A drug which makes a wide range of cancers more vulnerable to the body’s immune system is “exciting” and may mark a new era, say doctors. It strips cancer cells of the “camouflage” they use to evade attack by the immune system. In the most detailed study, published in Nature, some patients completely recovered from terminal bladder cancer. Cancer Research UK said the field of immunotherapy was delivering “a lot of very exciting results”. The immune system is in delicate balance with some chemicals in the body encouraging a strong vigorous response, while others try to dampen it down. Tumours can hijack this system to hide from the immune system. One trick which tumours use is a protein called PD-L1 which is normally used to prevent autoimmune diseases.

An international team of scientists has been trialling a drug to block PD-L1, produced by the company Roche, on 68 people with advanced bladder cancer. All the patients had tried chemotherapy and had been given six-to-eight months to live. More than half the patients, whose tumours were using PD-L1 to hide from the immune system, showed signs of recovery. In two patients there were no signs of cancer after the treatment. One in ten patients responded to the experimental therapy even if PD-L1 was not present in the tumour. Dr Tom Powles, an oncologist at the Barts Cancer Institute at Queen Mary University of London and part of the research team, said “There have been no new drugs for bladder cancer for 30 years.”The tumours have developed a camouflage layer, PD-L1, and by removing the camouflage the tumour becomes identifiable. “A subgroup of patients seems to do exceptionally well.” Dr Powles is funded by the NHS and receives no money from Roche. The drug has been given “breakthrough therapy” status in the US and could be used widely by patients there at the end of 2015, if a larger trial shows the same results. Much larger randomised clinical trials would be needed in order for the experimental therapy to be used in Europe.

A team at the Cancer Research UK London Research Institute, identified a critical pathway of molecular signals which throw a lifeline to cancer cells, enabling them to survive even though they contain vast DNA errors which would usually trigger cell death. The findings, published in Nature Communications, revealed that cancer cells use a new line of defense to evade cell death.

The PKCƐ signal pathway, which prevails in cancer cells but rarely in normal cells, could be important in targeting some cancer cells as they rely on this pathway to survive. The pathway assists the cancer cells in untangling and separating their DNA, ensuring they continue to survive. As shown from study, the pathway can overcome that survival challenge of cancer cells that DNA is more jumbled and prone to becoming tangled.

A major finding

The researchers found that turning off the pathway can trigger cancer cells to self-destruct. It is because the machinery used to untangle the DNA fails, meaning it is torn apart as the cell divides — ravaging and causing huge breaks in the code which lead to the cancer cells’ demise.

As a researcher said, halting this line of defence could be a powerful way to target the disease and re-program cancer cells to self-destruct. The next step is to understand which cancer types have this weak point and to look for a marker that will allow us to test patients for cancers with this flaw.

Although there is still a lot of work to do before this research leads to a new cancer treatment, it offers us a new strategy to beat the disease by helping us to understand what causes and drives cancer.

Reference:

Mitotic catenation is monitored and resolved by a PKCε-regulated pathway. Nature Communications, December 2014

In a study, scientists found a molecule-based approach to halting a genetic fault called 3q26.2 amplicon, which can cause real havoc. By manipulating a non-coding microRNA (miRNA) known as miR569 that is part of the amplicon, scientists were able to increase cell death in vitro and in vivo. For many cancers, including ovarian and breast cancers, the amplicon carries the most frequent chromosomal aberrations.

As known in the biomedical circle, MicroRNAs are short, non-coding RNA molecules that are important to controlling gene expression. The molecules can represent underexplored targets of genetic aberrations and emerging therapeutic targets.

The study showed that miR569, which is overexpressed in a subset of ovarian and breast cancers due in part to the 3q26.2 amplicon, can impact cell survival and proliferation. In order for miR69 to halt 3q26.2′s penchant for molecular mayhem, it must first alter expression levels of the tumor protein known as TP53INP1.

It is clearly demonstrated that TP53INP1 is a key target of miR569 both in vitro and in vivo. An increase in miR569 levels subsequently decreased TP53INP1 levels which was associated with worsened outcomes for ovarian patients.

However, when miR569 expression was “silenced” or decreased, TP53INP1 levels were increased and survivability outcomes improved. In effect, targeting miR569 sensitizes ovarian and breast cancer cells overexpressing miR569 to the commonly used chemotherapy agent cisplatin, which impacts its effectiveness.

The discovery that miRNAs are potent regulators of RNA stability and translation dramatically change current understanding of the mechanisms controlling protein levels, and further provided a therapeutic approach to a number of targets that have previously been designated as ‘undruggable’.

According to the research from the University of Eastern Finland, the expression of SIP1 protein in pharyngeal squamous cell carcinoma tumors often indicates an advanced tumour stage, a high risk of recurrence and a poor prognosis. Their study demonstrates that SIP1 is a potential new prognostic factor for clinical use. This finding was published in BMC Cancer.

Pharyngeal squamous cell carcinoma (PSCC) is a rather rare disease and its incidence has been increasing over the past three decades. The prognosis is one of the poorest of all the head and neck squamous cell carcinimas and it has not improved to any significant extent. In addition, Epithelial-mesenchymal transition (EMT) is a complex cellular process which is not only crucial for embryogenesis, but it is also activated during tumour progression enabling tumour cells to become invasive and to metastases.

In this study, for the first time, Scientists try to assess the role of EMT-related transcription factors in PSCC. The immunohistochmical expressions of transcription factors SNAI1, TWIST, SIP1, SLUG and ZEB1 were analysed in tumour cells, stomal and endothelial cell nuclei, as well as in cytoplasm of PSCC samples in an effort to evaluate the association of their expressions with clinicopathological variables and patient prognosis.

Tumor with positive epithelial nucleal SIP1 immustaining were more advanced and had more lymph node metastases. The expression of SIP1 was also linked to poorer disease-specific five-year survival and was an independent prognostic factor in multivariate analysis together with tumour size and general patient status.

Scientists from Dartmouth the Geisel School of Medicine have developed a new fluorescence imaging technique that can more accurately identify receptors for targeted cancer therapies without tissue biopsy. This study was published in Cancer Research.

Protein overexpression is a hallmark of certain cancers and is used in clinical oncology to personalize treatment through tumor detection, molecular therapies, and therapeutic monitoring. Protein expression is currently measured through a total protein analysis of tumor tissue.

In this study, researchers developed a dual-tracer in vivo receptor concentration imaging (RCI) technique that involves the simultaneous injection of both a targeted and non-targeted imaging agent. They found that the protein expression determined by RCI strongly correlated to that determined by tissue analysis. They also found that commonly used techniques of measuring protein expression, such as western blots of flow cytometry, did not correlate to the RCI values, and in fact over-predicted the number of receptors available for therapeutic or diagnostic targeting.

Accurately determining the population of protein receptors in a tumor available for targeting by molecular therapies or diagnostic imaging agents can greatly impact oncology patient outcomes. This new technique allows scientists to accurately determine the amount of protein receptors available for binding a drug without invasive biopsy. The next step of the study will be to look at tumors on a microscopic level in order to correlate receptor expression to distinct physiological features such as cellular viability, cellular type, vascularity, and overall tumor architecture.

Reference:Samkoe K S, Tichauer K M, Gunn J R, et al. Quantitative in vivo immunohistochemistry of epidermal growth factor receptor using a receptor concentration imaging approach[J]. Cancer research, 2014: canres. 0141.2014.

Interleukin-11 is the dominant il-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically.

Australian researchers found that the interleukin-11 may be the potential target during the therapy of the cancer. This research indicated that blocking the signal of the interleukin-11 might become the therapy of the cancer that included the bowel cancer and the stomach cancer. This study was published on the Cancer Cell.

Among the cytokines linked to inflammation-associated cancer, interleukin (IL)-6 drives many of the cancer “hallmarks” through downstream activation of the gp130/STAT3 signaling pathway. However, this study showed that the related cytokine IL-11 has a stronger correlation with elevated STAT3 activation in human gastrointestinal cancers. IL-11 has a more prominent role compared to IL-6 during the progression of sporadic and inflammation-associated colon and gastric cancers. Accordingly, in the models and in human tumor cell line xenograft models, pharmacologic inhibition of IL-11 signaling alleviated STAT3 activation, suppressed tumor cell proliferation, and reduced the invasive capacity and growth of tumors.

These results identify IL-11 signaling as a potential therapeutic target for the treatment of gastrointestinal cancers.

Reference:

Putoczki TL1, Thiem S, et al. Interleukin-11 Is the Dominant IL-6 Family Cytokine during Gastrointestinal Tumorigenesis and Can Be Targeted Therapeutically [J].Cancer Cell,2014; 24(2):257-71.

What are the mutational landscape and significance of cancer? A recent study from Cyriac Kandoth and Michael D. McLellan told us the answer by a research across 12 major cancer types.

They have performed systematic analysis of the TCGA Pan-Cancer mutation data set, finding key insights for cancer genomes, as summarized in Extended Data Fig. . The data set contains 127 diverse SMGs, demonstrating that many cellular and enzymatic processes are involved in tumorigenesis. Notably, 66 of them are also on the ‘mut-driver genes’ list generated by a ratiometric method using COSMIC mutations. Although a common set of driver mutations exists in each cancer type, the combination of drivers within a cancer type and their distribution within the founding clone and subclones varies for individual patients. This suggests that knowing the clonal architecture of each patient’s tumour will be crucial for optimizing their treatment.

Given the rate at which TCGA and International Cancer Genome Consortium projects are generating genomic data, there are reasonable chances of identifying the ‘core’ cancer genes and pathways and tumour-type-specific genes and pathways in the near term. These results will be immediately circulated within the research community to assess their potential for candidate targets for diverse tumour types or for specific tumour type. Ultimately, these data and their associations with different clinical features and subtypes should contribute to the formulation of a reference candidate gene panel for all tumour types that could be helpful for prognosis at various clinical time points.

Reference

Cyriac Kandoth and Michael D. McLellan,etc., Mutational landscape and significance across 12 major cancer types, Nature 502,333–339(17 October 2013)︱doi:10.1038/nature12634

A study, published in the journey Cancer Research, reports that the receptor CCR5 best known for its role in HIV therapy, may also be involved in driving the spread of prostate cancer to the bone. The findings offer a promising avenue for blocking bone metastases, thereby evading the high lethal risks.

A scientific team performed this study based on previous research that showed that CCR5 signaling was key in the spread of aggressive forms of breast cancer to the lungs. And they found that breast cancer cells carrying the CCR5 receptor on their surface were drawn to the lung. Given that prostate cancer cells were attracted to the bone and brain, they investigated whether CCR5 could play a role in prostate cancer metastases as well.

Investigators need to overcome a existing challenge that there was no immune competent mouse model of prostate cancer that reliably developed bone and brain metastases. So they developed a prostate cancer cell line that regularly caused bone metastases in immune-competent mouse models. Because the immune system is so important in human prostate cancer it was important to develop a model that reflected human disease.

In the CCR5 signaling pathway, the scientists found certain cancer-driving genes via analyzing the genes of the metastasized bone and brain tumors. Further, they administered the CCR5-blocking drug maraviroc to the new prostate cancer mouse model. In contrast to control animals, maraviroc dramatically reduced the overall metastatic load by 60 percent in the bone, brain and other organs.

To examine whether a similar mechanism might be at play in human prostate cancer, the investigators unearthed the genomic data of patients with prostate cancer and found that CCR5 was more highly expressed in prostate cancer tissue compared with normal tissue, and even more highly expressed in metastases compared with primary tumors. They also noticed that patients who had a lower expression of the CCR5-pathway genes had a longer survival times, whereas high expression of these CCR5 genes was associated with a shorter overall survival.

The next steps for the researchers are to develop clinical trials using CCR5 pathway activation as a companion diagnostic for the trial

Reference:

CCR5 Receptor Antagonists Block Metastasis to Bone of v-Src Oncogene-Transformed Metastatic Prostate Cancer Cell Lines. Cancer Research, 2014; 74 (23): 7103

The scientists from HuaZhong University of Science and Technology and Chinese academy of sciences Shanghai life science research institutions confirmed that MPHOSPH1 is a potential therapeutic target during hepatocellular carcinoma in the new study.

MPHOSPH1 is a critical kinesin protein that functions in cytokinesis. This study showed that MPHOSPH1 is overexpressed in hepatocellular carcinoma (HCC) cells, where it is essential for proliferation. Attenuating MPHOSPH1 expression with a tumor-selective shRNA-expressing adenovirus (Ad-shMPP1) was sufficient to arrest HCC cell proliferation in a manner associated with an accumulation of multinucleated polyploid cells, induction of postmitotic apoptosis, and increased sensitivity to taxol cytotoxicity. And attenuation of MPHOSPH1 stabilized p53, blocked STAT3 phosphorylation, and prolonged mitotic arrest. In a mouse subcutaneous xenograft model of HCC, tumoral injection of Ad-shMPP1 inhibited MPHOSPH1 expression and tumor growth in a manner correlated with induction of apoptosis. Combining Ad-shMPP1 injection with taxol administration enhanced antitumor efficacy relative to taxol alone.

Furthermore, Ad-shMPP1 tail vein injection suppressed formation of orthotopic liver nodules and prevented hepatic dysfunction. Above all the results identify MPHOSPH1 as an oncogenic driver and candidate therapeutic target in HCC.

Reference:

MPHOSPH1: A Potential Therapeutic Target for Hepatocellular Carcinoma [J]. Cancer Res,2014.74(22); 6623–34.

A team of researchers from the University of Granada has indicated that the efficacy of a new drug against cacnerogenic stem cells, called Bozepinib, has proved to be effective in tests with mice. This finding was published on Oncotarget.

Cancerogenic stem cells appear in small quantities in tumors, and one of their important features is that they contribute to the formation of metastasis in different places within the original tumour. Cancerongenic stem cells remain dormant under normal conditions. Conventional chemotherapy and radiotherapy act upon those cancer cells which are clearly differentiated, but they cannot destroy these dormant cancerognic stem cells.

During the last few years, research in fight against cancer has focused on the search for new drugs that can selectively attack these cancerogenic stem cells. If they can be eliminated, the tumour will then be eliminated in its entirety, which will lead to the complete cure of patients.

The new drug was developed by the team is called Bozepinib. It shows a selective type of activity against cancerogenic stem cells in breast, colon, and skin cancers. The powerful anti-tumour activity of Bozepinib is due to the inhibition of the HER2 signaling pathway, and to the fact that this drug inhibits the invasiveness and the formation of new vessels in the tumour. Researchers have also revealed the specific mechanism by means of which Bozepinib acts against cancerogenic stem cells.

Researchers will conducting safety tests and they expect that this new drug can be run through clinical tests with actual patients in the future.