Targeted cancer therapy kills prostate tumor cells, study finds

ScienceDaily (June 6, 2011) — A new targeted therapy for prostate cancer halts tumor growth in animals with advanced prostate cancer that is resistant to hormone therapy, a new study finds.

See Also:Health & MedicineProstate CancerMen's HealthProstate HealthUrologyCancerBreast CancerReferenceMetastasisEmbryonic stem cellUrologyTumor suppressor gene

The results are being presented at The Endocrine Society's 93rd Annual Meeting in Boston.

"This targeted therapy may provide a treatment breakthrough that will extend the lives of men with advanced, hormone-refractory prostate cancer," said lead investigator Shuk-mei Ho, PhD, chairwoman of the Department of Environmental Health at the University of Cincinnati.

Men with prostate cancer that has recurred or has spread outside the prostate routinely receive androgen deprivation therapy, which blocks the action of the male hormones. This castration occurs through surgical removal of both testes or more often with medications. Although effective, this hormone-blocking treatment eventually stops working in some patients, Ho said.

"These patients are left with very few treatment options and usually succumb quickly to the disease," she said.

Ho's team previously found they can inhibit the growth of prostate cancer cell lines in culture by targeting and activating a protein called G protein-coupled receptor 30 (GPR30) using the experimental drug G-1, a GPR30 agonist, or stimulator.

In their new study, funded by the Veterans Affairs and the National Institutes of Health, Ho and her co-workers tested G-1 in an animal model of castration-resistant prostate cancer. They implanted human prostate cancer cells beneath the skin of male mice. The established tumor regressed upon castration and after the cancer relapsed, they injected the mice with a low dose of G-1. They also gave G-1 to noncastrated, or "intact," male mice that had prostate tumors. In these intact mice that still had male hormones, G-1 did not stop growth of the prostate tumors or cause substantial death of tumor cells (necrosis), they found.

"Surprisingly, G-1 was highly effective in halting the growth of the tumors that re-emerged after castration," Ho said.

The castration-resistant tumors showed a 65 percent necrosis. These mice had increased expression of GPR30 after castration, which Ho believes sensitized prostate tumors to the cell growth-inhibiting effects of G-1.

"These results mean G-1 won't work without androgen deprivation therapy," she said.

Therefore, Ho reported, the window of time when this targeted therapy might be effective for treating hormone-resistant prostate cancer is after androgen deprivation therapy. She said she believes G-1 can make androgen blockade more effective. G-1 caused no harm to the prostate or other vital organs in mice, she added.

Although GPR30 may have a role in cell growth in female tissues, Ho said it appears to have the opposite effect in men with hormone-resistant prostate cancer. "The beauty of this GPR30 is that it does not have any estrogen, and so it will not cause any side effects of estrogen," she said.

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Survival niche for cancer cells

ScienceDaily (June 6, 2011) — Cancer cells do not grow equally well everywhere in the body. Often, they first create the conditions in which they can grow. Many years ago researchers discovered that solid tumors attract blood vessels to ensure their supply of nutrients by secreting specific factors. Now the immunologist Dr. Uta Höpken (Tumor and Immunogenetics Research Group at the Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch in the Helmholtz Association) and the hematologist Dr. Armin Rehm (Charité -- Virchow-Klinikum, Department of Hematology, Oncology and Tumor Immunology, MDC) have shown for the first time that specific forms of lymphoma also create their own survival niche.

See Also:Health & MedicineLymphomaImmune SystemStem CellsBrain TumorCancerProstate CancerReferenceLymph nodeLymphatic systemMetastasisHodgkin's lymphoma

Lymphoma is the term used to describe a group of cancers of the lymphatic system. Lymphoma cells are abnormal immune cells (B cells or T cells), a specific group of white blood cells (lymphocytes). Using a mouse model, Dr. Rehm and Dr. Höpken demonstrated for the first time that the dissemination of lymphoma cells and their accumulation in the lymph nodes or spleen is dependent on specific signaling or growth substances, the chemokines CCL19 or CCL21.

Chemokines normally attract immune cells to a site of infection or inflammation. As former immune cells, lymphoma cells have special antennas (receptors) on their cell surface to which these signaling substances bind. If the lymphoma cells receive the signal via their CCR7 receptor, they migrate into the lymph nodes and into specific areas within the spleen.

Paradox

CCR7 not only mediates the migration of the lymphoma cells, it is also apparently crucial for their development and survival. As the two researchers showed in a next step, the lymphoma cells proliferate in the lymph nodes or in the spleen very slowly if this receptor is absent.

However, with the aid of CCR7 the cancer cells find their survival niche in the T-cell zones of the lymph nodes and the spleen. In these zones T cells are usually made fit for defense. "It is paradoxical that lymphoma cells as former B cells find an absolutely optimal microenvironment for their growth in these T-cell zones," Dr. Höpken said.

There the lymphoma cells crosstalk with stromal cells (connective tissue cells), which subsequently secrete increased quantities of the chemokines CCL19/CCL21. The CCR7 receptor not only mediates the homing of additional lymphoma cells to the lymph nodes or spleen, but also stimulates their proliferation.

On the other hand, the lymphoma cells themselves secrete a signaling substance (lymphotoxin) which induces the stromal cells to secrete more and more chemokines. In this way the lymphoma cells ensure their survival. This may also explain why some lymphomas are so aggressive.

In mice the researchers succeeded in breaking this vicious cycle. Using an active substance that blocks the binding of the lymphotoxins to the stromal cells, they were able to stop tumor growth. "In the future," Dr. Rehm said, "it may be that therapeutic strategies will not target the lymphoma cells directly, but rather the connective tissue so vital for their survival."

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Immune cells link pregnancy and tumor spread

ScienceDaily (June 6, 2011) — Individuals with cancer often do not die as a result of their initial tumor but as a result of tumors at distant sites that are derived from the initial tumor. Pregnancy is a condition that seems to be permissive for tumor dissemination, as breast tumors arising during pregnancy display a tendency for early spread to distant sites (metastasis). Research in mice, led by Ivan Stamenkovic, at the University of Lausanne, Switzerland, has now uncovered a possible reason for this.

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Stamenkovic and colleagues found that the increased metastasis from tumors of several different types that they observed in pregnant mice was a result of decreased activity of immune cells known as NK cells. Furthermore, at least part of the inhibitory effect on NK cells was mediated by another group of immune cells, myeloid-derived suppressor cells. Consistent with this, the gene expression profile of the lungs of pregnant mice (a site to which many of the tumors metastasized) was reflective of myeloid-derived suppressor cell accumulation.

Of clinical interest, the majority of genes downregulated in the lungs of pregnant mice were also expressed at lower levels in samples from lung cancer patients with poor prognosis than in samples from patients with better prognosis. The authors therefore suggest that myeloid-derived suppressor cells may represent a shared mechanism of immune suppression during pregnancy and tumor growth.

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Breast cancer drug pushes colon cancer cells to their death

ScienceDaily (June 9, 2011) — A new treatment for colon cancer that combines a chemotherapy agent approved to treat breast cancer and a cancer-fighting antibody is ready for clinical trials, according to Penn State College of Medicine researchers.

See Also:Health & MedicineColon CancerLung CancerCancerBreast CancerBrain TumorLymphomaReferenceTumor suppressor geneMonoclonal antibody therapyMetastasisTumor

More than 150,000 cases of colorectal cancer are diagnosed each year, and about 50,000 people die from colorectal cancer yearly. Currently there are limited chemotherapy treatments for colorectal cancer with little that has been in the pipeline in recent years.

Wafik S. El-Deiry, M.D. Ph.D., American Cancer Society Research Professor and Rose Dunlap Professor and chief of hematology/oncology, and his team have tested lapatinib, a targeted chemotherapy agent currently approved for breast cancer treatment, in a new combination with artificial antibodies that mimic a natural cancer-fighting protein produced in the human body. The monoclonal antibodies mapatumumab and lexatumumab act similarly to TRAIL -- tumor necrosis factor

Signaling pathways point to vulnerability in breast cancer stem cells

ScienceDaily (June 11, 2011) — Whitehead Institute researchers have identified signals from breast epithelial cells that can induce those cells to transition to and maintain a mesenchymal and stem cell-like cell state that imbues both normal and cancer cells with a greater ability to migrate and self-renew. Interrupting these signals strips the cells of the migratory, invasive and self-renewal abilities used by cancer stem cells to seed new tumors.

See Also:Health & MedicineStem CellsCancerBreast CancerSkin CancerProstate CancerBrain TumorReferenceEmbryonic stem cellTumorSomatic cellHealing

"Stem cells are important in both cancers and normal tissues. On the one hand we'd like to know what creates so-called cancer stem cells in tumors and on the other hand we'd like to know what creates normal stem cells in normal epithelial tissues," says Whitehead Founding Member Robert Weinberg. "We have reason to believe that these two dynamics are orchestrated by a common regulatory machinery. So this work may be applicable for understanding both breast cancer cells and normal epithelial cells, such as the normal cells in the normal mammary ducts."

During an epithelial-to-mesenchymal transition (EMT), epithelial cells acquire the traits of mesenchymal cells. Unlike the tightly-packed epithelial cells that stick to one another, mesenchymal cells are loose and free to move around a tissue. The attributes of mesenchymal cells are beneficial during development, but when hijacked by cancer cells, confer the ability to migrate to distant sites. In addition, the passage through an EMT enables adult cancer cells to seed new tumors with high efficiency, the hallmark trait of cancer stem cells. Although passage through an EMT is recognized as an important step in the formation of cancer stem cells, scientists have been unable to clearly identify the cues in a cell's microenvironment that induce an EMT.

By studying human breast epithelial cells, Christina Scheel, a postdoctoral researcher in the Weinberg lab, pinpointed three signaling pathways (TGF-beta, non-canonical Wnts, and canonical Wnts) that work together to maintain migratory and self-renewing traits of both normal breast epithelial and breast cancer cells. These pathways are continuously activated in the stem cells by autocrine signals; that is, signals produced by the cells themselves. Studying how these autocrine signals function in breast epithelial cells allowed Scheel to specify the signals that allow these cells to pass through an EMT and enter into a mesenchymal and stem cell-like state in the first place. Her findings are published in the June 10 issue of Cell.

Interestingly, Scheel discovered that epithelial cells are kept in their differentiation state via inhibition of the three signaling pathways, that is, normal epithelial cells naturally produce proteins that block these signaling proteins. To push normal breast epithelial cells through an EMT in vitro, she removed these endogenous inhibitors by administering a cocktail of neutralizing antibodies and added growth factors that stimulate the three pathways, thereby mimicking the autocrine signaling found in mesenchymal cells. By applying the resulting EMT-inducing cocktail continuously, Scheel pushed the cells into a mesenchymal and stem cell-like state, with associated increased migratory ability and stem cell-like characteristics. Eventually, the former epithelial cells stabilized this state through autocrine signaling and were no longer dependent on the EMT cocktail.

To see the effects of blocking this autocrine signaling in an animal model, Scheel implanted into mice human breast cancer epithelial cells that had passed through an EMT. She then injected the implantation site with proteins that block the three pathways. The injected mice had one-tenth the number of tumors found in mice that did not receive the inhibitory proteins. In addition, breast cancer cells that were pre-treated in vitro with these proteins displayed a greatly reduced ability to metastasize when subsequently implanted into mice.

Scheel notes that these experiments show how cancer cells' knack for usurping normal cell functions could ultimately lead to their downfall.

"These autocrine signals are not something breast cancer cells invent anew, but derive instead an activation of normal stem cell programs," says Scheel. "Breast cancer stem cells rely on these signals to maintain themselves, so they remain susceptible to blocking this autocrine signaling. It might be a terrific way to target breast cancer stem cells. In addition, our gain in understanding how both migratory and self-renewal traits are activated in normal breast epithelial cells might further our understanding of normal tissue homeostasis and might be of great utility in the area of regenerative medicine, where it would be highly desirable to create great numbers of epithelial stem cells without resorting to genetic intervention."

Although Scheel's research gives new insight into how both cancer and normal breast cells transition to and maintain a mesenchymal cell state, she and Weinberg caution that the same signals and signaling pathways may not apply for non-breast cells.

"Are the same agents signaling the EMT in non-mammary tissues -- the skin, liver, the gut, pancreas and so forth? We don't know the generalizability of Scheel's findings yet, although I can imagine that there are many commonalities," says Weinberg, who is also a professor of biology at MIT and the Director of the MIT/Ludwig Center for Molecular Oncology. "Secondly, we don't know if these three signaling pathways are ultimately those that are critically important for activating the EMT in non-mammary cell types. Alternatively, there may be other contextual signals besides these three that play an equally important role in triggering an EMT in non-mammary cells? Whether these signaling pathways turn out to have a degree of universality, we just don't know."

This research was supported by the National Institutes of Health/National Cancer Institute (NIH/NCI), Massachusetts Institute of Technology Ludwig Center for Molecular Oncology, Ludwig Fellowship for Metastasis Research, Breast Cancer Research Foundation, Harvard Breast Cancer Specialized Program of Research Excellence (SPORE), Department of Defense Breast Cancer Research Program Idea Award, and Samuel Waxman Foundation.

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How killer immune cells avoid killing themselves

ScienceDaily (June 9, 2011) — After eight years of work, researchers have unearthed what has been a well-kept secret of our immune system's success. The findings published online on June 9th in Immunity, a Cell Press publication, offer an explanation for how specialized immune cells are able to kill infected or cancerous cells without killing themselves in the process.

See Also:Health & MedicineImmune SystemLymphomaStem CellsBrain TumorLung CancerNervous SystemReferenceNatural killer cellT cellImmune systemWhite blood cell

The focus of the study is a molecule known as perforin, whose job it is to open up a pore in cells targeted for destruction. With that pore in place, proteases known as granzymes can enter target cells and destroy them.

Perforin is one of the most critical ingredients for a functional immune system. Without it, mice succumb to viral illness and lymphoma. Humans born without a working perforin gene develop an aggressive immunoregulatory disorder in the first few months of life and usually die unless treated with cytoxic drugs or a bone marrow transplant.

But perforin itself is an incredibly destructive molecule. "Perforin forms a massive pore," said Ilia Voskoboinik of the Peter MacCallum Cancer Centre in Australia. "It allows almost any protein to diffuse into a target cell. A few hundred molecules of perforin is sufficient to obliterate any cell."

When the immune cells known as cytotoxic lymphocytes (including cytotoxic T lymphocytes and natural killer cells) are activated, "they produce a massive amount of perforin, yet the cells are fine," Voskoboinik said. The question was: how do our immune cells manage such toxic cargo without endangering themselves?

Before perforin is released, the cells that produce it have to transport it from one part of the cell to another. That transport chain starts in a component of the cell known as the endoplasmic reticulum (ER). From there, it moves to the Golgi and into secretory granules where it is packaged together with granzymes. It is those secretory granules that ultimately fuse with the plasma membrane of the cytotoxic cell and allow its release into the junctions between the immune cell and the cell it aims to kill.

Scientists used to think perforin had an inhibitory domain within its structure that was only removed once they were safely stored in the secretory granules. (The acidic environment within secretory granules keeps perforin inactive until its release.) But Voskoboinik's team purified perforin and found that the protein was always active regardless of whether they had removed the supposed inhibitory domain or not.

"It seeded doubt about how perforin is inhibited," he says. "It was a puzzle. Perforin was fully functional but for some reason it couldn't kill the cell

New malaria protein structure upends theory of how cells grow and move

ScienceDaily (May 30, 2011) — Researchers from the Walter and Eliza Hall Institute have overturned conventional wisdom on how cell movement across all species is controlled, solving the structure of a protein that cuts power to the cell 'motor'. The protein could be a potential drug target for future malaria and anti-cancer treatments.

See Also:Health & MedicineMalariaLung CancerStem CellsPlants & AnimalsMolecular BiologyGeneticsBiotechnologyReferenceHeat shock proteinMyosinVector (biology)Plant cell

By studying the structure of actin-depolymerising factor 1 (ADF1), a key protein involved in controlling the movement of malaria parasites, the researchers have demonstrated that scientists' decades-long understanding of the relationship between protein structure and cell movement is flawed.

Dr Jake Baum and Mr Wilson Wong from the institute's Infection and Immunity division and Dr Jacqui Gulbis from the Structural Biology division, in collaboration with Dr Dave Kovar from the University of Chicago, US, led the research, which appears in the May 31 edition of the Proceedings of the National Academy of Sciences USA.

Dr Baum said actin-depolymerising factors (ADFs) and their genetic regulators have long been known to be involved in controlling cell movement, including the movement of malaria parasites and movement of cancer cells through the body. Anti-cancer treatments that exploit this knowledge are under development.

"ADFs help the cell to recycle actin, a protein which controls critical functions such as cell motility, muscle contraction, and cell division and signaling," Dr Baum said. "Actin has unusual properties, being able to spontaneously form polymers which are used by cells to engage internal molecular motors -- much like a clutch does in the engine of your car. A suite of accessory proteins control how the clutch is engaged, including those that dismantle or 'cut' these polymers, such as ADF1.

"For many years research in yeast, plants and humans has suggested that the ability of ADFs to dismantle actin polymers -- effectively disengaging the clutch -- required a small molecular 'finger' to break the actin in two," Dr Baum said. "However, when we looked at the malaria ADF1 protein, we were surprised to discover that it lacked this molecular 'finger', yet remarkably was still able to cut the polymers. We discovered that a previously overlooked part of the protein, effectively the 'knuckle' of the finger-like protrusion, was responsible for dismantling the actin; we then discovered this 'hidden' domain was present across all ADFs."

Mr Wong said that the Australian Synchrotron was critical in providing the extraordinary detail that helped the team pinpoint the protein 'knuckle'. "This is the first time a 3D image of the ADF protein has been captured in such detail from any cell type," Mr Wong said. "Imaging the protein structure at such high resolution was critical in proving beyond question the segment of the protein responsible for cutting actin polymers. Obtaining that image would have been impossible without the synchrotron facilities."

Dr Baum said the new knowledge will give researchers a much clearer understanding of one of the fundamental steps governing how cells across all species grow, divide and, importantly, move. "Knowing that this one small segment of the protein is singularly responsible for ADF1 function means that we need to focus on an entirely new target not only for developing anti-malarial treatments, but also other diseases where potential treatments target actin, such as anti-cancer therapeutics," Dr Baum said. "Malaria researchers are normally used to following insights from other biological systems; this is a case of the exception proving the rule: where the malaria parasite, being so unusual, reveals how all other ADFs across nature work."

More than 250 million people contract malaria each year, and almost one million people, mostly children, die from the disease. The malaria parasite has developed resistance to most of the therapeutic agents available for treating the disease, so identifying novel ways of targeting the parasite is crucial.

Dr Baum said that the discovery could lead to development of drugs entirely geared toward preventing malaria infection, without adverse effects on human cells. "One of the primary goals of the global fight against malaria is to develop novel drugs that prevent infection and transmission in all hosts, to break the malaria cycle," Dr Baum said. "There is a very real possibility that, in the future, drugs could be developed that 'jam' this molecular 'clutch', meaning the malaria parasite cannot move and continue to infect cells in any of its conventional hosts, which would be a huge breakthrough for the field."

This project was funded by the National Health and Medical Research Council (NHMRC).

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Experimental vaccine made from frozen immune cells shows promise for prostate cancer patients

ScienceDaily (June 3, 2011) — Metastatic prostate cancer patients who received an investigational vaccine made from their own frozen immune cells lived 10 months longer than those not treated with it, according to data being presented by researchers from the Kimmel Cancer Center at Jefferson at the 2011 American Society of Clinical Oncology annual meeting in Chicago.

See Also:Health & MedicineProstate CancerMen's HealthDiseases and ConditionsUrologyBreast CancerCancerReferenceClinical trialMetastasisDouble blindHealth benefits of tea

In an exploratory, multi-institutional analysis, researchers administered the vaccine APC8015F to a group of patients from the control arm of three randomized, Phase 3 clinical trials evaluating sipuleucel-T, a similar, FDA-approved cancer vaccine for metastatic castrate resistant prostate cancer.

APC8015F is made from immune system cells taken from a patient with prostate cancer; however, unlike sipuleucel-T, which is never frozen, APC8015F is cryopreserved at a time before the disease progressed.

Results from the analysis showed that patients treated with APC8015F had improved survival relative to the patients who were not treated in the control arm. Following disease progression, the median survival of patients treated with APC8015F was 20.0 months compared to 9.8 months for control patients.

"The study is important because it suggests that the sipuleucel-T therapy may have extended survival for a longer time than estimated in the clinical trials due to the beneficial effects of the frozen product on some men who initially received the placebo," said Leonard Gomella, M.D., Chair of Urology at Jefferson's Kimmel Cancer Center in Philadelphia. "Further, the clinical activity of the frozen-activated product is maintained."

Post-progression treatment with APC8015F, which is not FDA approved, may have extended survival of subjects, potentially reducing the magnitude of survival difference observed between sipuleucel-T and controls in randomized controlled trials.

Sipuleucel-T is FDA approved under the brand name Provenge to treat men with advanced prostate cancer that is asymptomatic or minimally symptomatic and no longer responding to hormonal therapy.

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Gene expression changes in nasal cells may help identify lung cancer in earliest stages

ScienceDaily (May 16, 2011) — A simple, minimally-invasive technique using cells from the interior of the nose could help clinicians detect lung cancer in its earliest -- and most treatable -- stages, according to a study conducted by researchers in Boston.

See Also:Health & MedicineLung CancerLung DiseaseDiseases and ConditionsCancerBreast CancerColon CancerReferenceTumor suppressor geneMetastasisTumorMinimally invasive procedure

The study was presented at the ATS 2011 International Conference.

"Our data suggests that evaluating gene expression changes in nasal cells found in the interior surface of the nose may serve as a non-invasive approach for the early detection of lung cancer in smokers," said study author Christina Anderlind, MD, Instructor of medicine at Boston University Medical Center.

Lung cancer is the most common cause of cancer mortality, with an average five-year survival rate of only 15 percent. However, survival rates are highly dependent upon how advanced the cancer is when detected.

"At an early stage, the five-year survival rate is 60 percent compared to only 2 percent at a late stage," Dr. Anderlind noted. "Despite this fact, early diagnosis is hard to achieve since the diagnostic tests currently available are highly invasive, such as open lung biopsy. We wanted to determine if a minimally invasive site like the nose could be used to diagnose cancer in its early stages, when there is a much greater chance of long-term survival."

For their study, the researchers collected nasal epithelial cells from thirty three smokers who were undergoing medically-indicated bronchoscopies for suspicion of lung cancer. Of these patients, eleven were found to have benign disease and twenty two had lung cancer. Brushings were taken from the right or left nostril and profiled on microarrays, a process that allows researchers to study gene expression changes.

"Microarrays allow us to get a detailed portrait of the expression levels of a large number of genes simultaneously, with our goal being to then sort through all these expression levels to find genes that differ in their expression between patients with lung cancer and those with benign disease," Dr. Anderlind said.

The researchers identified 170 genes that were differentially expressed between patients with and without lung cancer. They also found that genes linked to colon cancer and adenocarcinoma, as well as genes that trigger cell division and blood vessel growth, were expressed more heavily in patients with cancer. Genes involved in tumor suppression were also expressed at lower levels in these patients.

Earlier studies have used gene expression differences in the bronchial airways to identify lung cancer in its early stages. Dr. Anderlind said she and her colleagues relied on those results to design the current study.

"In this study we used the same principle as we used in our earlier studies of bronchial tissue, only this time, those methods were used to study nasal cells," she said. "Our hypothesis was that the upper airway epithelium of smokers with lung cancer displays a cancer-specific gene expression pattern, and that this airway nasal gene expression signature reflects the changes that occur in lung tissue."

Dr. Anderlind said the results of the current study are an initial indication that simple nasal brushings could offer an alternative to lung biopsy and other invasive techniques aimed at identifying lung cancer in its early stages.

"This study is a pilot study and our results are preliminary," she said. "Although we did have some indication based on previous studies that we might find gene expression changes in nasal cells, it was unexpected that normal-looking airway cells located at a distance from the lungs would show a specific gene signature that distinguishes patients with cancer from those with benign disease," she said.

A larger study funded by the National Cancer Institute's Early Detection Research Network (EDRN) in collaboration with Steven Dubinett and David Elashoff at UCLA and with Allegro Diagnostics Inc, is planned to confirm the results, she noted.

"The development of a nasal biomarker for diagnosis of lung cancer would make early diagnosis of lung cancer more feasible, allowing patients with radiographic findings that are suspicious for lung cancer to be evaluated in the clinic with nose brushings," Dr. Anderlind said. "We are planning to analyze at least 100 more samples from patients with benign disease and lung cancer, to be able to validate our results and to work toward the development of a nasal biomarker for early detection of lung cancer."

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Cancer scientists discover new way breast cancer cells adapt to environmental stress

ScienceDaily (May 14, 2011) — An international research team led by Dr. Tak Mak, Director, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital (PMH), has discovered a new aspect of "metabolic transformation," the process whereby tumour cells adapt and survive under conditions that would kill normal cells.

See Also:Health & MedicineBreast CancerCancerBrain TumorLymphomaSkin CancerOvarian CancerReferenceHeat shock proteinHealth benefits of teaBRCA1Metastasis

The findings, published May 15 in Genes and Development, show how breast cancer cells can thrive when deprived of their usual diet of glucose (sugar) and oxygen by turning to fatty acids for energy generation.

"Our results demonstrate that a protein not previously associated with breast cancer is involved in helping these cells to adapt to starvation conditions and to continue their uncontrolled growth," says Dr. Mak, principal investigator and Weekend to End Breast Cancer Chair in Breast Cancer Research at PMH. Dr. Mak is also a Professor at the University of Toronto in the Departments of Medical Biophysics and Immunology.

In the lab, researchers used an anticancer drug called rapamycin to block a molecular signalling pathway within breast cancer cells that stimulates sugar metabolism. However, instead of dying of starvation, the cells continued to multiply. The team also observed an increase in these cells of carnitine palmitoyltransferase 1C (CPT1C), a protein usually found only in the brains of healthy individuals. Moreover, cells engineered to produce high levels of CPT1C were also able to adapt their metabolism as a survival technique.

"In other words," says Dr. Mak, "The cancer cells acted like cheaters on a diet and found a new food source in fatty acids.

"The fact that CPT1C becomes expressed under conditions of metabolic stress highlights the resilience of cancer cells. They are able to adapt to environmental challenges and find alternative sources of food in order to flourish where healthy cells would not survive."

"Our discovery that deprivation of either sugar or oxygen spurs CPT1C expression in tumour cells marks this protein as a potential target for new drug development," says Dr. Mak.

"We also demonstrated that cells that were prevented from using CPT1C to cope with a disruption in sugar metabolism became more sensitive to environmental stress. These findings represent an important stepping stone to developing targeted therapies that can block cancer cells from adapting to environmental challenges and surviving efforts to kill them."

This most recent discovery builds on Dr. Mak's impressive body of work, which has led to important breakthroughs in immunology and our understanding of cancer at the molecular level. Dr. Mak is known for his 1984 landmark scientific paper on the cloning of the genes for the T cell receptor, a key component of the human immune system.

The research published May 15 was financially supported by grants from the Canadian Institutes of Health Research, The Princess Margaret Hospital Foundation, The Canadian Cancer Society, the Forschungskredit of the University of Zurich and Oncosuisse.

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Leucine deprivation proves deadly to malignant melanoma cells

ScienceDaily (May 16, 2011) — Whitehead Institute researchers have found that depriving human melanoma cells of the essential amino acid leucine can be lethal to the cells, suggesting a possible strategy for therapeutic intervention.

See Also:Health & MedicineSkin CancerBrain TumorStem CellsLymphomaDietary SupplementLung CancerReferenceEssential nutrientBiochemistryGlutamic acidCells of the stomach

The researchers observed the effect in melanoma cells with a mutation in the RAS/MEK signaling pathway -- the most common mutation found in the deadliest form of skin cancer.

Leucine is one of nine essential amino acids humans must ingest, as we are unable to synthesize them. These nine, along with 12 non-essential amino acids, are the building blocks of proteins used in muscle production and normal cell functions. Cellular amino acid levels and other nutrients are monitored by the mTOR pathway. Typically, when levels of one or more amino acids drop too low, the mTOR pathway is turned off, which activates a process called autophagy.

During autophagy, the cell attempts to boost amino acid levels by breaking down the cell's protein-based structures back into their amino acid components. This is similar to the entire body breaking down fat and muscle when it is on a diet. For a cell, autophagy is a short-term survival mechanism.

According to their paper published in the May 17 issue of Cancer Cell, researchers in the lab of Whitehead Institute Member David Sabatini found that melanoma cells with RAS/MEK pathway mutations short-circuit this chain of events.

"The odd thing is that if you remove this one essential amino acid, leucine, the melanoma cells don't activate autophagy," says Sabatini, who is also a professor of biology at MIT and a Howard Hughes Medical Institute (HHMI) investigator. "Because leucine is essential, they eventually die. Potentially, that could be used as a way of targeting the melanoma cells if one could mimic the lack of leucine."

When melanoma cells with RAS/MEK pathway mutations are deprived of leucine, mTOR does not sense it, so mTOR does not turn off, and autophagy never begins. Instead, the cells behave as if there were no nutrient shortage until they reach a metabolic crisis and die.

Although cells in a test tube can be deprived of leucine completely, removing leucine from a mouse or a human is almost impossible, due to large leucine reservoirs in muscles. To test how leucine deprivation works in an animal model, Joon-Ho Sheen, who is first author of the Cancer Cell paper, implanted human melanoma tumors with RAS/MEK pathway mutations into mice. He then fed the mice a leucine-free diet. Within a few days, the leucine concentration in the mice's blood dropped from about 110 micromoles to 60 or 70 micromoles. As the blood leucine levels dropped, so too did the leucine levels within the mice's cells. Still, the drop in leucine wasn't sufficient to kill the melanoma cells in vivo.

Sheen then gave the mice the drug chloroquine along with a leucine-free diet. Chloroquine, which is an anti-malaria drug, inhibits autophagy. With the one-two punch of chloroquine and a leucine-free diet, the melanoma cells died, significantly reducing tumor sizes compared with mice fed either a normal diet or a leucine-free diet without chloroquine.

For Sheen, these results raised more questions, particularly with regard to potential therapeutic applications.

"Thanks to the pioneering work by others in the autophagy field, we were able to show that leucine deprivation triggers apoptosis in melanoma cells. I think our work provides a framework, but there are many areas to fill in," says Sheen, who is a postdoctoral researcher in the Sabatini lab. "In practice, how can you deprive just leucine in humans? Maybe using some sort of enzyme that degrades leucine or a small molecule inhibitor that blocks leucine's uptake by cells. And we need a better way to target autophagy; chloroquine isn't very efficient at this. And those are just the immediate, foreseeable issues."

This research was supported by the National Institutes of Health (NIH), the U.S. Department of Defense (DoD), the Jane Coffin Childs Memorial Fund for Medical Research, and the American Brain Tumor Association.

David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

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Common anti-inflammatory coaxes liver cancer cells to commit suicide

ScienceDaily (May 16, 2011) — The anti-inflammatory drug celecoxib, known by the brand name Celebrex, triggers liver cancer cell death by reacting with a protein in a way that makes those cells commit suicide, according to a new study.

See Also:Health & MedicineBreast CancerLung CancerCancerColon CancerLiver DiseaseProstate CancerReferenceCOX-2 inhibitorAnalgesicNanomedicineAntiviral drug

Researchers also found that the combination of celecoxib with each of two chemotherapy drugs killed more liver cancer cells in culture, making those combinations more effective than either drug on its own.

"Each chemotherapy drug alone will reduce the growth of cancer cells, but when each single drug is combined with Celebrex, a greater growth suppression effect was observed," said Jiayuh Lin, senior author of the study and an associate professor of pediatrics at Ohio State University. "For clinicians, this research suggests the possibility of a new therapeutic strategy."

Celecoxib has this effect by acting on STAT3, a gene inside liver cancer cells that, when activated, allows those cancer cells to resist the effects of chemotherapy drugs. The researchers determined that the celecoxib molecule binds to STAT3 on so-called "hot spots," effectively blocking its ability to function.

Powerful computing techniques were employed before the researchers ever considered celecoxib as a potential treatment for cancer. Celebrex is a nonsteroidal anti-inflammatory drug, or NSAID, and a Cox-2 inhibitor, meaning it helps control inflammation by inhibiting an enzyme known as cyclooxygenase-2. It is most commonly prescribed to treat the pain of arthritis.

Chenglong Li, an assistant professor of medicinal chemistry and pharmacognosy at Ohio State, has developed computer simulations to identify optimal drug fragment combinations that attach simultaneously to proteins in ways that block the proteins' functions. By searching a database of existing federally approved drugs, he found that celecoxib was structurally similar to a template molecule that he had determined would most effectively bind to STAT3 and inhibit its function.

"Normally, STAT3 is persistently activated in cancer cells. If you have a good molecule that sticks to STAT3, it will prevent its activation," Li said. And when STAT3 is inhibited, cellular survival pathways are blocked that cause the cancer cell to chop itself up and die.

The research appears online and is scheduled for later print publication in the journal Cancer Prevention Research.

The biological portion of the study further defined the role of a pro-inflammatory protein in liver cancer's development. The protein, called interleukin-6, or IL-6, is a cytokine, a chemical messenger that causes inflammation, which can have both beneficial and damaging effects in the body. Previous research by other scientists has shown that high levels of IL-6 in the blood are associated with hepatocellular carcinoma, the most common type of liver cancer.

Lin and colleagues determined that IL-6 initiates a chemical reaction called phosphorylation of STAT3. That reaction activates STAT3 inside liver cancer cells, where STAT3 in turn activates at least three other known genes that allow the cells to resist the effects of chemotherapy.

The scientists treated five different types of hepatocellular carcinoma cells with two different doses of celecoxib for two hours, and followed by giving them IL-6 for 30 minutes. The pre-treatment with the lower dose of celecoxib inhibited IL-6's ability to start the reaction that activates STAT3. The higher dose blocked STAT3 altogether.

The researchers then treated a line of liver cancer cells with celecoxib in combination with two chemotherapy drugs: doxorubicin, which is used to treat breast, ovarian, gastric, thyroid and several other cancers, and sorafenib, which is the only chemotherapy medication approved by the Food and Drug Administration for liver cancer treatment. Its brand name is Nexavar.

With both drugs, the addition of celecoxib treatment reduced the number of viable liver cancer cells by anywhere from approximately 50 percent to more than 90 percent, depending on the doses. The combination of celecoxib and sorafenib also significantly limited the cancer cells' ability to form colonies, a key element of tumor growth and survival after the drug treatment.

"Because liver cancer has a very low five-year survival rate, it is most likely that even sorafenib alone may not be effective to cure the cancer," said Lin, also an investigator in Ohio State's Comprehensive Cancer Center and the Center for Childhood Cancer at Nationwide Children's Hospital. "We hope that using both drugs together could be more effective. Both celecoxib and sorafenib are already approved by the FDA, so we think this combined treatment should be able to be used in the clinic pretty quickly."

The fifth most common cancer in humans, liver cancer remains one of the most difficult to successfully treat. Patients' overall five-year survival rate is about 10 percent, according to the American Cancer Society.

These experiments were conducted in cell cultures. Further testing would be needed to determine celecoxib's effectiveness in human cancers, Lin noted.

And the powerful computational work led by Li, also an investigator in Ohio State's Comprehensive Cancer Center, is likely to lead to the development of new molecules with even more precise structural relationships with the proteins they are designed to block.

Li's method is called Multiple Ligand Simultaneous Docking. In this work, he used computer simulations to identify "hot spots" on the STAT3 protein -- tiny pockets to which molecules could most successfully attach to inhibit the protein's activity. He then searched through drug banks containing more than 7,500 existing and experimental medications to find the most suitable molecular fragments that could be pieced together to produce a new molecule shaped in such a way that it would fit into those pockets.

After designing a template molecule that would most effectively bind to STAT3, he compared that template to the 1,400 federally approved drugs already on the market.

"Celecoxib is almost identical to the molecule template. It attaches to STAT3 in three places. We can optimize celecoxib, and that is expected to come soon. But applying our technique to find those pieces and determining that they come from an existing drug makes the discovery process much faster," said Li, a key co-author of the paper and frequent research collaborator with Lin.

Li has termed this approach as in silico (computer-driven) drug repositioning or repurposing.

The discovery that celecoxib can bind to STAT3 also appears to apply to other cancers. Both Lin and Li were key authors on a recent paper that suggested that celecoxib's ability to block STAT3's function might also make it effective as a treatment for rhabdomyosarcoma, the most common soft tissue cancer in children and adolescents. This research was published in the April 15 issue of the journal Biochemical and Biophysical Research Communications.

Co-authors of the liver cancer and rhabdomyosarcoma studies include Yan Liu, Aiguo Liu and Suzanne Reed of the Center for Childhood Cancer at Nationwide Children's Hospital (Aiguo Liu is also affiliated with Tongji Hospital at Huazhong University of Science and Technology in Wuhan, China); and Huameng Li of Ohio State's Division of Medicinal Chemistry and Pharmacognosy and the Biophysics Graduate Program.

This work was supported by grants from the National Institutes of Health and the Department of Defense Congressionally Directed Medical Research Programs.

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Gene-modified stem cells help protect bone marrow from toxic side effects of chemotherapy

ScienceDaily (May 21, 2011) — Although chemotherapy is used to kill cancer cells, it can also have a strong toxic effect on normal cells such as bone marrow and blood cells, often limiting the ability to use and manage the chemotherapy treatment. Researchers at Fred Hutchinson Cancer Research Center reported at the annual meeting of the American Society of Gene and Cell Therapy in Seattle that one possible approach to reduce this toxic effect on bone marrow cells is to modify the cells with a gene that makes them resistant to chemotherapy.

See Also:Health & MedicineLeukemiaBrain TumorStem CellsLung CancerColon CancerLymphomaReferenceGliomaMetastasisStem cell treatmentsTumor suppressor gene

Hans-Peter Kiem, M.D., a member of the Hutchinson Center's Clinical Research Division, and colleagues Jennifer Adair, Ph.D., a research associate in the Clinical Research Division, and Maciej Mrugala, M.D., Ph.D., M.P.H., a neuro-oncololgist at the Seattle Cancer Care Alliance and the University of Washington, presented data from a clinical trial in which bone marrow stem cells from patients with brain tumors were removed and modified with a retrovirus vector to introduce the chemotherapy-resistant gene. The cells were then re-infused into the patients. In the trial, which was designed to evaluate safety and feasibility, patients were safely administered gene-modified blood stem cells that persisted for more than one year and did not show any apparent harmful effects.

This approach was first attempted in patients with a terminal form of brain cancer called glioblastoma. Currently, median survival for glioblastoma patients is just 12 to 15 months. The prognosis for glioblastoma patients is poor not only because no curative treatment is available but because doctors cannot effectively use the treatment that does exist. Glioblastoma cells make a large amount of a protein called MGMT that makes them resistant to chemotherapy, so doctors use a second drug, called benzylguanine, to knock down MGMT and make the tumor cells susceptible to the chemotherapy. However, this potent one-two punch is not limited to the brain tumor cells. Benzylguanine also disables MGMT in normal blood and bone marrow cells, leaving them also susceptible to the effects of chemotherapy. The effects on patients' blood and bone marrow can be pronounced and often limit the ability to effectively administer the chemotherapy.

"Our initial results are encouraging because our first patient is still alive and without evidence of disease progression almost two years after diagnosis," Kiem said.

The results of the trial suggest the administration of the modified cells represent a safe method for protecting marrow and blood cells from the harmful effects of chemotherapy in brain tumor patients. Future clinical trials will be done to determine whether this combination chemotherapy will also improve the survival of patients with glioblastoma.

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