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.
The BiTE® principle
Image: Wikipedia – Anypodetos
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
, 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.
Image: Flickr - zaxl4
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.
Image: Flickr - Esther Kirby
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.
Scanning electron micrograph showing asbestos fibres; Source – Wikimedia Commons
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.
Image: Flickr - garlandcannon
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.
Image: Flickr - elektroholunder
One problem associated with the treatment of solid tumours is that chemotherapeutic agents have difficulty in penetrating more than a few cell diameters from the vasculature. Higher doses of drug are required and, because some tumour cells are not reached, the risk of recurrence is high. To address this issue, researchers at Sanford-Burnham Medical Research Institute
have now described a peptide able to enhance the ability of drugs to access tumour tissue.
Some years ago it was shown that peptides containing the RGD (Arg-Gly-Asp) sequence recognise a family of cell-surface receptors, integrins, which mediate the interaction of cells with the extracellular matrix (ECM) components fibronectin and type I collagen and are important for the migration and invasion of tumour cells. RGD peptides have been used for homing to malignant tissue and the Sanford-Burnham team have taken this a step further. The new agent is a cyclic nona-peptide (CRGDK/RGPD/EC), referred to as iRGD. The contained RGD sequence targets the agent to tumour tissue where it is cleaved to reveal a ‘CendR’ sequence that binds to neuropilin-1, mediating an active transport system.
In a paper published in Cancer Cell late last year, the research team showed that coupling iRGD to anti-cancer drugs allowed them to penetrate deep into tumours, effectively increasing the activity of the drugs. In their latest study, published in Science, the team have shown that the chemotherapeutic agents do not need to be conjugated to the peptide. Co-administration of iRGD with a variety of drugs, including a small molecule (doxorubicin), nanoparticles (nab-paclitaxel and doxorubicin liposomes), and a monoclonal antibody (trastuzumab), improved their therapeutic index.
The team hope that iRGD may be a valuable adjunct to enhance efficacy of anti-cancer agents, whilst reducing side-effects.
Image: Wikimedia Commons
For many people, the word ‘arsenic’ conjures up thoughts of murder mysteries and, in fact, arsenic has been a popular murder weapon since the middle ages. In the Victorian era, arsenic trioxide found favour as a cosmetic and it has also been used in both Chinese and Western medicine. Most recently, arsenic trioxide has been used to treat acute promyelocytic leukaemia (APL) that is unresponsive to first line therapies.
Arsenic trioxide is able to induce complete remission in patients with relapsed or refractory APL and is generally well-tolerated with minimal chemotherapy-related side effects. How arsenic trioxide kills cancer cells is not clear but scientists in China and France believe they have made a key step towards solving the mystery. APL cells are characterised by the occurrence of chromosomal translocations involving the retinoic acid receptor α gene (RARα)and the promyelocytic leukaemia gene (PML). These translocations lead to production of a fusion protein, PML-RORα that has altered functions and protects the cells from apoptosis. Arsenic trioxide triggers small ubiquitin-like modifier (SUMO) proteins to tag PML-RORα as part of a degradation mechanism. The new study has shown that the arsenic binds directly to cysteine residues in zinc fingers located within RBCC (N-terminal RING finger/B-box/coiled coil) domains of PML causing cross-linking and oligomerisation. The aggregated protein then undergoes SUMO modification and degradation. The identification of PML as a direct target of arsenic trioxide provides new insights into how the drug is able to treat APL and may lead to new treatment options.
The study is published in the journal Science.