On the 31st October, the World Cancer Research Fund published an updated report entitled Food, Nutrition, Physical Activity, and the Prevention of Cancer, listing a series of diet- and exercise-related recommendations issued by a panel of 21 world-renowned scientists. Nine academic institutions across the world were involved in the literature-based research process, which covered published data from the 1960s onwards and took over 5 years to complete. It is, to date, the most comprehensive report available on the risks posed by diet and low physical activity in developing cancer. Of all the available 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 of between 20–25 to significantly lower the chances of developing a malignant tumor. In addition to body fat, alcohol consumption should be limited to 2 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 in colorectal cancer, increasing risk by, on average, 30% in individuals consuming high quantities. Interestingly, data on the value of high fruit and vegetable intakes, as well as that of dietary supplements, remain inconclusive. Nevertheless, the panel upheld the recommended consumption of five portions of fruit and vegetables per day. The major novelty in the report relates to the link between breastfeeding and reduced breast cancer risk; data in the literature suggest that breastfeeding for 6 months can be significantly protective.
The report provides important findings as well as trustworthy, expert-issued guidelines. However, much further research is needed to identify possible risk factors and benefits related to diet. In the meantime, a well-balanced diet and adequate 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 Peter Carmeliet’s team in Belgium, undertaken in collaboration with ThromboGenics, provides evidence that inhibition of a lesser-known growth factor closely related to VEGF, known as PIGF, significantly reduced tumor growth and metastasis in 12 different murine models. Importantly, the monoclonal antibody had a similar effect on tumors resistant to conventional antiangiogenic VEGF inhibitors, thus opening up the possibility that it may become an interesting target at the human level. Contrary to its name, PIGF is not required for fetal development, in contrast to VEGF, and its baseline expression in tissues is negligible. These features make it an ideal candidate for the treatment of children and pregnant women, where anti-VEGF therapy is out of the question due to severe side effects. In addition to its success as a monotherapy, anti-αPIGF was shown to consistently enhance the antitumor effects of chemotherapy and VEGF inhibitors, without leading to the activation of hypoxia-induced angiogenic rescue mechanisms that are common with current antiangiogenic therapies. Anti-αPIGF is, in fact, better classified as an anti-inflammatory rather than an antiangiogenic. Thus, inhibition of PIGF in combination with existing VEGF inhibitors has the potential to provide a much-needed improvement in the area of antiangiogenic therapy of cancer, especially because 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 Cancer Research demonstrates, for the first time, how silencing a cytoskeletal protein can substantially ameliorate responsiveness of non-small-cell lung carcinoma (NSCLC) cell lines to combination therapy. NSCLC is the most common form of lung cancer and also the leading cause of cancer-related death. Standard nonsurgical treatment involves combinations of chemotherapy, radiotherapy and molecular-targeted drugs. As is the case for many other types of cancer, drug resistance is a major issue. In the specific case of NSCLC, one of the current treatments involves administration of a tubulin-binding agent (TBA), resulting in the abrogation of α/β-tubulin-dependent mitosis and, consequently, tumor growth arrest. However, a common problem that has been encountered is resistance to TBA administered in combination with DNA-damaging agents, a feature thought to arise from upregulation of class III β-tubulin. Maria Kavallaris and her team at the Children’s Cancer Institute Australia (CCIA) for Medical Research addressed this question by investigating how silencing this protein with siRNA in two NSCLC cell lines affects the outcome of TBA/DNA-damaging agent double therapy. In both cell lines, βIII-tubulin–siRNA cells were significantly more responsive to TBAs (paclitaxel, vincristine and vinorelbine) and also to DNA-damaging agents (cisplatin, doxorubicin and etoposide). As a proof of efficacy, βIII-tubulin–siRNA dose-dependently upregulated the expression of annexin V, a marker of cell apoptosis, when given in conjunction with either a TBA or a DNA-damaging agent, and decreased the number of cells accumulating at the G2-M (mitotic) stage of the cell cycle. According to the authors, the role of βIII-tubulin overexpression in conferring drug resistance has important implications for all cancers that are unresponsive to chemotherapeutic drugs, and has the potential to provide a novel target for cancer treatment.
Source: Gan PP, Pasquier E, Kavallaris M. Class III b-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, the herpes virus does not come across as being a particularly attractive tool to fight cancer. Nevertheless, recent preclinical studies undertaken at Louisiana State University prove the virus has great potential as a therapeutic nanotool. The team engineered the virus to attack and destroy exclusively cancerous cells, leaving healthy cells unharmed. In addition, the engineered virus also stimulates T-cell function, thus restoring adequate levels of immune responsiveness. Importantly, the virus acts as a vector and lacks the ability to replicate within normal cells, meaning that patients would not contract the actual herpes zoster virus.
A German company, MediGene Ltd, is currently performing Phase III clinical trials on one of their own engineered herpes viruses aimed at liver cancer treatment. Provisional data suggest it is effective, although Konstantin Kousoulas, Professor of Virology at Louisiana State University, is certain that his virus “has been improved beyond the 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 targeted therapies is yielding interesting results in many areas of research. In the area of colon cancer, researchers at Johns Hopkins have recently uncovered what could, potentially, be a highly successful new way to selectively target and destroy cancer cells: radioactive phosphorous-bearing small peptides. These contain less than ten amino acids, in contrast to clinically approved antibodies that contain over a thousand. The issue of selective targeting and cell entry has, indeed, been a constant limitation of radiation- or drug-bearing antibodies, hence undermining their efficacy. John Abraham and Stephen Meltzer, together with other members of their team, generated phosphorus 32P-linked small peptides and investigated their ability to enter different types of cancerous cells. To their surprise, adenocarcinoma cells ingested the most potent peptide, MA5, with an efficacy 150-times greater than that of other cell types, and at a rate of under 2 h. Also, the peptides were able to migrate through tissues up to 5 mm thick, a characteristic uncommon among antibodies. This opens up the possibility of using this technology to selectively target adenocarcinomas at both early and later stages: the former because the migration of phosphorous-labeled peptides can be followed with the use of automated isotope monitoring systems, hence localizing even small metastases; and the latter because of their ability to enter large, thick tumors. Although this novel nanotechnology is still in its infancy, it holds great promise and may, the authors hope, be developed into an effective therapeutic tool.
Source: The Johns Hopkins University Gazette www.jhu.edu/~gazette/2007/22oct07/22inside.html
Missing link between heparanase and tumor malignancy
Heparan sulphate proteoglycans (HSPGs), members of the glycosaminoglycan family of carbohydrates and closely related to heparin, are known to be ubiquitously expressed on cell surfaces, and have important functions in development, as well as during wound healing, coagulation, angiogenesis and tumor metastasis. The extensive presence of N-sulfated domains is the key structural parameter responsible for the protein-binding capabilities of HSPGs. The enzyme heparanse is known to cleave HSPGs and heparin moieties, converting them into shorter polysaccharides. Heparanase has been connected to events such as cell migration, angiogenesis and inflammation, primarily because it is found to be overexpressed in cancerous cells, the level of expression also being closely correlated to the degree of malignancy. A paper published in Nature Chemical Biology by Galvis et al. provides further support for the notion that inhibition of heparanase could be an effective new therapeutic tool in cancer treatment. Using a heparanase transgenic mouse, the researchers showed not only that tumors do indeed overexpress heparanase, but also that this results in cleavage and oversulfation of HSPG moieties. The new acquired characteristics of HSPG then translate into an increased ability to bind well-known angiogenic growth factors, such as FGF-1 and -2, thus enhancing growth factor signaling. This novel pathway firmly establishes the previously known link between heparanase overexpression, tumor malignancy and metastatic potential, thus providing novel targets for the development of anticancer therapies.
Source: Escobar Galvis ML, Jia J, Zhang X et al. Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate. Nat. Chem. Biol. 3(12), 773–778 (2007).
High doses of polyphenols are antiangiogenic
Polyphenols, at low doses equivalent to one glass of red wine a day, are known to have beneficial effects on blood circulation and prevent both cerebral and cardiac ischemia. Found mainly in red wine, green tea and grapes, polyphenols have, however, been associated with antiangiogenic properties when administered in vitro. A team of collaborating CNRS and INSERM French researchers demonstrate, in vivo, how polyphenols can have such contrasting effects. They found that this paradox is explained by dosage: low levels of polyphenols stimulate VEGF and nitric oxide synthesis resulting in increased neovascularization within the ischemic tissue, whereas high doses, equivalent to one bottle of wine per day, do the opposite, hence suggesting they may be used as an antiangiogenic therapy for cancer. Of course, red wine consumption of the order of one bottle per day would cancel out any therapeutic benefit derived from the polyphenols contained within. Therefore, the authors suggest extracting polyphenols from red wine and plants and converting them into a pill, with all the benefits of being inexpensive, easily produced and orally bioavailable.
Source: Baron-Menguy C, Bocquet A, Guihot A et al. Effects of red wine polyphenols on postischemic 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, for the first time, that levels of the tumor- suppressor p53 decline significantly with age, thus explaining how deleterious DNA mutations are more likely to become fixed in older individuals.
Often referred to as the ‘guardian of the genome’, p53 is well known for its anticancer properties resulting from its ability to stimulate DNA repair and induce apoptosis or senescence of damaged cells. In healthy cells, p53 is kept in an inactive state, allowing the cell to follow a normal cell replication cycle. The problems arise when p53, or its gene TP53, are damaged or inactivated, as is thought to occur in approximately 50% of human tumors; mutated, potentially cancerous cells are then free to undergo uncontrolled replication. For instance, the human papilloma virus induces cervical cancer by producing a protein, E6, that binds and inactivates p53. Being such a central element of cancer, research on p53 is still ongoing, even though it was identified well over 30 years ago. A study published in the October issue of Proceedings of the National Academy of Science provides new evidence to suggest a link between p53 levels and increased cancer risk with aging. The risk of developing cancer is known to increase many-fold with age; previously, this was thought to be a consequence of the accumulation of genetic mutations. This study revisits this notion by demonstrating that, not only do mutations increase with age, but p53 activity also significantly declines. They used different strains of mice, each with its own typical age span, to model their hypothesis, and found that the decline in protection provided by p53 in response to γ-irradiation correlated with age. This may, then, explain how stress-induced genetic mutations are more likely to survive and hence become an integral part of the 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 licensing of a novel, orally bioavailable, systemic treatment for hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Sorafenib (marketed by Bayer Schering Pharma under the brand name Nexavar®) is the first systemic therapy available in the UK that has been proven to significantly increase the overall survival time of patients affected by advanced HCC, as demonstrated by the Phase III, placebo-controlled sorafenib HCC Assessment Randomized Protocol (SHARP) trial. The drug improved the overall survival time by 44%, increasing it from 7.9 months in patients administered placebo to 10.7 months in those receiving sorafenib. The drug had previously been approved by the EMEA in July 2006 for the treatment of advanced renal cell carcinoma, and is currently undergoing Phase III clinical trials for the treatment of metastatic melanoma and NSCLC. Regarding its mechanisms of action, sorafenib is a small-molecule kinase inhibitor targeting PDGF receptor-B, VEGF receptors-2 and -3, c-Kit (receptor for stem cell factor) and Ras kinase, as well as inhibiting the MAPK pathway, within which Raf, MEK and ERK are pivotal in regulating cell proliferation, survival and apoptosis. Simultaneous inhibition of the kinases involved in both angiogenesis and cell proliferation is what makes sorafenib so successful in reducing cancer growth and, ultimately, prolonging patients’ lives.
Source: Bayer Schering Pharma Press Release www.bayer.co.uk