Out of every hundred investigational cancer drugs that enter clinical trials, only eight prove to be sufficiently safe and effective for FDA approval. Scientists at the Dana-Faber Cancer Institute believe that those odds can be shortened by taking into account neighbouring cells in the tumour microenvironment in preclinical testing.

Although both non-malignant cells and secreted proteins from tumour and stromal cells are recognised to be active participants in cancer progression, early laboratory testing is typically carried out using homogeneous populations of tumour cells. The Dana-Faber group have now developed a tumour cell-specific in vitro bioluminescence imaging (CS-BLI) assay that is suitable for high throughput screening. Cell viability can be measured in tumour cells stably expressing luciferase in the presence or absence of non-malignant accessory cells (for example, stromal cells) or drug treatment.

Unlike conventional screening methods, CS-BLI was able to identify compounds with increased activity against tumour cells interacting with stroma. For example, reversine showed more potent activity in an orthotopic model of diffuse myeloma bone lesions than in conventional subcutaneous xenografts. CS-BLI was also able to identify stroma-induced chemo-resistance such as imatinib resistance in leukaemia cells. The use of CS-BLI should help to identify preclinical candidates that overcome stroma-mediated drug resistance as well as those that can act in a synthetic lethal manner in the context of tumour-stroma interactions, thereby increasing the chances of clinical success.

The study is published in Nature Methods.

Tau proteins interact with tubulin to stabilise microtubules and are abundant in neurons but less common in non-neuronal cells. Recently, tau proteins have received a bad press because of the association between tangles of hyperphosphorylated tau and Alzheimer’s disease and now researchers at the University of Maryland have reported that tau proteins may also play a role in tumour metastasis. Tau was found to promote formation of extensions of the plasma membrane or ‘microtentacles’ on breast cancer cells which break away from the primary tumour and circulate in the bloodstream. The microtentacles then increase the ability of the cells to attach to the walls of capillaries in the lung and seed new tumours. Tau protein has previously been associated with chemotherapy-resistant breast cancers and a poor prognosis but this is the first time that it has been implicated in metastasis. In the present study involving 102 breast cancer patients, 52% showed tau expression in metastases and 26% showed significantly increased tau expression as the disease progressed.

The team hope that drugs might be identified which will prevent the growth of microtentacles and inhibit tumour metastasis. Although current breast cancer treatments are often effective in treating the primary tumour, they are less effective in treating metastatic cancer which can develop years after the primary tumour is discovered and is the leading cause of death in cancer patients.

The study is published in the journal Oncogene.

Gene expression profiling is used to guide treatment options for women with breast cancer. Endocrine therapies – tamoxifen or aromatase inhibitors – are offered to women whose cancer is oestrogen receptor (ER) positive whilst the monoclonal antibody, trastuzumab (Herceptin®) and the small molecule, lapatinib (Tykerb®) are used to treat women whose cancer overexpresses the HER2 receptor. About 15% of breast cancers – the so-called triple negative breast cancers that don’t have receptors for oestrogen, progesterone or HER2 – don’t respond to hormone therapy or to HER2 blockers and the prognosis for women with these cancers is relatively poor.

Researchers at Washington University University School of Medicine in St. Louis have now identified a gene that is overexpressed mainly in ER-negative, HER2-negative and triple negative breast cancers, leading to the possibility of a new clinical biomarker and potential treatments. Upregulation of Wnt signalling coreceptor, LRP6 (low-density lipoprotein receptor-related protein 6), was found in about a quarter of the breast cancer samples that the researchers examined. Previous studies had shown that the protein Mesd (mesoderm development) blocks LRP6 and was able to slow the growth of cultured breast cancer cells. Mesd also inhibits the development of mammary tumours in mice, without producing known pathway-dependent side-effects such as bone lesions, skin disorders or intestinal malfunctions. A smaller fragment of Mesd was found to be as effective as full length Mesd and to have improved stability.

The study is published in the Proceedings of the National Academy of Sciences.

Although the study offers the prospect of targeted therapy for women with breast cancer that is currently difficult to treat, both screening and prescribing practices need to improve for such discoveries to realise their full potential. A recent news feature in Nature Biotechnology highlights differing views on testing as well as the problems associated with diagnostic tests for HER2 – both of which may be compromising women’s access to appropriate and effective treatment.

Compared with the genome of a normal cell, that of a cancer cell has sections that are missing, repeated or scrambled. Although some of the mutations are probably driving the cancer, others may have little relevance to the cancer’s progression. To understand which mutations are important in the development and spread of cancer, a multi-national team including researchers from the Broad Institute and the Dana-Farber Cancer Institute have studied over 3000 primary human cancer specimens representing more than 26 cancer types, including lung, prostate, breast, ovarian, colon, oesophageal, liver, brain, and blood cancers.

Classically, cancers have been classified (and treated) by their tissue of origin but, more recently, it has been realised that oncogenes are not restricted to one type of cancer. In the new study, the team found that amplifications and deletions of regions of the genome, known as somatic copy-number alterations or SCNAs, are not evenly distributed across the cancer genome but are concentrated in less gene-rich regions where they may be better tolerated. As with other mutations seen in cancer cells, many SCNAs may not play an important role in cancer growth but some will identify genes that help to promote and maintain cancers.

The most common SCNAs were found to be either relatively long (the length of an entire chromosome or a single chromosome arm) or short (about 1.8 million base pairs). More than 150 regions of short, or focal, SCNA – which because of their compact size are more likely to pinpoint important cancer-linked genes – were found to be altered at significant frequency across several cancer types. Of these, 122 did not coincide with genes already known to be amplified or deleted in cancer but the team also found copy number changes in BCL2 family genes – which are already linked to cancer and are the target of some cancer drugs – in over half of all samples. Most focal SCNAs were not unique to one type of cancer suggesting that common genetic mutations underlie different types of tumour, a finding which may lead to improved diagnosis and more targeted treatments for cancer.

The study is published in the journal Nature and the researchers have also built an online tool, the Tumorscape portal, to allow other researchers to freely access their data.

Around 85% of all tumours are epithelial in origin and have epithelial markers on the cell surfaces. In breast, ovarian, pancreatic and colon-rectal cancers, metastasis – when cells break away from the primary tumour to initiate a new tumour elsewhere in the body – is often fatal. A process known as epithelial-mesenchymal transdifferentiation (EMT) plays a role in releasing epithelial cells from the surface of solid tumours and transforming them into transient mesenchymal cells which have reduced cell-cell adhesion properties and increased ability to migrate and establish new tumours. It was already known that transforming growth factor-β (TGF-β) induces EMT but the downstream events were unclear.

Scientists in the US have now shown that TGF-β triggers the formation of a protein known as disabled-2 (Dab2) which, in turn, activates the EMT process. An increased understanding of the signalling pathway for modulating EMT could lead to the design of drugs to delay or halt EMT and control tumour metastasis. The discovery may also help to understand the progression of other diseases.

The study is published in Nature Cell Biology.

Protein kinases play important roles in regulating most cellular processes and are commonly activated in cancer cells. A number of kinase inhibitors – including antibodies and small molecules –have already been approved for the treatment of cancer and many others are currently being tested. The majority of kinase inhibitors developed so far are ATP mimetics identified by high-throughput screening of catalytic kinase domains at low ATP concentration. Such compounds – so-called type I inhibitors – may lack specificity for individual kinases and/or be less effective when ATP concentrations are high. Crystal structures have revealed that some compounds – the type II inhibitors – occupy an allosteric site accessible only in the inactive conformation of the kinase and researchers at the Moores Cancer Center at the University of California have now designed selective type II inhibitors of PDGFRβ (important for pericyte recruitment) and B-RAF (important for endothelial cell survival).

Using the X-ray crystallographic structure of the type II inhibitor, sorafenib, bound to B-RAF, the team designed a small library of compounds based on a constrained amino-triazole scaffold predicted to stabilise kinases in the inactive state. The compounds were then tested for antivascular activity in both cell-based models and a zebrafish embryogenesis model. Compound 6 was found to inhibit both PDGFRβ and B-RAF cellular signalling – which produces a synergistic effect on tumour growth – but to have no effect on a variety of other cellular targets. The compound showed antiangiogenic activity in both zebrafish and murine models of angiogenesis and was also shown to suppress murine orthotopic tumors in both the kidney and pancreas.

The study is published in the Proceedings of the National Academy of Sciences.

Despite a growing understanding that the conversion of normal cells into cancerous cells is accompanied by metabolic changes, it remains unclear whether many of these changes play crucial roles in malignancy and disease progression. Increased lipid synthesis by fatty acid synthase has been suggested to contribute to cancer growth through both metabolic and signalling pathways. Researchers at the Scripps Institute reasoned that increased lipid synthesis must be accompanied by a lipolytic pathway to liberate stored fatty acids and have now shown that levels of monoacylglycerol lipase (MAGL) are highly elevated in aggressive cancer cells compared with less aggressive cancer cells and that this lipase, through hydrolysis of monoacylglycerols (MAGs), controls free fatty acid (FFA) levels in cancer cells.

The resulting MAGL-FFA pathway promotes migration, survival, and in vivo tumour growth. Aggressive cancer cells thus partner lipogenesis with high lipolytic activity to generate an array of pro-tumorigenic signals that support their malignant behaviour. Treatment with the selective MAGL inhibitor, JZL184, significantly reduced FFA levels in aggressive cancer cells, a finding that contrasts with the function of MAGL in normal tissues, where the enzyme does not generally control FFA levels. Knock down of MAGL activity using shRNA probes in aggressive melanoma, ovarian and breast cancer cells reduced MAGL activity by 70%–80%, with corresponding elevations in MAGs and reductions in FFAs. shMAGL cancer cell lines showed reduced in vitro migration, invasion and survival under serum starvation conditions. Treatment with JZL184 also reduced cancer cell migration, but not survival, perhaps indicating that maximal effects on aggressiveness need sustained inhibition of MAGL. shMAGL cancer cells also showed markedly reduced tumour growth rates in subcutaneous xenograft transplantation studies performed in immune-deficient mice.

Daily treatment of mice bearing MAGL-expressing tumours with JZL184 (40 mg/kg po) produced similar impairments in tumour growth rates. Addition of palmitic or stearic acid, two principal FFAs regulated by MAGL in aggressive cancer cells, to cells with genetically or pharmacologically reduced levels of MAGL restored their migratory activity in vitro. Similarly, tumour growth was enhanced in MAGL-deficient xenografts when the mice were fed a high fat diet. Cancer cells engineered to stably over-express MAGL also showed significantly reduced MAGs and elevated FFAs, a profile that was accompanied by increased migration, invasion and survival in vitro and enhanced tumour growth in vivo.

The effects of MAGL on cancer aggressiveness were found not to be mediated by endocannabinoid signalling but are suggested instead to be, at least in part, caused by increased production of bioactive lipids such as LPA and PGE2 that act on GPCRs to promote high migratory activity.

Both in vitro and in vivo studies showed that aggressive cancer cells acquire the ability to liberate FFAs by increased expression of MAGL and that this contributes to the aggressive phenotype. Since MAGL is not required for cell survival, but instead promotes progression to a more aggressive phenotype, if shown to slow tumour progression in people, inhibitors of MAGL may have a better safety profile and offer advantages over existing treatments for cancer.

The study is published in the journal Cell.

Researchers in the US have shown that the COX-2 inhibitor, celecoxib, can slow the development of basal cell carcinoma. Although celecoxib was known to inhibit the development of squamous cell carcinoma in mice, and epidemiological studies had suggested a protective role in people, little was known about its efficacy in preventing the more common basal cell carcinoma. In mice with a genetic mutation similar to that which occurs in Gorin syndrome – a genetic condition which predisposes to basal cell carcinoma – deletion of the COX-1 or COX-2 gene reduced the microscopic tumour burden by 75% when the mice were exposed to ionising radiation. Treatment with celecoxib reduced the tumour burden by 35%. The overall size of the tumours was also shown to be doubled in mice engineered to overexpress COX-2.

In a planned 3-year, double-blinded, randomised clinical trial in 60 patients with Gorin syndrome, a trend towards reduced basal cell carcinoma burden was seen in all subjects receiving oral celecoxib (200mg bid). If only patients with less severe disease (less than 15 lesions at study entry) were included in the analysis, celecoxib significantly reduced basal cell carcinoma number and burden: subjects receiving placebo had a 50% increase in burden per year whereas subjects in the celecoxib group had a 20% increase. The study began recruiting in 2001 and was discontinued in 2004 when rofecoxib was withdrawn from the market amidst concerns about an association between long-term treatment with COX-2 inhibitors and increased incidence of heart attack and stroke. At that time, most patients had received celecoxib for 2 years and none had suffered cardiovascular side effects as a result of participation in the trial. Although safety concerns appear to preclude oral dosing, the researchers hope that topical application of celecoxib could provide safer, yet still effective, protection against basal cell carcinoma.

The study is published in the January issue of Cancer Prevention Research.

Epidemiological studies have also linked COX-2 inhibitor use to reduced incidence of other cancers, including colorectal cancer and breast cancer. Inhibition of the COX-2 pathway has been shown to reduce cancer cell proliferation, increase apoptosis and reduce angiogenesis, as well as modifying the immune response.

Cancer stem cells (CSCs) have been identified in a variety of tumour types, including breast tumours, and have been proposed to be responsible for recurrence, resistance to chemotherapy and, perhaps, metastasis of cancers. Targeting of these CSCs in the treatment of cancer is therefore of great interest. The ability of the ionophore antibiotic, salinomycin, to kill breast tumour CSCs was recently reported and now collaborators from the University of Michigan Comprehensive Cancer Center and the Centre de Recherche en Cancérologie de Marseille have identified a new potential drug target.

In this latest study the team identified overexpression of CXCR1, the receptor for interleukin-8 (IL-8), by the CSC subpopulation in a breast cancer cell line. Furthermore, addition of recombinant IL-8 increased the CSC population and enhanced the propensity for invasion. Conversely, use of CXCR1-blocking antibodies or repertaxin, a small-molecule CXCR1 antagonist, selectively depleted the breast CSCs both in vitro and in murine xenograft models.

CXCR1 blockade also induced massive apoptosis in bulk tumour cells, mediated by FASL/FAS signalling. The effects on CSC viability as well as FASL production were mediated by the focal adhesion kinase/AKT/forkhead transcription factor FKHRL1 (FAK/AKT/FOXO3A) pathway. Importantly, administration of repertaxin reduced tumour growth and the development of systemic breast cancer metastasis in NOD/SCID mice.

The authors of the study, published in the Journal of Clinical Investigation, suggest blockade of CXCR1 as a novel target for depletion of CSCs, potentially enhancing the efficacy of chemotherapeutic regimes.

We have previously reported on curcumin, the principal active ingredient of turmeric, which has been claimed to have activity against a variety of conditions. Now scientists at Wayne State University have explored the activity of curcumin against cancer stem cells (CSCs).

Colorectal cancer is the third most common form of cancer and, despite aggressive surgical intervention and chemotherapy, almost 50% of patients develop recurrent disease. In epithelial cancers, including colorectal cancer, growing evidence supports the hypothesis that tumour initiation and maintenance is driven by CSCs. Consequently, it is believed that failure to eliminate the underlying CSC population is responsible for cancer recurrence following therapy.

Curcumin has already been shown to have efficacy against a number of tumours in both animal models and early clinical trials. This latest study explored the activity of curcumin on colon cancer derived CSCs, either alone or in combination with the current standard treatment, FOLFOX (5-fluorouracil (5-FU) plus oxaliplatin). In cell culture experiments the researchers demonstrated that FOLFOX treatment increased the percentage of CSCs, presumably due to CSC-sparing. Treatment of these FOLFOX-surviving cells with curcumin alone or in combination with FOLFOX resulted in a marked reduction in the CSC population.

The study, published in Translational Oncology, went on to examine the potential mechanisms for the observed effects. The authors suggest that curcumin may represent a viable adjunct to current chemotherapy of colorectal cancer that could reduce rates of recurrence.