Debilitating muscle wasting or cachexia affects the majority of patients with advanced cancer but although the condition is believed to contribute to cancer-related deaths, the precise mechanisms by which cancer causes cachexia and those by which cachexia contributes to a poor prognosis are ill understood. There are currently limited treatment options for patients with cachexia, but scientists at Harvard Medical School and Amgen Research have now created a decoy receptor that can reverse cachexia in mice and increase survival, even though it has no effect on tumour growth.

ActRIIB is a high affinity activin type 2 receptor that mediates signalling by a subset of TGF-β family ligands, including myostatin, which inhibits muscle cell differentiation and growth, and activin, which is abundant in some cancer patients. Activation of ActRIIB initiates a signalling cascade that leads to increased degradation of myofibrillar proteins through the ubiquitin-proteasome pathway. In several mouse models of cachexia, administration of soluble ActRIIB (sActRIIB) was found not only to prevent further wasting but also to fully reverse both skeletal muscle loss and atrophy of the heart. Treatment with sActRIIB had no effect on fat mass or tumour growth and did not reduce elevated inflammatory cytokines, although it did stimulate feeding.

The study, which is published in the journal Cell, suggests that blocking the ActRIIB pathway has the potential to treat various muscle wasting diseases, particularly cancer cachexia, and if the results of the mouse studies translate to people, could also prolong the lives of cancer patients.

T-cell receptors are integral membrane proteins that recognise foreign antigens and initiate a series of intracellular signalling cascades that allow the immune system to fight infection. To avoid autoimmune diseases, T-cells must be able to discriminate between ‘self’ and ‘foreign’ antigens but this discrimination may also prevent the immune system from recognising and destroying tumour cells.

Researchers led by a team from the Max-Delbrück-Center for Molecular Medicine have now developed transgenic mice that produce T-cell receptors that recognise human cancer cell antigens and could potentially be introduced into the T cells of cancer patients. Using embryonic stem cells loaded with human DNA, the team generated transgenic mice that express the entire human T-cell repertoire. Negative selection normally removes maturing T-cells that are capable of binding strongly to ‘self’ antigens but the mouse does not recognise human cancer cell antigens as ‘self’ and T-cells expressing receptors to these antigens are allowed to survive. T-cells with such high affinity receptors for cancer cell antigens are not produced in humans and the researchers hope that introducing the high affinity receptors into the T-cells of cancer sufferers will boost the immune system’s ability to recognise and destroy tumour cells. A first clinical trial to evaluate the efficacy and tolerability of the methodology in cancer patients is planned.

The study is published in the journal Nature Medicine.

Despite its reputation as a poison, arsenic has long been used in Chinese medicine and, more recently, arsenic trioxide has been successfully used to treat acute promyelocytic leukaemia (APL). The drug has poor activity against solid tumours, however, probably because it is rapidly excreted. Attempting to address this, researchers at Northwestern University have packaged arsenic trioxide in nanoparticles.

These nanoparticles, termed nanobins, are composed of nanoparticulate arsenic trioxide encapsulated in liposomes. A second chemical layer provides protection for both the cargo and normal cells until the particle reaches its target. The nanoparticles concentrate at their target, as a consequence of the leaky blood vessels that characterise solid tumours, and release their toxic payload.

In the current study, published in Clinical Cancer Research, the researchers investigated the activity of arsenic nanobins against a panel of human breast cancer cell lines. Although less cytotoxic than free arsenic trioxide in vitro, the nanobins had dramatically enhanced efficacy in an in vivo model of triple-negative breast cancer. The scientists observed reduced plasma clearance, increased tumour uptake and induction of tumour cell apoptosis for the nanobins.

Triple negative breast cancer, in which the receptors for oestrogen, progesterone and Her2 are absent, is an aggressive cancer that often responds poorly to conventional chemotherapy. There is a high risk of metastatis and survival rates are low. Although at an early stage, the researchers anticipate that the nanobin technology could provide the means to increase the efficacy of a number of cytotoxic drugs against a range of tumours, whilst reducing general toxicity.

Whilst the effects of social and environmental factors on many aspects of health are relatively well understood, their influence on the progression of systemic cancer is much less well defined. A team of investigators led by scientists at The Ohio State University have now investigated the effect of an enriched environment – a more challenging setting that causes mild stress – on the growth of cancer in mice. The study found that an enriched environment – consisting of more complex housing, regular exposure to novel objects, and more exercise and social stimulation – led to a remarkable suppression of cancer proliferation in models of melanoma and colon cancer, even if delayed until the tumour was well established.

The researchers went on to identify the molecular pathways involved and discovered the enriched environment led to activation of a system known as the hypothalamic-sympathoneural-adipocyte (HSA) axis by brain-derived neurotrophic factor (BDNF). Activation of the HSA axis is proposed to increase sympathetic nervous system outflow to adipocytes, resulting ultimately in reduced secretion of leptin and increased secretion of adiponectin. The β-blocker, propanolol, was shown to inhibit the changes in circulating levels of leptin and adiponectin brought about by an enriched environment and also to block the inhibition of tumour growth, suggesting a link between β-adrenergic activity in white adipose tissue, circulating leptin/adiponectin levels and tumour growth.

The researchers propose that adipokines, released by white adipose tissue in response to hypothalamic BDNF-induced sympathetic outflow caused by mild stress, act as the major downstream effectors of a complex regulatory network leading to the antiproliferative phenotype. Direct gene transfer of BDNF was found to mimic the beneficial effects of an enriched environment, suggesting that either pharmacological or environmental induction of hypothalamic BDNF could slow the growth of tumours.

The study is published in the journal Cell.

The concept of bispecific antibodies – monoclonal antibodies able to recognise and engage two different antigens – has been explored for over twenty years. Development of therapies based on the approach has, however, been hampered by difficulties in their construction, poor efficacy and undesirable side-effects.

One particular subset of bispecific antibodies, the so-called bispecific T-cell engager (BiTE®), has nevertheless begun to show promise. Blinatumomab, developed by Micromet, targets the CD19 receptor of B-cells and CD3 on T-cells and is designed to direct cytotoxic T-cells to B-cell tumours. Interim data from a phase I trial in Non-Hodgkin’s Lymphoma patients have shown signs of clinical efficacy and additional clinical trials in acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are ongoing.

More recently, the Micromet team have reported on preclinical data using BiTE® antibodies targeting the EGFR receptor and CD3, incorporating the binding domains of either panitumumab or cetuximab. Panitumumab and cetuximab, as well as EGFR kinase inhibitors, are marketed for treatment of colorectal cancer (CRC) and primarily inhibit CRC growth by interfering with EGFR signalling. CRC patients whose tumours have mutated KRAS or BRAF, however, are resistant to treatment. This latest study, published in Proceedings of the National Academy of Sciences, showed that both EGFR-specific BiTE® antibodies mediated potent redirected lysis of KRAS- and BRAF-mutated CRC lines by human T cells at subpicomolar concentrations. The cetuximab-based BiTE® antibody also inhibited growth of tumours from KRAS- and BRAF-mutated human CRC xenografts, whereas cetuximab was not effective. The researchers also report preliminary safety data in non-human primates and conclude that EGFR-specific BiTE® antibodies may have potential to treat CRC that does not respond to conventional antibodies.

Regular use of NSAIDS has been linked to reduced incidence of certain types of cancer but the underlying protective mechanisms are unclear. Some of the anticancer effects are believed to be mediated through inhibition of COX-2, but a study led by investigators at Sanford-Burnham Medical Research Institute has now identified another mechanism by which the sulindac sulfide (the NSAID metabolite of sulindac) inhibits tumour growth. The team found that sulindac sulfide induces apoptosis by binding to retinoid X receptor-α (RXRα), a member of the nuclear hormone receptor family which had been already been identified as a potential target for cancer therapy. In cancer cells, levels of RXRα are often reduced, at least in part because of proteolytic processing to a truncated form, tRXRα. As with other nuclear receptors, RXRα regulates transcription of target genes by binding to DNA response elements but accumulating evidence suggests that RXRα may also have extranuclear activity. Both RXRα and tRXRα can exist in the cytoplasm and the study showed that cytoplasmic tRXRα can activate the PI3K/AKT survival pathway by interaction with the p85a subunit of PI3K, leading to anchorage-independent cell growth in vitro, and tumour growth in animals. Sulindac sulfide was found to inhibit the tRXRα-mediated PI3K/AKT activation, suggesting that the compound could provide a useful lead for anti-cancer drugs targeting this pathway.

The use of NSAIDs to reduce the incidence of cancer has been limited by the risk of major cardiovascular events and the Sanford-Burnham have identified an analogue of sulindac sulfide, K-80003 which has improved affinity for RXRα but lacks significant COX-2 inhibitory activity. K-80003 inhibited the growth of cancer cells in vitro and in animals and would be expected to have reduced COX-2-associated side effects.

The study is published in the journal Cancer Cell.

The cytoskeleton plays a key role in regulating many cellular functions; it maintains cell shape, protects the cell, enables cellular motion, and has important roles in proliferation and differentiation. Metastasising cancer cells exploit the cytoskeleton to produce protrusions that allow them to invade surrounding tissue and enter the blood system from where they can spread to distant tissues and seed new tumours.

The protrusions, known as pseudopodia, are highly specialised ‘feet’ that the cell uses to pull itself forward across the underlying surface. A team led by researchers at the University of California, San Diego has now identified a previously unknown kinase – termed pseudopodium-enriched atypical kinase one or PEAK1 – that regulates the cytoskeleton and plays a central role in the formation of pseudopodia. Preliminary studies in mice suggest that PEAK1 is important during tumour growth and the team also showed that PEAK1 levels are increased in primary and metastatic samples from human colon cancer patients. Whether PEAK1 is capable of transforming non-tumour cells into cancer cells has not yet been determined but the fact that PEAK1 has kinase activity suggests that it may be possible to design specific inhibitors which could help to elucidate its role in both normal and cancer cells. PEAK1, which is a 190-kDa non-receptor tyrosine kinase, could serve as a clinical biomarker that predicts whether a cancer is likely to metastasise and could also be a target for future cancer treatments.

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

Programmed cell death (apoptosis) is essential to maintain homeostasis within living organisms and is controlled by a variety of intra- and extra-cellular signals. Activation of the death receptor CD95 (also known as Fas or Apo-1) by its physiological ligand, CD95 ligand (Fas ligand), leads to apoptosis in many tissues and is especially important in the immune system.

Resistance to apoptosis is also key to the survival of malignant cells but the role of CD95 in cancer progression is complex: although the down-regulation of CD95 that is frequently observed in tumour cells could contribute to their survival, complete loss of CD95 is rare in human cancers. On the other hand, many cancer cells express large quantities of CD95 and are highly sensitive to CD95-mediated apoptosis in vitro. Cancer patients often have high levels of CD95 ligand, suggesting that CD95 could perhaps promote the growth of tumours through non-apoptotic activities. Scientists from the University of Chicago and Northwestern University Feinberg School of Medicine have further investigated the role of CD95 in several human cancer cell lines and in mouse models of liver and ovarian cancer. Cancer cells – regardless of their sensitivity to CD95-mediated apotosis – were found to produce CD95 ligand and to depend on constitutive activity of CD95 for optimal growth. In the mouse models, deletion of CD95 reduced both the incidence and size of tumours. In further studies, the tumour promoting activity of CD95 was shown to be mediated by pathways involving JNK and Jun but not caspase-8.

The study, which is published in Nature, suggests that, paradoxically, reducing rather than enhancing activity of the death receptor CD95 may be an effective way to control the growth and proliferation of cancer cells. Further research is needed to understand the switch between signalling ‘die’ and ‘grow’, but eventually soluble CD95 or antibodies against CD95 ligand could find a role in the treatment of cancer.

MicroRNAs (miRNAs) are small (21-23 nucleotides), single-stranded RNA molecules that function as regulators of gene expression. The human genome encodes several hundred miRNAs and abnormal expression of these has been associated with cancer progression. We have previously reported on miRNA involvement in cholesterol regulation, amyotrophic lateral sclerosis and liver cancer. Now a collaboration between Rosetta Genomics, NYU Langone Medical Center and Vanderbilt School of Medicine has identified the potential utility of miR-33 for development of therapies targeting malignant mesothelioma (MM).

MM is a rare cancer that has been associated with exposure to asbestos dust (although a small proportion of patients have never been exposed). Taking anywhere between 20 and 50 years for symptoms to develop, the cancer affects the mesothelium, a thin layer of tissue surrounding the internal organs. The most common form of MM is pleural, involving the lining of the lungs, but it may also affect other tissues such as the peritoneum. Current treatment options, including surgery and chemotherapy, are limited and often confounded by late diagnosis because of the absence of symptoms.

This latest study found that MM cell lines derived from patients with aggressive disease failed to express miR-31, a microRNA that has also been linked to suppression of breast cancer metastasis. Functional studies, where miR-31 was reintroduced to the cells, showed that the microRNA could inhibit proliferation, migration, invasion, and clonogenicity of mesothelioma cells. miR-31 suppressed expression of a number of factors associated with maintenance of DNA replication and cell cycle progression, including the pro-survival phosphatase PPP6C. The mRNA for PPP6C, which contains three miR-31-binding sites in its 3′-UTR, was down-regulated when miR-31 was present and up-regulated in clinical MM specimens compared to matched normal tissues.

Whilst the study, published in the Journal of Biological Chemistry, reveals a key role for miR-31 in MM, considerable challenges remain to exploit this finding for therapy of the disease.

To ensure normal growth and avoid tumour formation, cell division must be tightly regulated. Remarkably, many cells from species as diverse as single celled organisms and humans only divide at certain times of the day, suggesting that division is under the control of a circadian clock. The evolutionary explanation put forward for this is a selective advantage for organisms with cells that divide at night when the mutational effects of ultraviolet light are lowest.

It has been proposed that the uncontrolled growth shown by tumour cells is caused by fault in the biological clock but a study by researchers at Vanderbilt University has now shown that although immortalised rat fibroblasts have functioning clocks, the clocks don’t control the rate at which the cells divide and grow. Similar results were seen in preliminary experiments with lung cancer cells. If follow-up studies confirm that control of cell cycle by circadian rhythm has been lost in immortalised cells, the research may suggest new targets for cancer therapy.

The study is published in PNAS.