10.1586/14737140.7.12.1695 © 2007 Future Drugs Ltd ISSN 1473-7140 1695

News in Brief

Body fat, alcohol and red meat:

culprits in increased cancer riskOn the 31st October, the World Cancer Research Fund published an updated reportentitled Food, Nutrition, Physical Activity, and the Prevention of Cancer, listing a series ofdiet- and exercise-related recommendations issued by a panel of 21 world-renownedscientists. Nine academic institutions across the world were involved in the literature-

based research process, which covered published data from the1960s onwards and took over 5 years to complete. It is, to date,the most comprehensive report available on the risks posed bydiet and low physical activity in developing cancer. Of all theavailable data, 7000 reports were chosen for their relevance and

experimental robustness. As expected, the influence of body fat on increasing cancer risk

was found to be highly convincing for six types of cancer: esophageal,colorectal, pancreatic, endometrial, kidney and postmenopausal cancer.

Hence, experts recommend maintaining a healthy body weight and a BMI ofbetween 20–25 to significantly lower the chances of developing a malignanttumor. In addition to body fat, alcohol consumption should be limited to2 units per day for men and 1 unit for women, as the evidence suggesting a

role for alcohol in cancer is, according to the report, irrefutable.Processed and red meats stand out as being major contributors incolorectal cancer, increasing risk by, on average, 30% in individuals

consuming high quantities. Interestingly, data on the value of high fruitand vegetable intakes, as well as that of dietary supplements, remain inconclusive. Never-theless, the panel upheld the recommended consumption of five portions offruit and vegetables per day. The major novelty in the report relatesto the link between breastfeeding and reduced breast cancerrisk; data in the literature suggest that breastfeeding for6 months can be significantly protective.

The report provides important findings as well as trust-worthy, expert-issued guidelines. However, much furtherresearch is needed to identify possible risk factors and ben-efits related to diet. In the meantime, a well-balanced diet andadequate physical activity seem to provide the best protective effects.

Source: World Cancer Research Fund Press Release, October 31st, 2007 www.wcrf-uk.org

Anti-PIGF: an effective inhibitor of resistant tumor growth

An elegant study published by PeterCarmeliet’s team in Belgium, undertakenin collaboration with ThromboGenics,provides evidence that inhibition of alesser-known growth factor closely relatedto VEGF, known as PIGF, significantlyreduced tumor growth and metastasis in

12 different murine models. Importantly,the monoclonal antibody had a similareffect on tumors resistant to conventionalantiangiogenic VEGF inhibitors, thusopening up the possibility that it maybecome an interesting target at the humanlevel. Contrary to its name, PIGF is notrequired for fetal development, in contrastto VEGF, and its baseline expression in tis-sues is negligible. These features make it an

ideal candidate for the treatment of chil-dren and pregnant women, where anti-VEGF therapy is out of the question dueto severe side effects. In addition to its suc-cess as a monotherapy, anti-αPIGF wasshown to consistently enhance the antitu-mor effects of chemotherapy and VEGFinhibitors, without leading to the activa-tion of hypoxia-induced angiogenic rescuemechanisms that are common with cur-rent antiangiogenic therapies. Anti-αPIGFis, in fact, better classified as an anti-inflammatory rather than an anti-angiogenic. Thus, inhibition of PIGF incombination with existing VEGF inhibi-tors has the potential to provide a much-needed improvement in the area of anti-angiogenic therapy of cancer, especiallybecause of its excellent safety profile.

Source: Fischer C, Jonckx B, Mazzone M et al.

Cell 131, 463–475 (2007).

Inhibition of a cytoskeletal protein as a therapy for

non-small-cell lung carcinoma

A recent study published in CancerResearch demonstrates, for the first time,how silencing a cytoskeletal protein can

substantially ameliorate responsiveness ofnon-small-cell lung carcinoma (NSCLC)cell lines to combination therapy. NSCLCis the most common form of lung cancerand also the leading cause of cancer-relateddeath. Standard nonsurgical treatmentinvolves combinations of chemotherapy,radiotherapy and molecular-targeted drugs.As is the case for many other types of can-cer, drug resistance is a major issue. In thespecific case of NSCLC, one of the currenttreatments involves administration of atubulin-binding agent (TBA), resulting inthe abrogation of α/β-tubulin-dependentmitosis and, consequently, tumor growtharrest. However, a common problem thathas been encountered is resistance to TBAadministered in combination with DNA-damaging agents, a feature thought to arise

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News in Brief

1696 Expert Rev. Anticancer Ther. 7(12), (2007)

from upregulation of class III β-tubulin.Maria Kavallaris and her team at the Chil-dren’s Cancer Institute Australia (CCIA)for Medical Research addressed this ques-tion by investigating how silencing thisprotein with siRNA in two NSCLC celllines affects the outcome of TBA/DNA-damaging agent double therapy. In bothcell lines, βIII-tubulin–siRNA cells weresignificantly more responsive to TBAs(paclitaxel, vincristine and vinorelbine)and also to DNA-damaging agents (cisp-latin, doxorubicin and etoposide). As aproof of efficacy, βIII-tubulin–siRNAdose-dependently upregulated the expres-sion of annexin V, a marker of cell apop-tosis, when given in conjunction witheither a TBA or a DNA-damaging agent,and decreased the number of cells accu-mulating at the G2-M (mitotic) stage ofthe cell cycle. According to the authors,the role of βIII-tubulin overexpression inconferring drug resistance has importantimplications for all cancers that are unre-sponsive to chemotherapeutic drugs, andhas the potential to provide a novel targetfor cancer treatment.

Source: Gan PP, Pasquier E, Kavallaris M. Class III

β-tubulin mediates sensitivity to chemotherapeutic

drugs in non small cell lung cancer. Cancer Res. 67,

9356–9363 (2007).

Herpes virus to fight breast cancer

Normally associated with cold sores, theherpes virus does not come across asbeing a particularly attractive tool to fightcancer. Nevertheless, recent preclinicalstudies undertaken at Louisiana StateUniversity prove the virus has greatpotential as a therapeutic nanotool. Theteam engineered the virus to attack anddestroy exclusively cancerous cells, leavinghealthy cells unharmed. In addition, theengineered virus also stimulates T-cellfunction, thus restoring adequate levels ofimmune responsiveness. Importantly, thevirus acts as a vector and lacks the abilityto replicate within normal cells, meaningthat patients would not contract theactual herpes zoster virus.

A German company, MediGene Ltd, iscurrently performing Phase III clinical trialson one of their own engineered herpesviruses aimed at liver cancer treatment. Pro-visional data suggest it is effective, althoughKonstantin Kousoulas, Professor of Virol-ogy at Louisiana State University, is certainthat his virus “has been improved beyondthe capabilities of MediGene’s virus.”

Source: Louisiana State University. Herpes virus

can be used as nanomachines for cancer treatment

www.sciencedaily.com-/releases/2007/10/

071016093219.htm

Improved efficacy of small peptides versus antibodies

The ongoing search for better targetedtherapies is yielding interesting results inmany areas of research. In the area of coloncancer, researchers at Johns Hopkins haverecently uncovered what could, potentially,be a highly successful new way to selec-tively target and destroy cancer cells: radio-active phosphorous-bearing small peptides.These contain less than ten amino acids, incontrast to clinically approved antibodiesthat contain over a thousand. The issue ofselective targeting and cell entry has,indeed, been a constant limitation of radia-tion- or drug-bearing antibodies, henceundermining their efficacy. John Abra-ham and Stephen Melt-zer, together with othermembers of their team,generated phosphorus32P-linked smallpeptides andinvestigated theirability to enterdifferent types ofcancerous cells. Totheir surprise, adeno-carcinoma cells ingestedthe most potent peptide, MA5,with an efficacy 150-times greaterthan that of other cell types, and at a rate ofunder 2 h. Also, the peptides were able tomigrate through tissues up to 5 mm thick,a characteristic uncommon among anti-bodies. This opens up the possibility ofusing this technology to selectively target

adenocarcinomas at both early and laterstages: the former because the migration ofphosphorous-labeled peptides can be fol-lowed with the use of automated isotopemonitoring systems, hence localizing evensmall metastases; and the latter because oftheir ability to enter large, thick tumors.Although this novel nanotechnology is stillin its infancy, it holds great promise andmay, the authors hope, be developed intoan effective therapeutic tool.

Source: The Johns Hopkins University Gazette

www.jhu.edu/~gazette/2007/22oct07/22inside.html

Missing link between heparanase and

tumor malignancyHeparan sulphate proteoglycans (HSPGs),members of the glycosaminoglycan familyof carbohydrates and closely related toheparin, are known to be ubiquitouslyexpressed on cell surfaces, and have impor-tant functions in development, as well asduring wound healing, coagulation, angio-genesis and tumor metastasis. The exten-sive presence of N-sulfated domains is thekey structural parameter responsible forthe protein-binding capabilities ofHSPGs. The enzyme heparanse is knownto cleave HSPGs and heparin moieties,converting them into shorter polysaccha-

rides. Heparanase has been connectedto events such as cell migration, angio-genesis and inflammation, primarilybecause it is found to be overexpressed

in cancerous cells, the level ofexpression also being closelycorrelated to the degree of

malignancy. A paper publishedin Nature Chemical Biology by

Galvis et al. provides furthersupport for the notion thatinhibition of heparanase

could be an effective new therapeutic toolin cancer treatment. Using a heparanasetransgenic mouse, the researchers showednot only that tumors do indeed over-express heparanase, but also that thisresults in cleavage and oversulfation ofHSPG moieties. The new acquired char-acteristics of HSPG then translate into an

News in Brief

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increased ability to bind well-known ang-iogenic growth factors, such as FGF-1and -2, thus enhancing growth factor sig-naling. This novel pathway firmly estab-lishes the previously known link betweenheparanase overexpression, tumor malig-nancy and metastatic potential, thus pro-viding novel targets for the developmentof anticancer therapies.

Source: Escobar Galvis ML, Jia J, Zhang X et al.

Transgenic or tumor-induced expression of hepara-

nase upregulates sulfation of heparan sulfate.

Nat. Chem. Biol. 3(12), 773–778 (2007).

High doses of polyphenols are antiangiogenic

Polyphenols, at low doses equivalent toone glass of red wine a day, are known tohave beneficial effects on blood circulationand prevent both cerebral and cardiacischemia. Found mainly in red wine, greentea and grapes, polyphenols have, how-ever, been associated with antiangiogenicproperties when administered in vitro. Ateam of collaborating CNRS andINSERM French researchers demonstrate,in vivo, how polyphenols can have suchcontrasting effects. They found that thisparadox is explained by dosage: low levelsof polyphenols stimulate VEGF and nitricoxide synthesis resulting in increased neo-vascularization within the ischemic tissue,whereas high doses, equivalent to one bot-tle of wine per day, do the opposite, hencesuggesting they may be used as anantiangiogenic therapy for cancer. Ofcourse, red wine consumption of the orderof one bottle per day would cancel out anytherapeutic benefit derived from thepolyphenols contained within. Therefore,the authors suggest extracting polyphenolsfrom red wine and plants and convertingthem into a pill, with all the benefits ofbeing inexpensive, easily produced andorally bioavailable.

Source: Baron-Menguy C, Bocquet A, Guihot A

et al. Effects of red wine polyphenols on pos-

tischemic neovascularization model in rats: low

doses are proangiogenic, high doses anti-angiogenic.

FASEB 21, 3511–3521 (2007).

Tumor suppressor p53 declines with age

Researchers in the USA demonstrate, forthe first time, that levels of the tumor-suppressor p53 decline significantly withage, thus explaining how deleteriousDNA mutations are more likely tobecome fixed in older individuals.

Often referred to as the ‘guardian of thegenome’, p53 is well known for its anti-cancer properties resulting from its abilityto stimulate DNA repair and induceapoptosis or senescence of damaged cells.In healthy cells, p53 is kept in an inactivestate, allowing the cell to follow a normalcell replication cycle. The problems arisewhen p53, or its gene TP53, are damagedor inactivated, as is thought to occur inapproximately 50% of human tumors;mutated, potentially cancerous cells arethen free to undergo uncontrolled replica-tion. For instance, the human papillomavirus induces cervical cancer by producinga protein, E6, that binds and inactivatesp53. Being such a central element ofcancer, research on p53 isstill ongoing, even though itwas identified well over 30years ago. A study published inthe October issue of Proceed-ings of the National Academy of Sci-ence provides new evidence tosuggest a link between p53 levelsand increased cancer risk with aging.The risk of developing cancer isknown to increase many-fold with age;previously, this was thought to be a conse-quence of the accumulation of geneticmutations. This study revisits this notionby demonstrating that, not only do muta-tions increase with age, but p53 activityalso significantly declines. They used dif-ferent strains of mice, each with its owntypical age span, to model their hypothe-sis, and found that the decline in protec-tion provided by p53 in response toγ-irradiation correlated with age. Thismay, then, explain how stress-inducedgenetic mutations are more likely to sur-vive and hence become an integral part ofthe genome, in older individuals.

Source: Feng Z, Hu W, Teresky AK et al. Proc. Natl

Acad. Sci. 104(42),16633–16638 (2007).

New drug launched in the UK for treatment of hepatocellular carcinoma

The European Medicines Agency(EMEA) has recently approved licensingof a novel, orally bioavailable, systemictreatment for hepatocellular carcinoma(HCC), the most common form of pri-mary liver cancer. Sorafenib (marketedby Bayer Schering Pharma under thebrand name Nexavar®) is the first sys-temic therapy available in the UK thathas been proven to significantly increasethe overall survival time of patientsaffected by advanced HCC, as demon-strated by the Phase III, placebo-control-led sorafenib HCC Assessment Rand-omized Protocol (SHARP) trial. Thedrug improved the overall survival timeby 44%, increasing it from 7.9 monthsin patients administered placebo to10.7 months in those receiving sorafenib.The drug had previously been approvedby the EMEA in July 2006 for the treat-ment of advanced renal cell carcinoma,and is currently undergoing Phase IIIclinical trials for the treatment of meta-

static melanoma and NSCLC.Regarding its mechanisms of action,

sorafenib is a small-moleculekinase inhibitor targeting PDGFreceptor-B, VEGF receptors-2

and -3, c-Kit (receptor for stemcell factor) and Ras kinase, as

well as inhibiting the MAPKpathway, within which Raf,

MEK and ERK are pivotal in regu-lating cell proliferation, survival andapoptosis. Simultaneous inhibition of thekinases involved in both angiogenesisand cell proliferation is what makes sor-afenib so successful in reducing cancergrowth and, ultimately, prolongingpatients’ lives.

Source: Bayer Schering Pharma Press Release

www.bayer.co.uk