autophagy, which means, literally, "self eating."When cells die, the body cleans up the debris by using special cells that ingest and process the cell's component parts so that they can be recycled and used again. During this process, these parts are revealed so that roving protective cells of the immune system can determine if what was inside the cell was potentially harmful. If deemed dangerous, the immune system goes on permanent watch for these molecules so that they can be destroyed.

Cancer cells can die in several ways, Weiner says. One is a natural process called apoptosis, or programmed cell death, which is a way that the body keeps the cells growing within an organ or body in check. "This is a normal process, so the immune system ignores those cells," Weiner says. Many cancer drugs are designed to promote apoptosis.

The other way is autophagy, which can occur when cancer cells are distressed or under attack from toxic agents. Autophagy, which literally means "self-eating," involves the digestion of some parts of a cell to create energy and keep that cell alive. This process triggers the immune system to recognize the cells as a foreign invader that should be destroyed.

What hadn't been known until the Cell study was how the body's immune cells "see" cancer cells as foreign during autophagy – what is it within the cancerous cell that alerts those fighters to be on patrol for development of new cancer cells? "Cancer cells are derived from normal human cells, so something unusual alerts the immune system during autophagy," Weiner says.

In the Cell study, the French researchers discovered that when cancer cells are dying via autophagy, it is the release of energy in the cancer cell, in the form of the chemical ATP, that alerts immune cells to the existence of a big problem. This ATP activates toll-like immune cell receptors, which are a very primitive group of proteins that play a key role in the innate immune system by acting as alarms. (It is important to note that the two scientists who discovered the toll-like immune cell receptors shared the 2011 Nobel Prize in Medicine or Physiology).

The implication for cancer care, then, is to "look at how different drugs kill cancer, and find those that result in autophagy," he says. Additionally, drugs could be designed that force cancer cells to produce ATP when they are sick and dying, Weiner says. "That way, the immune system is primed to attack cancer that recurs."

In order for this strategy to be effective, researchers will have to develop ways to measure how effectively cancer drugs promote autophagy, he says. "So instead of looking at how many cancer cells a drug can kill, we should think about developing drugs that help cells die the way we want them to die," Weiner says. Still, there is a lot of work to do, Weiner says. "No tools exist today to measure which chemotherapy agent or combinations act by stimulating the immune system to control cancers."

Progress in this area will require a "change in thinking.""For many years, it has been thought that chemotherapy damages the immune system, lowering the levels of white blood cells that can fight invaders," he says. "But now researchers are beginning to realize that certain types of chemotherapy and other biologic and targeted treatments may be stimulating a powerful immune response.

"No doubt modern chemotherapeutic and targeted therapy have a powerful impact on the well-being of people with cancer," Weiner says. "But it is also true that we have a long way to go, and this new potential strategy is truly exciting."

Georgetown University Medical Center [url]http://www.nejm.org/doi/full/10.1056/NEJMcibr1114526?query=TOC&
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Old 03-24-2012, 04:13 PM
gdpawel gdpawel is offline
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Default Potential Strategy Aims To Stimulate The Immune System To Defeat Cancers

Cells have their own recycling system: discarded cellular components, from individual proteins through to whole cellular organs, are degraded and the building blocks re-used in a different place. The scientific term for this recycling process is autophagy. In severely damaged cells, autophagy can also be a form of programmed cell death.

In this case, the cell uses the mechanism for complete self-decomposition. It is assumed that highly aggressive cancer cells use autophagy to resist tumor therapy. Investigations are leading to whether blocking the recycling system (autophagy) might be useful to support anti-cancer therapies. They are bascially rediscovering something reported 20 years ago (JNCI, 83:37-42, 1991).

This study had lead to the focus on the human tumor primary culture microspheroid (microclusters) platform. The functional profiling platform studies cancer response to drugs from actual human microspheroids (tumor microenvironment), enabling it to provide clinically relevant predictions to individual cancer patients.

This is why the functional profiling platform has recognized interplay between cells, stroma, fibroblasts, vascular elements, cytokines, macrophages, lymphocytes and other extracellular material like autophagy. This had lead to the focus on the human tumor primary culture microspheroid (microclusters), which contains all of these elements.

The functional profiling platform studies cancer response to drugs (from actual human microspheroids), within this microenvironment, enabling it to provide clinically relevant predictions to individual cancer patients. It is their capacity to study "human" tumor microenvironments that distinguishes it from other platforms in the field.

"No tools exist today to measure which chemotherapy agent or combinations act by stimulating the immune system to control cancers?" Dr. Larry Weisenthal, of the Weisenthal Cancer Group, had reported on a tumor immunotherapy study back in the early 90's. It was a concept of in situ cancer vaccination based upon studies of biologic response modifiers in an assay.

Preliminary results found a striking association between the activity of biologic response modifiers which activate macrophages and the prior treatment status of patients with breast and ovarian cancers. Effective chemotherapy produced a massive release and processing of tumor antigens, which led to a state in which the human immune system, via in situ cancer vaccination, responded to exogenous macrophage activation signals with potent and specific anti-tumor effects.

Because all research was prematurely abandon back then, Dr. Weisenthal had to refocus gears and today has brought us the latest technology called Functional Tumor Cell Profiling (recently known as Personalized Cancer Cytometrics). However, one of the themes at the 2012 American Association for Cancer Research (AACR) meeting held in Chicago was the growing development of meaningfully effective immune therapies. There was evidence of a renewed interest in tissue cultures as the best platform to study drug effects and interactions.

Literature Citation:

Weisenthal LM, Dill PL, Pearson FC (1991) Effect of prior cancer chemotherapy on human tumor-specific cytotoxicity in vitro in response to immunopotentiating biologic response modifiers. J Natl Cancer Inst 83: 37-42

Weisenthal LM (1991) Effect of prior chemotherapy on biologic response modifier activity. J Natl Cancer Inst 83: 790-791

Windbichler GH, Hausmaninger H, Stummvoll W, Graf AH, et al. (2000) Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase 3 trial. Br J Cancer 82:1138-1144, 2000.

[url]http://jnci.oxfordjournals.org/content/83/1/37.short
[url]http://www.wipo.int/patentscope/search/en/WO1989003995
[url]http://www.google.com/patents?hl=en&lr=&vid=USPAT4996145&id=waMaAAAAEBAJ &oi=fnd&printsec=abstract#v=onepage&q&f=false
[url]http://www.google.com/patents?hl=en&lr=&vid=USPAT5149527&id=vO4fAAAAEBAJ &oi=fnd&dq=weisenthal+immune&printsec=abstract# v=o nepage&q=weisenthal%20immune&f=false
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Old 03-29-2012, 12:59 PM
gdpawel gdpawel is offline
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Default Immunotherapy: A prematurely-abandoned treatment option in ovarian and breast cancers

Larry Weisenthal, M.D., PhD.
Medical and Lab Director
Weisenthal Cancer Group; Huntington Beach, CA

Clinical trials are warranted to test macrophage-activating biologic response modifiers administered following chemotherapy of ovarian and breast cancers. This is based on (1) striking in vitro findings in fresh human tumor cell culture assays, (2) supportive data from pilot clinical trials, and (3) a sound mechanistic rationale. I would advocate sequential administration of (1) assay-directed chemotherapy, (2) "non-specific" immunotherapy (e.g. antigens derived from bacteria), and (3) more "specific" cytokine therapy (e.g. interferon gamma).

In 1991, my colleagues and I published a study (1,2) in the Journal of the National Cancer Institute which I hoped would receive scrutiny and follow-up. This was a tumor immunology study which grew out of a contract research project. Continuing this research was at the time not an option, as my priorities were to establish a clinical laboratory to provide cell culture drug resistance testing.

In the 1991 study, we presented the concept of "in situ vaccination," based upon our studies of biologic response modifiers in the DISC assay. We found that there was a striking association between the activity of biologic response modifiers which activate macrophages and the prior treatment status of patients with breast and ovarian cancers. Color photomicrographs illustrating method.

[url]http://weisenthal.org/jnci83_38_91f1.jpg

The following agents were dramatically more active in fresh tumor specimens from previously-treated breast and ovarian cancer patients than against specimens from untreated patients:

1. ImuVert (a potent macrophage activator derived from Serratia marcescens)
2. Interferon gamma, and
3. Tumor necrosis factor

This greater activity in specimens from treated versus non-treated patients was not observed in adenocarcinomas known to be relatively resistant to chemotherapy (colon cancer, non-small cell lung cancer, etc.). Graphs showing representative results.

[url]http://weisenthal.org/jnci83_39_91.jpg

This differential activity was also not observed in agents which are not potent macrophage activators (interleukin-2 and interferon alpha).

Based on these findings (and supported by anecdotal studies in the clinical trials literature), we proposed that effective chemotherapy produces massive release and processing of tumor antigens, which leads to a state in which the human immune system is primed (via "in situ vaccination") to respond to exogenous macrophage-activation signals with potent, specific antitumor effects.

In the above-quoted study (1), I reviewed a diverse clinical trials literature which supported this concept. More recently published was a randomized trial in previously untreated ovarian cancer (3) , in which cisplatin/cyclophosphamide was compared to the same chemotherapy plus interferon gamma, administered subcutaneously three times a week, every other week, for the duration of chemotherapy (6 plannned treatment cycles). The study was prematurely closed because chemotherapy standard treatment had changed from platinum/cyclophosphamide to platinum/Taxol, but, even with the low power of the small numbers of patients accrued to show a difference, there was a significant advantage to combined treatment in progression-free survival and a soft trend for improved overall survival. The authors quoted our earlier work1 in providing a mechanism for their positive results and called for follow-up clinical trials. Progression-free survival curves.

[url]http://weisenthal.org/bjc82_1138_00.jpg

As noted above, my preferred trial design would be (1) first complete (preferably assay-directed) chemotherapy, then (2) administer non-specific immunotherapy to responders, then (3) provide more specific cytokine therapy, e.g. interferon gamma.

Literature Citation:

1. Weisenthal LM, Dill PL, Pearson FC (1991) Effect of prior cancer chemotherapy on human tumor-specific cytotoxicity in vitro in response to immunopotentiating biologic response modifiers. J Natl Cancer Inst 83: 37-42

2. Weisenthal LM (1991) Effect of prior chemotherapy on biologic response modifier activity. J Natl Cancer Inst 83: 790-791

3. Windbichler GH, Hausmaninger H, Stummvoll W, Graf AH, et al. (2000) Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase 3 trial. Br J Cancer 82:1138-1144, 2000.

Method for detecting immune-mediated cytotoxicity

ABSTRACT

A method for detecting the sensitivity of tumor cells to immune effector substances by using an assay that distinguishes living tumor cells from dead cells in mixed populations of cells. Acquired resistance to immune effectors used in therapy may be determined and used to identify methods to circumvent such resistance using the method.

[url]http://www.google.com/patents/US4996145
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Old 03-30-2012, 08:24 PM
gdpawel gdpawel is offline
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Default Mechanisms Involved with Tumor Relapse Identified

Researchers at Virginia Commonwealth University's Massey Cancer Center studying the interaction between the immune system and cancer cells have identified interferon gamma as one of the signaling proteins involved with tumor relapse.

The findings may help researchers develop tailored vaccines and other immunotherapeutic strategies to fight a number of cancers. Immunotherapy involves the manipulation of the immune system, by introducing an antibody or lymphocytes, or immunization with a tumor vaccine, to recognize and eradicate tumor cells.

Using a transgenic mouse model of breast cancer, researchers found that interferon gamma, a cytokine or chemical messenger that is produced by cells of the immune system upon activation, plays a role in tumor relapse. In humans, interferon gamma is also produced by white blood cells of the immune system in response to invasion by pathogens or tumors in order to protect the host against infection or cancers. Production of interferon gamma by lymphocytes against tumors is considered a sign of good prognosis; however, recent study findings indicate that this may not be the case. The findings were reported in the March 2007 issue of the European Journal of Immunology, the official journal of the European Federation of Immunological Societies.

"By understanding the molecular mechanisms involved with tumor relapse, we can create tailored vaccines that can induce specific types of immune responses in patients, rather than inducing a broad range of immune responses - some of which may be detrimental or may induce tumor relapse," said lead investigator, Masoud H. Manjili, D.V.M., Ph.D., a member scientist with the Massey Cancer Center.

"Ultimately, we hope to offer a new polypeptide vaccine approach that induces tumor killing without causing HER-2/neu loss. Loss of HER-2/neu is a mechanism that tumors utilize to escape the immune-mediated destruction," he said.

Since 2000, Manjili and his colleagues have been employing animal models of breast cancer to evaluate anti-tumor efficacy of a vaccine formulation they created. This vaccine formulation combines a heat shock protein 110 (HSP110), as an adjuvant, with a tumor antigen HER-2/neu, as a protein target expressed in breast tumors. Adjuvants are agents that are able to modify another agent, basically working as a chemical catalyst.

Manjili, who is an assistant professor in the Department of Microbiology and Immunology in the VCU School of Medicine, collaborated with VCU researchers Maciej Kmieciak, Ph.D., with the Department of Microbiology and Immunology, and Catherine I. Dumur, Ph.D., with the Department of Pathology; and Keith L. Knutson, Ph.D., with the Department of Immunology at the Mayo Clinic College of Medicine in Rochester, Minn.

The work is supported by the National Cancer Institute and the Susan G. Komen Breast Cancer Foundation.

Science magazine science story of the year: cancer immunotherapy

[url]http://www.sciencemag.org/content/342/6165/1432.full
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Old 03-30-2012, 08:29 PM
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Default Pathway links inflammation, angiogenesis and breast cancer

A well-known inflammatory protein spawns an enzyme that inactivates two tumor-suppressing genes, ultimately triggering production of new blood vessels to nourish breast cancer cells, researchers at The University of Texas M. D. Anderson Cancer Center report in the August 2007 edition of the journal Cell.

"This is a completely new pathway for inflammation-induced cancer and may provide new targets for clinical intervention," senior author Mien-Chie Hung, Ph.D., professor and chair of M. D. Anderson's Department of Molecular and Cellular Oncology says of the chain of events described in the journal.

Inflammation is linked to breast cancer, liver cancer and cancers of the gastrointestinal tract. The research team set out to discover whether angiogenesis - the creation of new blood vessels - plays a role in cancer formation related to the inflammatory protein Tumor Necrosis Factor alpha (TNFa).

"What we found is a previously unrecognized role for IKKbeta, a protein kinase activated by TNFa," Hung says. IKKß inactivates a cancer-suppressing protein complex, which frees a cancer-inducing pathway to generate new blood vessels to supply tumors.

The chain of events, painstakingly worked out by Hung, first author and doctoral student Dung-Fang Lee, and colleagues works like this:

TNFa activates IKKß, which as a kinase works by attaching phosphate groups to other proteins.

IKKß phosphorylates tuberous sclerosis 1 (TSC1) blocking it from working with its ally, tuberous sclerosis 2, to repress the mammalian target of rapamycin (mTOR) pathway.

With the tumor suppressors inactivated, mTOR is freed to produce vascular endothelial growth factor (VEGFterm), which creates new blood vessels to feed breast cancer.

The team confirmed the lab findings in mice. Mice with active IKKß had mean tumor volumes of 1,200 milimeters at 31 days, while those with inactive IKKß or with active IKKß and rapamycin injections to inhibit mTOR had mean volumes of less than 100 milimeters. Similar disparate tumor sizes were found when the tumor-suppressing TSC1 was inactivated. Tumors with TSC1 inactivated also were found to have greater blood vessel density - a measure of angiogenesis.

The researchers tested the theory by analyzing breast cancer tumors from 116 patients. They found breast cancer patients whose tumors had the TSC1/TSC2 tumor suppressor complex blocked by phosphorylation did not survive as long as those with an active TSC1/TSC2 (46 percent survival at 60 months vs. 65 percent).

Rapamycin is a powerful immune system suppressor used to protect organ transplant recipients against rejection of their new organs by suppressing mTOR. Rapamycin and similar mTOR inhibitors are in early clinical trials for a number of cancers at M. D. Anderson and elsewhere. One drug, temsirolimusterm, has been approved to treat renal cell carcinomaterm.

Hung's lab is exploring the possibility that this TNFa-driven activation of mTOR is the molecular link between obesity and heightened cancer risk. Obese mammals have high levels of TNFa secreted by their fat cells.

For Hung, the Cell paper is part of an ongoing effort to define the cancer-inducing activity of IKKß and its sibling, IKKa. He has found that the two, known to have a cancer-inducing affect working together, also have separate effects individually.

In the Cell paper, researchers show IKKß does its damage working in the cytosol of the cell, the internal fluid outside of the nucleus. Together, the two kinases previously were known to free the oncoprotein nuclear factor kappa B (NF"B) from the cytosol, allowing it to move to the nucleus and activate genes that promote cancer growth.

IKKa throws switch between tumor promotion and suppression

Earlier, in a paper published in Molecular Cell, Hung's lab established that IKKa works individually by following NF"B into the nucleus, where IKKa plays the pivotal role in the oncogene's competition with the tumor-suppressing gene p53 for access to CREB-binding protein (CBP).

Both p53 and NF-kB covet CBP, an extremely popular activator of genes that interacts with hundreds of other proteins, Hung notes. In the case of the tumor suppressor and the oncogene, CBP will bind to only one at a time.

"You can think of them as a good guy, and a bad guy, with a gun lying between them. Who gets the gun" And how does one get it"" says Hung.

Hung and colleagues showed that IKKa phosphorylates CBP in the nucleus, switching CBP's binding preference to the NF"B oncogene, promoting cell growth. Unphosphorylated CBP helps p53 do its job suppressing cancer by forcing defective cells to kill themselves, programmed cell death known as apoptosis.

"If you can control IKKa, you get a double-dip effect," Hung says. "You not only activate p53, the good guy, you keep the bad guy out of the contest."

IKKa and IKKß together help NF"B escape into the nucleus, where it promotes cell growth and blocks programmed cell death. IKKa then works separately in the nucleus and IKKß in the cytosol to induce cancer through separate pathways.
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Old 04-14-2012, 09:40 PM
gdpawel gdpawel is offline
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Default Functional assessment and specific depletion of alloreactive human T cells

Functional assessment and specific depletion of alloreactive human T cells using flow cytometry

Human T-cell alloreactivity plays an important role in many disease processes, including the rejection of solid organ grafts and graft-versus-host disease (GVHD) following allogeneic stem cell transplantation. To develop a better understanding of the T cells involved in alloreactivity in humans, we developed a cytokine flow cytometry (CFC) assay that enabled us to characterize the phenotypic and functional characteristic of T cells responding to allogeneic stimuli. Using this approach, we determined that most T-cell alloreactivity resided within the CD4 (T-cell subset), as assessed by activation marker expression and the production of effector cytokines (eg, tumor necrosis factor alpha [TNF]alpha) implicated in human GVHD. Following prolonged stimulation in vitro using either allogeneic stimulator cells or viral antigens, we found that coexpression of activation markers within the CD4 (T-cell subset) occurred exclusively within a subpopulation of T cells that significantly increased their surface expression of CD4. We then developed a simple sorting strategy that exploited these phenotypic characteristics to specifically deplete alloreactive T cells while retaining broad specificity for other stimuli, including viral antigens and third-party alloantigens. This approach also was applied to specifically enrich or deplete human virus-specific T cells.

Martins SL, St John LS, Champlin RE, Wieder ED, McMannis J, Molldrem JJ, Komanduri KV.

Transplant Immunology Section, Department of Blood and Marrow Transplantation, MD Anderson Cancer Center, SCRB 3.3019, Unit 900, 7455 Fannin St, Houston, TX 77030, USA.
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Old 04-30-2012, 07:10 PM
gdpawel gdpawel is offline
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Default Cancer drugs should force dying cells to alert immune response

Cells have their own recycling system: discarded cellular components, from individual proteins through to whole cellular organs, are degraded and the building blocks re-used in a different place. The scientific term for this recycling process is autophagy. In severely damaged cells, autophagy can also be a form of programmed cell death.

In this case, the cell uses the mechanism for complete self-decomposition. It is assumed that highly aggressive cancer cells use autophagy to resist tumor therapy. Investigations are leading to whether blocking the recycling system (autophagy) might be useful to support anti-cancer therapies.

In the laboratory, a first generation specific protease inhibitor designed for HIV, nelfinavir or Viracept, seems to exercise a broad-spectrum cancer killing effect through multiple pathways: apoptosis, necrosis and autophagy (Clin Cancer Res 13(17):5183-94, 2007), and noted to have antiangiogenic and immunomodulatory ability.

Also, we are not taking advantage of the available drugs that reduce oxidative stress and autophagy, including metformin, chloroquine and N-acetyl cystenine. Since there is genetic proof that oxidative stress and resulting autophagy are important for driving tumor growth, we should re-consider using antioxidants and autophagy inhibitors as anti-cancer agents.

The diabetic drugs metformin and chloroquine prevent a loss of Cav-1 in cancer associated fibroblasts (which is due to oxidative stress), functionally cutting off the fuel supply to cancer cells. Cav-1 is a biomarker that functions as a tumor suppressor and is the single strongest predictor of breast cancer patient outcome.

For example, if a woman has triple negative breast cancer and is Cav-1 positive in the stroma, her survival is greater than 75 percent at 12 years, versus less than 10 percent at 5 years if she doesn't have the Cav-1 protein.

[url]http://medicalxpress.com/news/2012-03-impact-cancer-drugs-dying-cells.html

Cell recycling protects tumor cells from anti-cancer therapy

Cells have their own recycling system: Discarded cellular components, from individual proteins through to whole cellular organs, are degraded and the building blocks re-used in a different place. The scientific term for this recycling process is autophagy. In severely damaged cells, autophagy can also be a form of programmed cell death. In this case, the cell uses the mechanism for complete self-decomposition.

Cancer cells, too, make use of autophagy, especially after radiation or chemotherapy. However, why autophagy is activated in this context, is not clear. It is possible that the process contributes to the death of the treated tumor cells. But autophagy might also be an attempt by the cells to survive. Autophagy is also switched on specifically, for example, when the cell does not have enough nutrients at its disposal, explains Professor Ingrid Herr, head of the Research Group Molecular OncoSurgery of the German Cancer Research Center.

Working together with Dr. Anja Apel and scientists of the University of Tbingen, Ingrid Herr has studied the role of autophagy in cancer treatment. To this end, the investigators switched off a number of genes in tumor cells that are essential for autophagy. Subsequently, they irradiated the cells and then examined how many cells had survived the treatment. They found out that cells that had been almost completely resistant to radiation became more sensitive to radiotherapy due to blocked autophagy. No effect was found on cancer cells that had already responded well to radiotherapy before. Therefore, the researchers assume that highly aggressive cancer cells use autophagy to resist tumor therapy. The Heidelberg researchers will now investigate whether blocking the recycling system might be useful to support anti-cancer therapies.

At the 2012 Keystone Symposia on Cancer and Metabolism

According to postdoctoral fellow Jonathan Mandelbaum, the autophagy pathway was a focus for several talks at the 2012 Keystone Symposia on Cancer and Metabolism. This pathway is important for cells to cope with metabolic stress, and cancer cells face challenges such as hypoxia and nutrient deprivation, targetingautophagy might be a beneficial therapeutic strategy for cancer treatment.

Utimately, understanding how different genetic dependencies in cancer reprograms cells to be specifically reliant on certain metabolic pathways, might provide synthetic lethal opportunities for drugs that target metabolic enzymes in those pathways. From a drug discovery perspective, the conference highlighted two critical challenges going forwar:

1. What therapeutic window might exist for drugs targeting metabolic pathways? Activated lymphocytes are dependent on glycolysis, similar to cancer cells, for their survival. This, agents targeting glycolysis might very well have immunological side effects.

2. In the symposia, many talks highlighted the plastic and redundant nature of metabolic pathways. Inhibiting one pathway can lead to adaptive flux through another pathway, or even drive metabolic enzymatic reactions in reverse, in order to compensate for that initial block. Understanding and overcoming these pathway redundancies (somewhat similar to the current state of signal transduction drug discovery) will be a key challenge going forward for cancer metabolism translational research.
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Old 02-15-2013, 01:47 AM
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Default Cancer Explained The Role of 'Cell Death'

Robert A. Nagourney, M.D.

I would like to examine the very basis of what is known as carcinogenesis, the process by which cancer comes to exist.

For more than a century, scientists believed that cancer cells were growing more rapidly than normal cells. They based this on serial measurements of patients tumors, which revealed that tumor dimensions increased. A small lump in the breast measuring one-half inch in diameter would be found six months later to be one inch in diameter. And six months after that it was two inches in diameter. This was growth, plain and simple, and so it was reasoned that cancer cells must be growing too much. As such, cancer therapies, per force of necessity, would need to stop cancer cells from growing if they were to work at all.

And then, in 1972, a paper was published in the British Journal of Cancer that described the phenomenon of apoptosis, a form of programmed cell death. Although it would be almost a decade before cancer researchers fully grasped the implications of this paper, it represented a sea change in our understanding of human tumor biology.

Lets use the example of a simple mathematical equation. Every child would recognize the principles of the following formula:

Tumor mass = growth rate death rate

This simple equation represents the principle of modern cancer biology. Where cancer researchers went wrong was that they mistakenly posited that the only way a tumor mass could increase was through an increase in the growth rate. However, as any child will tell you, a negative of a negative is a positive. That is, at a given growth rate, the tumor mass can also increase if you reduce the death rate. Thus, the growth so obvious to earlier investigators did not reflect an increase in proliferation but instead a decrease in cell attrition. Cancer didnt grow too much it died too little, but the end result was exactly the same.

It should now be abundantly clear exactly why chemotherapy drugs, designed to stop cells from growing, didnt work. Yes, the drugs stopped cells from growing, and yes any population of growing cells would suffer the effect. But they didnt cure cancers because the cancers werent growing particularly fast. Indeed, the fact that chemotherapy works at all is almost an accident. Contrary to our long held belief that we were inhibiting cell proliferation, chemotherapy drugs designed to damage DNA and disrupt mitosis, were actually working (when they did at all) by forcing the cells to take inventory and decide whether they could continue to survive. If the injury were too extreme, the cells would commit suicide through the process of cell death. If the cells were not severely damaged or could repair the damage, then they carried on to fight another day. None of this, however, had anything to do with cell growth.
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