As tumors progress they develop ways to escape recognition and attack by cells of the immune system. However, the mechanisms by which tumors modify the immune system have not been clearly determined. New insight into the way in which chronic lymphocytic leukemia (CLL) cells limit immune cell attack has now been provided by John Gribben and colleagues, at Barts and The London School of Medicine, United Kingdom.

For immune cells known as CD4+ and CD8+ T cells to become activated they must contact other cells known as APCs. The area of contact is known as the immunological synapse and it is highly organized. In the study, CD4+ and CD8+ T cells from patients with CLL were found to exhibit defective immunological synapse formation with APCs. Further, if CD4+ and CD8+ T cells from healthy individuals were cultured with CLL APCs, they also showed defective immunological synapse formation. As treatment with an immune system–modifying drug improved immunological synapse formation, the authors suggest that approaches to overcoming immunological synapse defects might improve the efficacy of new ways to treat cancer that are currently being developed and that are based on enhancing the antitumor activity of CD4+ and CD8+ T cells.

The development of resistance to anticancer chemotherapeutic agents remains a large problem. In some cases, such resistance is associated with altered control of a cellular process known as translation, which is central to the generation of proteins. New data, generated by Jerry Pelletier and colleagues, at McGill University, Montreal, have identified a drug that can enhance the sensitivity of mouse cancer cells to standard anticancer chemotherapeutic agents.

In the study, small molecules were screened for their ability to inhibit the initiation of translation by modifying the function of a protein known as eIF4A, which has a central role in translation initiation. A class of natural drugs known as cyclopenta[b]benzofuran flavaglines were found to have the desired effects and one member of this class of compounds was shown to reverse the resistance of cancer cells to anticancer chemotherapeutic agents in a mouse model of lymphoma. The authors therefore suggest that developing approaches to inhibit translation initiation by targeting eIF4A might provide a way to altering drug resistance in cancers exhibiting altered control of translation initiation.

Primary tumors can encourage the growth of stray cancer cells lurking elsewhere in the body that otherwise may not have amounted to much, according to a new study in the June 13 issue of the journal Cell, a publication of Cell Press. As people age, most may have such indolent cancer cells given the sheer number of cells in the body, although their rarity makes them impossible to detect, the researchers said.

The primary tumors under study, which were derived from human breast cancers, seem to “instigate” the growth of other cancers by mobilizing bone marrow cells, which then feed the secondary tumors’ growth, they report.

One key to the process is the secretion of a substance known as osteopontin by the instigating tumor, a finding that may have therapeutic implications. Indeed, the researchers noted that osteopontin is present at elevated levels in women with metastatic breast cancer, supporting the notion that the new findings may hold clinical significance.

” If metastases depend on stimulation by primary tumors, interception of the signal through neutralizing antibodies” might block cancer spread, said Robert Weinberg of the Massachusetts Institute of Technology. “That’s still speculative, but it’s an interesting idea to ponder,” he added, noting that treatments today don’t specifically target metastases, which are responsible for the vast majority of cancer deaths.

The researchers noted that while the effects of the tumor microenvironment has been much studied, much less was known about how the systemic environment in the body contributes to tumor growth. Several earlier reports had shown that assorted bone marrow-derived cells can be incorporated to various extents into the supportive framework, or stroma, of tumors. However, it wasn’t clear whether tumors actively recruit stromal cells by directly perturbing other cell reservoirs, such as the bone marrow, or whether tumors are just passive recipients of stromal cell precursors that normally circulate throughout the body.

In the new study, the researchers injected “instigating” human tumor cells into mice along with indolent “responding” cancer cells also derived from humans. Those indolent cells formed vigorously growing tumors only in the presence of the instigating tumor cells, they reported. They found further evidence that the instigating tumor somehow perturbs the makeup of the bone marrow, although Weinberg said they don’t really know how that happens. They also show that osteopontin is necessary to the process, but that it does not act alone.

Finally, they showed that the same instigation process can encourage the growth of disseminated metastatic cancer cells. Instigating breast tumors in the mice also drove the growth of implanted fragments of human colon tumors, a finding that they said shows the generality of the physiologic signaling.

Nonetheless, the researchers said they don’t yet know how universal this systemic instigation of tumor growth might be. Still, the findings challenge the “prevailing view that primary tumors suppress the growth of derived metastases,” Weinberg said. “We argue they can foster cancer’s spread by activating bone marrow that is then recruited by distant metastases.”

The findings also have important implications for the preclinical study of human cancers, Weinberg emphasized.

” The ability of instigating tumors to foster the growth of a human colon tumor surgical specimen underscores the powers of systemic instigation,” the researchers wrote. “Indeed, to our knowledge, methods to expedite the growth of human tumor surgical specimens in vivo have not been previously described. These results suggest that the presently described procedure can be used to study aspects of human tumor biology that would otherwise be difficult if not impossible to study.

” In the longer term, identification of additional tumor-derived factors that perturb the host systemic environment in one way or another may allow one to predict the effects that a given primary tumor type has on the outgrowth of indolent cancer cells that have disseminated to distant sites.”

Individuals who have health conditions associated with chronic inflammation are often at increased risk of developing cancer at the site of the chronic inflammation.  For example, individuals with inflammatory bowel disease and those who are chronically infected with the bacterium Helicobacter pylori are at increased risk of colon cancer and stomach cancer, respectively.  New insight into the mechanisms by which chronic inflammation can contribute to the development cancer has been generated in mice by Leona Samson and colleagues, at Massachusetts Institute of Technology, Boston.

Using mice lacking the protein Aag, which is involved in the repair of DNA damaged by inflammation-associated molecules known as reactive oxygen and nitrogen species (RONS), it was shown that Aag-mediated DNA repair limits cell damage in a mouse model of episodic inflammatory bowel disease and reduces the severity of the colon cancer that develops in the mice experiencing episodic bowel inflammation.  In addition, in a mouse model of Helicobacter pylori infection, Aag-deficient mice were found to exhibit more severe cell damage and the damaged area of the stomach resembled that observed prior to the development of stomach cancer.  The authors therefore conclude that repair of DNA damage caused by RONS seems to be important for protection against chronic inflammation–induced cancer.

Uncontrolled blood vessel growth is a key feature of many pathological conditions, including the degenerative diabetic eye disease known as diabetic retinopathy.  Understanding the factors involved in the process is vital to developing treatments for the disease.  In a new study, a team of researchers at Keio University, Japan, has revealed a role for the protein LIF in blood vessel growth in mice.

Specifically, mice lacking LIF were observed to have increased blood vessel growth in many regions of the body, but as this study was focused on the eye, the authors homed in on the increased blood vessel growth in the retina of the eye.  Further analysis showed that mice lacking LIF developed more aberrant blood vessels in a model of retinopathy.  Mechanistically, LIF was found to inhibit the proliferation of brain cells known as astrocytes as well as inhibit their production of a factor known to promote blood vessel growth, VEGF.  It therefore seems that LIF is an important part of the communication between tissues and developing blood vessels, meaning that LIF and the signaling pathway it triggers might serve as a target for new treatment approaches for preventing diabetic retinopathy and other diseases that are associated with uncontrolled blood vessel growth, such as cancer.

New data, generated by Hongbing Shen and colleagues, at the Cancer Center of Nanjing Medical University, People’s Republic of China, has identified a genetic variation that seems to help predict survival in individuals with non–small cell lung cancer (NSCLC).

A systematic screen of the DNA carrying the information for generating regulatory RNA molecules known as a microRNAs identified a specific genetic variant that was associated with decreased survival in individuals with NSCLC.  The specific genetic variation resulted in increased levels of expression of the functional miRNA molecule.  This was not because more of the miRNA was made but because more of the precursor form of the functional molecule was processed to become functional.  The functional miRNA molecule generated by the genetic variation also had different functional properties.  The authors hope that further characterization of genetic variations that modify miRNA expression and/or function will uncover other indicators of survival and opportunities for developing new therapeutics.

The investigational chemotherapeutic agent eribulin mesylate (E7389) demonstrated activity in a heavily pretreated population of women with locally advanced or metastatic breast cancer, according to results of a multi-center Phase II clinical trial. The study also suggests that eribulin mesylate has a manageable tolerability profile, with a low incidence of Grade 3 (severe) and no Grade 4 (disabling or life-threatening) neuropathy. These data (abstract #1084) will be presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) on Monday, June 2 from 2 to 6 p.m. at S Hall A1 of McCormick Place.¡°The anti-tumor activity of eribulin mesylate, as observed in this study, is encouraging, given the limited treatment options for women with advanced breast cancer who have previously received multiple lines of therapy,¡± said lead investigator Linda T. Vahdat, MD, of Weill Cornell Medical College in New York. ¡°The subjects in this trial had received a median of four prior chemotherapy regimens that included an anthracycline, a taxane and capecitabine.¡±

About Study 211 Study 211 is a Phase II, open-label, single-arm study evaluating the efficacy and safety of eribulin mesylate in patients with locally advanced or metastatic breast cancer who had received an anthracycline, a taxane and capecitabine as prior therapy, and who were refractory to their last chemotherapy regimen, as documented by progression on or within six months of that therapy.

Of 299 patients enrolled in the study, 291 were treated with eribulin mesylate. The median age of those patients was 56 years (range: 26-80 years). Eribulin mesylate was administered at a dose of 1.4mg/m2 as a 2- to 5-minute intravenous infusion on Days 1 and 8 of a 21-day cycle. Patients received a median of four cycles of eribulin mesylate (range 1-27). No premedication to prevent hypersensitivity was required.

Two-hundred sixty-nine patients met the key inclusion criteria. In patients who received a median of four cycles of eribulin mesylate, Overall Response Rate (ORR) by Independent Review (IR) was 9.3% (all Partial Responses (PR); 95% confidence interval [CI]: 6.1%-13.4%). Investigator-assessed ORR was 14.1% (1 CR; 95% CI: 10.2%-18.9%). Nearly half (46.5%) the patients had stable disease (SD) after treatment with eribulin mesylate. The clinical benefit rate (CBR, defined as CR+PR+SD ¡Ý6 months) was 17.1% (95% CI: 12.8%-22.1%).

The median duration of response was 4.2 months (126 days, range: 42 -258 days; 95% CI: 86-147). Median progression-free survival (PFS) was 2.6 months (79 days, range: 1*-397 days), and the median overall survival (OS) rate was 10.3 months (315 days, range: 19-604 days; 95% CI: 279-350). The six-month PFS and OS rates were 16.0% (95% CI: 8.6-17.0) and 72.3%, respectively (95% CI: 66.9-77.6).

The safety analysis included all 291 patients who received treatment with eribulin mesylate. Patients with up to Grade 2 peripheral neuropathy were included in the study. The most frequently reported Grade 3 (severe) or Grade 4 (disabling or life- threatening) adverse events were neutropenia (a decrease in the number of granular white blood cells, 54%); febrile neutropenia, 5.5%, leukopenia (low white blood cell count, 14%), and weakness/fatigue (10%; no Grade 4 events). Grade 3 peripheral neuropathy (a functional disturbance or damage to nerves outside the brain and spinal cord) was reported in 5.5% of patients. No Grade 4 peripheral neuropathy events were reported. No correlation was seen between Grade 2 peripheral neuropathy and deterioration.

“In this study, eribulin mesylate appeared to have an acceptable tolerability profile, particularly with regard to the low incidence of peripheral neuropathy,” noted Vahdat. “None of the reported cases of neuropathy were disabling, suggesting that eribulin mesylate, if approved, may be a useful addition to the treatment armamentarium for advanced breast cancer.”

Magnetic nanoparticles (with a size of some few to several hundred nanometres) are a new, promising means of fighting cancer. The particles serve as a carrier for drugs: “loaded” with the drugs, the nanoparticles are released into the blood stream, where they move until they come under the influence of a targeting magnetic field which holds them on to the tumour - until the drug has released its active agent. Besides this pharmaceutical effect, also a physical action can be applied: an electromagnetic a.c. field heats up the accumulated particles so much that they destroy the tumour. Both therapeutic concepts have the advantage of largely avoiding undesired side effects on the healthy tissue.

These procedures have already been successfully been applied in the animal model and have, in part, already been tested on patients. Here it is important to know before application whether the particles tend to aggregate and thus might occlude blood vessels. Information about this can be gained by magnetorelaxometry developed at the PTB. In this procedure, the particles are shortly magnetised by a strong magnetic field in order to measure their relaxation after the switch-off of the field by means of superconducting quantum interferometers, so-called “SQUIDs”. Conclusions on their aggregation behaviour in these media can be drawn from measurements of suspensions of nanoparticles in the serum or in whole blood. As an example, it could be shown in this way that certain nanoparticles in the blood serum form clusters with a diameter of up to 200 nm - a clear indication of aggregation, so that these nanoparticles do not appear to be suitable for therapy.

At present, the high technical effort connected with the use of helium-cooled magnetic field sensors is still standing in the way of using this method routinely in practice. In a joint project with Braunschweig Technical University supported by the Ministry of Education and Research (BMBF), the procedure is currently being transferred to a simpler technology based on fluxgate magnetometers.

The results of the first orders from customers have served, for example, to optimise the paint drying process in the automobile industry, the thermal design of furnaces as well as the monitoring of glass forming processes.

Another measuring facility is currently being set up in the PTB which will allow emissivity measurements to be performed under vacuum conditions in an extended temperature and wavelength range - in particular for space applications.

Genetic changes during the initiation and progression of prostate cancer have eluded scientists to date. Now for the first time researchers have identified a specific gene expression profile of prostate cancer stem cells, with important implications for future treatments. The findings, published in BioMed Central’s open access journal Genome Biology, revealed 581 genes that are differentially expressed in certain prostate cancer cells, highlighting several pathways important in the cancer stem-cells biology, and offering targets for new chemopreventative and chemotherapeutic approaches.

The cells in the study represent less than 0.1% of prostate cancer tumors, and have properties that mark them out as cancer stem cells. The cells renew themselves, are highly invasive, and have a longer lifetime than normal stem cells. They also feature a primitive epithelial phenotype and can differentiate to recapitulate phenotypes seen in prostate tumors. The cells are found in all stages and types of prostate cancer.

Expression profiling of prostate cancers typically uses tumor cell mass samples to identify individual genes. In this study, researchers harnessed advances in microarray and target labelling technologies to produce a functionally annotated expression profile of these prostate cancer stem cells.

The team, from the YCR Cancer Research Unit at the University of York and Pro-cure Therapeutics Ltd, created a malignant stem cell signature by combining genes significantly overexpressed in stem cells with those significantly overexpressed in malignant stem cells. Quantitative RT-PCR, flow cytometry and immunocytochemistry were used to validate the gene expression changes.

Genes associated with inflammation were prominent in the cancer stem cell expression profile. Potential therapeutic target NFκB is known to promote cell survival. The researchers showed that an NFκB inhibitor triggered programmed cell death in cancer stem cells, but spared normal stem cells. This provides a potential therapeutic target for this rare group of cells, which are unlikely to be affected by current chemotherapy regimens.

“For the first time we are looking at the subpopulation of cancer cells which actually initiate new tumors” explains Anne Collins, who coordinated the study. “The genetic profiling we have carried out should stimulate new lines of research directed towards stem cell treatments for cancer”

New research suggests that the form of tomato product one eats could be the key to unlocking its prostate cancer-fighting potential, according to a report in the June 1 issue of Cancer Research, a journal of the American Association for Cancer Research.“Processing of many edible plants through heating, grinding, mixing or drying dramatically increases their nutrition value, including their cancer prevention potential. It appears that the greatest protective effect from tomatoes comes by rehydrating tomato powder into tomato paste,” said Valeri V. Mossine, Ph.D., research assistant professor of biochemistry at the University of Missouri.

The protective effect of tomato products against prostate cancer has been suggested in many studies, but researchers remain uncertain about the exact mechanisms. Mossine and colleagues demonstrated that FruHis, an organic carbohydrate present in dehydrated tomato products, exerts a strong protective effect.

Researchers divided rats into groups of 20 and fed them a control diet or a diet that included tomato paste, tomato powder or tomato paste plus additional FruHis. All animals were then injected with prostate cancer-causing chemicals.

Animals fed the tomato paste plus FruHis diet had the longest survival from cancer at 51 weeks compared with 50 weeks in the tomato powder group, 45 weeks in the tomato paste alone group and 40 weeks in the control group.

On post-mortem exam, prostate tumors were found in 10 percent of the rats that had been given a combination of tomato paste and FruHis, compared with 30 percent of animals in the tomato powder group, 25 percent in the tomato paste alone group and 60 percent in the control group.

Mossine said the protective effect of tomato-based products was restricted to prostate tumors, which is consistent with other research on tomatoes and cancer. Incidence of other tumors was too small to examine.

In vitro, Mossine and colleagues evaluated the anti-cancer properties of FruHis and 14 other D-fructose amino acids and found that FruHis in a concentrated form protected against DNA damage known to lead to prostate cancer. When combined with lycopene, FruHis stopped cancerous cell growth more than 98 percent of the time.

“Before this study, researchers attributed the protective effect of tomatoes to ascorbic acid, carotenoids, or phenolic compounds,” Mossine said. “FruHis may represent a novel type of potential dietary antioxidant. Experiments like these suggest that a combination of FruHis and lycopene should be investigated as a potential therapeutic anti-tumor agent, not just a prevention strategy.”

Although Mossine cautioned against drawing broad conclusions from this animal study, he said, “the result may introduce an additional intrigue into an ongoing dispute over the beneficial effects of dietary lycopene and tomato products in lowering the risk of prostate cancer. Human trials are certainly warranted.”

Many long-term survivors of cancer are not receiving the necessary symptom management that they require to help them live with the consequences of their disease, its treatment, or both, according to a leading professor of palliative medicine.

Currently, there are approximately 25 million people around the world (10 million in the USA) living with cancer, and over 60% of adults newly diagnosed with cancer can expect to live at least five years or more. Marie Fallon, Professor of Palliative Medicine at the University of Edinburgh, says many of these patients are living in limbo with unmet needs that should be addressed urgently.

“Traditionally, palliative care has been aimed at one end of the spectrum where it is used to help patients near the end of their lives,” she says. “However, there is an enormous population of long-term survivors of cancer, many of whom are living with a range of symptoms. Some of them will not know whether they are cured and whether the symptoms they are experiencing are treatment-related or whether they are related to recurrence of the disease that has not yet been diagnosed.

“These patients exist in a limbo. They fall between two stools: they have finished being treated by oncologists, but are not receiving the care and support from palliative care teams that patients at the end of life receive. Yet the impact of cancer and cancer treatment on the long-term health of survivors is substantial and many of them remain very symptomatic, with poor quality of life. Clearly a proportion will unfortunately be diagnosed with recurrent cancer at some point.”

The problems cancer survivors face can include pain, sexual difficulties, troublesome lymphoedema (chronic swelling caused by the failure of lymph glands to drain properly, often triggered by surgery and radiotherapy), and psychosocial problems including depression and anxiety.

To highlight these “large gaps in patient care”, Prof Fallon and John Smyth, Professor of Medical Oncology (also at the University of Edinburgh), have co-edited a special issue of the European Journal of Cancer on Palliative Care [1], timed to coincide with one of the world’s largest cancer conferences, the American Society of Clinical Oncology (ASCO) conference, which starts tomorrow (Friday 30 May) in Chicago (USA).

The EJC is the official journal of ECCO – the European CanCer Organisation – and Prof Smyth is its editor-in-chief as well as being a past president of ECCO.

“We aim to use this special issue to bridge the gap between oncology and palliative care, and to encourage integration between the two disciplines,” says Prof Fallon. “Collaborations and systems need to be developed to care for patients at all stages of their disease and not just those who have a formal diagnosis of recurrent or advanced cancer.”

In their EJC joint paper, Profs Fallon and Smyth write: “We need to develop a particular supportive care model for sick patients and traditional palliative care expertise should feed into this model. Life and illness are a continuum and our patients do not always fit into well-defined boxes. As specialists, our challenge is to accommodate this continuum rather than restrict it.”

Prof Smyth says: “Europe has led the way in the development of palliative care, which is now an increasing focus of attention in the USA.” The EJC special issue on Palliative Care will be available at ASCO and Prof Smyth will be highlighting it in discussions at the conference.

Professor Alexander M.M. Eggermont, current ECCO president, commented: “This is an important special issue of the EJC, for everyone to read and discuss its content. To be cured from cancer, but living with symptoms that are related to often complex multidisciplinary treatments involving surgery, radiation therapy and chemotherapy is already difficult enough. To reintegrate into society, resuming work full or part-time adds to the complexities and socio-psychological pressure that an ever-increasing number of ‘former-patients’ have to deal with. All this must be looked into and will need special initiatives to deal with these special and unmet needs of this population. We better start tackling these issues now as they will only increase in number and magnitude.”

A novel type of drug can shrink primary breast cancer tumors significantly in just 6 weeks Research provides leads to a new target in cancer treatment -the cancer stem cell.

(Berlin, Germany) A drug that targets the cell surface receptors that play an important role in many types of cancer can bring about significant tumour regression in breast cancer after only six weeks of use, a scientist told the 6th European Breast Cancer Conference (EBCC-6) today (Thursday 17 April).  Dr. Angel Rodriguez, from the Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, USA, said that the work demonstrated for the first time that the tyrosine kinase inhibitor lapatinib could decrease tumour-causing breast cancer stem cells in the primary breast cancers of women receiving neoadjuvant treatment (treatment given before the primary surgery for the disease).

Dr. Rodriguez and colleagues studied 45 patients with locally advanced breast cancer in which the gene HER-2 was over-expressed.  The patients received lapatinib for six weeks, followed by a combination of weekly trastuzumab and three-weekly docetaxel, given over 12 weeks, before primary surgery.  Biopsies were performed at the time of diagnosis and also after six weeks of lapatinib and cells from the tumours were obtained and analyzed.

“We saw significant tumour regression after six weeks of single agent lapatinib,” said Dr. Rodriguez.  “Bi-dimensional tumour measurements showed a median decrease of minus 60.8%. We had previously showed that tumour-causing breast cancer stem cells were resistant to conventional preoperative chemotherapy; indeed, residual cancers that were exposed to such chemotherapy showed an increase in tumour-causing cells and enhanced tumour initiation by the formation of mammospheres, small tumours that form when tumour-causing cells are cultured in a test tube, which reflect the capacity of the cells to self-renew.  So we were excited to see that the results with lapatinib were different.”

Dr. Rodriguez’s results suggest that specific signalling inhibitors of the pathways responsible for stem cell self-renewal could provide a possible therapy for eliminating tumour-causing cells in order to achieve the long-term eradication of cancer.

Cancer stem cells help maintain the malignant tissue in the tumour by regenerating the tumour after attack from chemotherapy drugs.  “This indicates that the stem cells themselves should be the specific target of chemotherapy drugs,” said Dr: Rodriguez.  “Rather than the broad brush approach, in which cells are killed indiscriminately, targeting the stem cells may be more effective and also prevent some of the unpleasant side effects associated with conventional chemotherapy treatment.”

Scientists believe that cancer stem cells come into being through damage to their own DNA, which affects the regulation of their self-renewal.  Other cells divide into two ‘daughter’ cells, but a stem cell can divide into a new stem cell and a ‘progenitor’ cell.  The progenitor cell loses the power of self-renewal, but can still change into the cell type of the tissue served by the stem cell.  The stem cell population then continues to renew itself as it generates new cells for the tissue.  “This means that, unlike other cells, the stem cell has lost control over its own population size,” said Dr. Rodriguez.

Lapatinib has few side effects, and those that exist are minimal, including diarrhoea and acne.  But it is expensive.  “In the US it costs between $2000 and $3000 a month,” he said.

“This is an exciting finding, and we will be starting further studies on stem cells in order to confirm it.  We will also look into its applicability in testing novel agents targeting tumour-initiating cells.  This finding should also apply to other types of cancers and research of tumour-initiating stem cells in other cancers is ongoing,” said Dr. Rodriguez.

“International studies are currently underway looking at the effect of lapatinib in lung, colon, head and neck, gastric, oesophageal, and bladder cancer and lymphoma, among others,” he said.

Note:  Lapatinib has not yet been licensed for use in the EU, although it has been approved in Switzerland and received a positive opinion regarding a conditional marketing authorisation from the European Medicines Agency in December.  This conditional authorisation refers to its use in patients with advanced or metastatic breast cancer with HER-2 over-expression in the tumours.

Catalogue no: 204, Thursday 18 April, 17.15 hrs CEST (Hall 1)

A new drug compound leads to the death of ovarian cancer cells resistant to chemotherapy.

Dr. Gil Mor, Associate Professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

Credit: Yale University

In a discovery that may be useful for maintaining remission in chemo-resistant ovarian cancer, Yale scientists report that pre-clinical studies have shown the drug compound NV-128 can induce the death of ovarian cancer cells by halting the activation of a protein pathway called mTOR.

Gil Mor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine, and associate research scientist Ayesha Alvero, M.D. presented the data April 15 during an oral presentation at the annual meeting of the American Association for Cancer Research.

In cancer cells, mTOR signals enhance tumor growth and may be associated with resistance to conventional therapies.  Inhibition of mTOR could shut down many of these survival pathways, including proteins that protect the mitochondria of cancer cells.

NV-128, developed by Novogen Limited, holds promise as a more targeted therapy for ovarian cancer because it works differently from traditional therapies that are dependent on enzymes known as caspases to trigger cell death.  Therapies using caspases to kill cancer cells can be ineffective in chemo-resistant cancer cells due to mutations that short-circuit signals that trigger cancer cell death.

“We consider that the capacity of NV-128 to trigger caspase-independent cell death, in otherwise chemoresistant ovarian cancer cells, opens new possibilities for the use of NV-128 as a potential addition to conventional chemotherapy targeting ovarian cancer cells,” said Mor.

In the context of developing therapies for late stage ovarian cancer, Mor said, the finding may be “a key step to the development of alternative targeted therapy for patients with cancer recurrence.”

Breast cancers behave differently before and after the age of 70 Do the immune defense mechanisms play a role?

Berlin, Germany: Researchers in Belgium have discovered that increasing age affects the way breast cancer behaves.  As women approach the age of 70, they become less likely to be diagnosed with aggressive tumours that have spread to the lymph nodes.  But after 70, the cancer is increasingly likely to spread, particularly if the tumours are small.

Until now, there has been conflicting evidence on aging and lymph node involvement and this study is the first to show clearly how the link between the two changes before and after the age of 70.

Professor Hans Wildiers told the 6th European Breast Cancer Conference (EBCC-6) in Berlin today (Friday), that he suspects that women older than 70 have decreased immune defence mechanisms, which are less able to deal with tumours that are likely to metastasise to other sites in the body.

“The effect of age of lymph node positivity is not straightforward.  There seems to be a different effect between women aged up to 70 years and women older than 70.  For the younger group of women, age appears to have a negative effect on lymph node status – the older they become, the less likely the cancer is to have spread to the lymph nodes.  For the older group of women (aged over 70), age appears to influence lymph node status in the opposite way – the older they become, the more likely they are to have cancer cells in the lymph nodes if the tumour is small,” said Prof Wildiers, who is adjunct head of clinic in the department of general medical oncology at the Multidisciplinary Breast Centre, University Hospitals Leuven, Belgium.

“There is an interaction between age and tumour size, suggesting that, up to the age of 70, age mainly has a positive effect on lymph node status for older women with small tumours.  A likely explanation is that breast tumours metastasise less frequently to lymph nodes with increasing age due to the decreased biological aggressiveness in these tumours.  On the other hand, over the age of 70, if the tumours have the potential to metastasise to lymph nodes, this occurs more rapidly in smaller tumours and this might be related to decreased immune defence mechanisms in elderly patients.”

Prof Wildiers and his colleagues investigated 2,227 women who had been treated for breast cancer between 2000 and 2006 at the University Hospitals Leuven.  Then they compared the results with a separate database of over 11,000 breast cancer patients on the Eindhoven Cancer Registry.

They found that for women aged 70 or younger, increasing age was associated with a decreased prevalence of cancer spreading to the lymph nodes.  The women’s risk of having positive lymph nodes decreased by 13% for every decade they aged, up to age 70.

Once aged 70 and over, the odds of lymph node involvement doubled with every 10-year increase in age for women who had tumours that were no bigger than 15mm across.  If the tumours were larger than 42-43 mm, then risk of lymph node involvement continued to decrease.

Prof Wildiers said: “We know that the elderly have depressed immune defences, and, therefore, it is possible that these decreased defences are unable to prevent invasion of the lymph nodes by metastases in a subset of breast tumours in elderly women.  Although breast cancer survival in older women appears to be similar to survival in the general population irrespective of disease status, it might well be that there is a balance in the elderly between, on the one hand, a less aggressive type of tumour, and, on the other hand, their decreased immunological defences.”

He said the findings supported the idea that there are two types of tumour in elderly women: ones that are slow-growing and don’t invade the lymph nodes even if the tumours are larger, and ones that are aggressive and metastasise very early to the lymph nodes.  Women with slow-growing tumours might benefit from less aggressive treatment, while the smaller tumours in the women aged over 70 might need to be treated more aggressively.

“Further research now needs to be conducted into the role the immune system plays in lymph node invasion,” he concluded.

Reference:
Catalogue no: 401, Friday, Poster discussion session, 14.30 hrs CEST (Hall 2)

An association between chronic inflammation and cancers of the prostate, colon, stomach and liver has been suggested recently by research. Scientists now at theNorthwestern University Feinberg School of Medicine report success in blocking an early step in metastasis of prostate cancer cells by interrupting the communication between the cancer cells and other cells that promote inflammation.Their success suggests new ways to control cancer spread and metastasis. The findings also provide an impetus to look more closely at existing inflammation-controlling drugs including non-steroidal anti-inflammatory drugs, cyclooxygenase inhibitors, antioxidants and statins. It is possible, says Dr. Paul Lindholm, that these widely available drugs could be used to control aggressive cancer cell growth and spread for these and other inflammation-associated cancers.

Dr. Lindholm presented results of the study on April 8 at the Experimental Biology 2008 meeting in San Diego. The presentation was part of the scientific program of the American Society for Investigative Pathology.

In earlier studies, Dr. Lindholm and his colleagues at Northwestern found that when compared to benign prostate tissues, prostate cancer tissue has a higher density of macrophages and the monocytes from which these immune system cells derive. These scavenger cells are vital to the regulation of immune responses and the development of inflammation. High grade and high stage prostate cancer tissues showed significantly increased numbers of macrophages compared to low grade and low stage tumors. When the researchers added monocyte-like cell lines or monocytes obtained from the blood of normal people to less aggressive prostate cancer cell lines, these cancer cells became more invasive, indicating that the cancer cells and the monocytes were indeed communicating with each other. But how?

In the study reported at Experimental Biology, the researchers demonstrated that the monocyte-like cells stimulate the cancer cells’ Nuclear Factor-kappaB, a gene regulating transcription factor able to stimulate gene activity. To test whether NF-kappaB activity was increasing the cancer cells’ movement and invasive activity, the researchers then introduced into the cancer cells biological inibitors that blocks NF-kappaB activity. The treatments that block NF-kappaB activity reduced the cancer cell movement and invasion through the basement membrane (a thin, delicate layer of connective tissue underlying the epithelium of many organs).

The researchers now plan to study the effects of macrophages and inflammation and NF-kappaB inhibiting treatments in vivo, in a specially designed mouse model of invasive prostate cancer. They also plan to extend these experiments to include drugs currently used in humans to control inflammation. If anti-inflammatory drugs block cancer cell NF-kappaB activity and spreading movement, as the researchers hope, these drugs may prove useful for patients whose cancers are discovered early but who are at risk for cancer spread. The results also could help identify biomarkers of early cancer, before it can be detected by current technology, and to monitor response to treatments designed to prevent cancer spread.