A New Drug Change The Human Tumor Metabolite

The Manchester scientists found a new drug, and the new drug can inhibit the tumor growth. The new drug, together with the radiation therapy, could be applied for effective treatment of tumor in the clinical.

In the process of tumor cell metabolism, the lactic acid was produced. The Lactic acid cause toxicity to tumor cells, so the lactic acid must be transferred by the molecular transporters (MCT) out of tumor cells. Astrazeneca pharmaceutical drug-AZD3965 inhibited a MCT1 in lung cancer cells. Researchers of the Manchester investigated the therapeutic effect of the drug combined with radiotherapy. The further study confirmed that the new drug, together with the radiation therapy, could be applied for effective treatment of tumor in the clinical.

Professor Ian Stratford said AZD3965 can inhibit MCT1, specifically targeting tumor by tumor metabolism. This drug was used as a single drug test in clinical trials. And he has shown that the drug combined with radiotherapy could be the new treatment of cancer patients.


Inhibition of Monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport [J]. Mol Cancer Ther, 2014; 13(12): 1-12.

Metabolic Reprogramming Induces Regression of Specific Tumors

Researchers from University of Texas MD Anderson cancer center have indicated that altering tumor suppressor gene p53 family members may induce rapid regression of tumors lack of p53. This study was published in Nature.

TP53 is commonly altered in human cancer and the Tp53 reactivation suppresses tumors in vivo in mice (TP53 and Tp53 are also known as p53). This strategy has proven difficult to implement therapeutically.


In this study, scientists try to examine an alternative strategy by manipulating the p53 family members, Tp63 and Tp73 (also known as p63 and p73). The acidic transactivation-domain bearing (TA) isoforms of p63 and p73 structurally and functionally resemble p53, whereas the δN isoforms of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53, TAp63 and TAp73 to inhibit their tumour-supressive functions. The researchers have shown that the deletion of δN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregualtion of IAPP, the gene that encodes amylin.

In addition, they found that IAPP is causally involved in this tumor regression and that amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis.

This study provides new insight of targeting tumors which are lack of p53 or with p53 mutation. Meanwhile, the researchers also identify the key receptors of cancer cells which are eliminated of p53 gene. These receptors may be potential prognostic markers to ensure if pramlintide will be effective to cure the patients with p53 mutation or lack of p53.


Venkatanarayan A, Raulji P, Norton W, et al. IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo[J]. Nature, 2014.

How Hedgehog Signaling Pathway Induces Breast Cancer Metastasis

Scientists from University of Texas MD Anderson cancer center have revealed that , a unique cell signaling pathway hedgehog, may be the mechanism behind breast cancer metastasis. The study was published in Cell.

Emerging evidence has purported long noncoding RNA (IncRNA) as a new class of players involved in the development and progression of cancer. However, the regulatory roles played by IncRNA in breast-cancer-associated aberrant signaling pathways/transcriptional programs are not completely understood.


In this study, researchers have reported a role for INcRNA BCAR4 in breast cancer metastasis that is mediated by chemokine-induced binding of BCAR4 to two transcription factors with extended regulatory consequences. BCAR4 binding of SNIP and PNUTS in response to CCL21 releases the SNIP1′s inhibition of p300-denpendent histone acetylation, which in turn enables the BCAR4-recruited PNUTS to bind H3K18ac and relieve inhibition of RNA pol Ⅱ via actication of the PP1 phosphatase. This mechanism activates a noncanonical Hedgehog/GLI2 transcriptional program that promotes cell migration. BCAR4 expression correlates with advanced breast cancers, and therapeutic delivery of locked nucleic acids (LNAs) targeting BCAR4 strongly suppresses breast cancer metastasis in mouse models.

Their finding have provided supporting evidence for the regulatory roles played by IncRNA in the progression of aggressive breast cancers. Broadly, the results of the therapeutic effectiveness breast cancer metastasis document an example showing the pharmacologic value of INcRNA in human cancer and other diseases.


Xing Z, Lin A, Li C, et al. lncRNA Directs Cooperative Epigenetic Regulation Downstream of Chemokine Signals[J]. Cell, 2014.

Endocan is as a potential diagnostic or prognostic biomarker for chronic kidney disease

A recent study shows that endocan is as a potential diagnostic or prognostic biomarker for chronic kidney disease.

In the study by Yilmaz et al., there are some limitations. They have performed just a single measurement of serum endocan. A single point measurement of serum endocan is a little relevant, but serial multiple measurements could give more information on prognostic outcome of CKD. For instance, Li and Wang et al. performed multiple point measurements of serum endocan level during evaluation of acute rejection after renal transplantation. Multiple measurement of serum endocan level could discriminate acute rejection from renal allograft dysfunction. They additionally showed that endocan expression was located mainly in glomeruli, which may give a clue to the origin of serum endocan in CKD patients. Another instance is a report on serum endocan levels in septic patients. The severity of sepsis showed positive correlation with initial serum endocan levels. Moreover, it was significantly increased in non-survivors.


However, the lack of multiple follow-up data on serum endocan levels prohibits the evaluation of sepsis treatment outcome, which requires multiple measurements. Another limitation is that Yilmaz et al.did not rule out accompanying cancers or other inflammatory diseases, which could be sources of serum endocan. Serum endocan is detected as a few hundred picograms in 1 ml of serum under normal physiologic conditions. Serum endocan solely could not inform regarding the location or kinds of diseases, but its detection over the normal range may give a clue to search for some diseases, such as systemic inflammatory diseases, cardiovascular diseases, and various cancers. Finally, it is unclear whether the increased serum endocan level in CKD patients was the result of an increased secretion or a decreased renal clearance. The clearance mechanism of endocan has not yet been identified. As renal function declines, serum endocan level increases, which may be due to increased production or decreased clearance. The former might be due to kidney inflammation, which is preferable. In this report, serum endocan levels of patients in the third quartile (6.6 ng/ml) or fourth quartile (13.3 ng/ml) in the CKD classification based on estimated glomerular filtration rate were significantly higher than those of patients in the first (1.2 ng/ml) and second quartiles (2.8 ng/ml). This pattern was the same for high-sensitivity C-reactive protein, which was induced considerably by kidney inflammation. However, the reason why serum endocan levels were significantly higher in CKD than in any other disease conditions must be evaluated. The possibility that the increased serum endocan levels in CKD patients resulted from decreased clearance could be evaluated simply by urine endocan level. Serial follow-up of serum endocan levels in CKD patients could also be informative in this regard.

In conclusion, Yilmaz et al. have reported an endocan as a novel prediction marker of all-cause mortality and cardiovascular events in CKD patients. More detailed study of molecular mechanisms in endocan expression and degradation in CKD may increase the value of serum endocan levels.


Endocan as a potential diagnostic or prognostic biomarker for chronic kidney disease, Kidney International (2014) 86, 1079–1081; doi:10.1038/ki.2014.292

Silence KRAS using siRNA to kill cancer cell

Recently, researchers have developed a new approach to block the KRAS oncogene, one of the most frequently mutated genes in human cancer. The approach relies upon siRNA to attack KRAS, which is tantalizing yet elusive target for drug developers.


The findings, published in the journal Molecular Cancer Therapeutics, show that using a form of siRNA to halt KRAS not only dramatically stunted the growth of lung and colon cancers in cultured cells and mice but also blocked metastasis.

As known in the biomedical circle, KRAS is a signaling molecule — a protein switch that triggers a cascade of molecular events that tell cells to grow and survive. Mutations in the KRAS gene create a switch that is perpetually “on,” causing cells to divide uncontrollably. KRAS mutations are present in approximately 30% of human cancers, particularly lung, colon, pancreatic, and thyroid cancer.

Over the past decades, KRAS has been widely regarded as undruggable target, since it lacks good pockets or binding sites for small molecules and drug to bind to. Some researchers have tried instead to target the proteins downstream in the KRAS signaling cascade, but those attempts have also had limited success.

Instead of other conventional methods, a new genetic tool known as RNA interference (also called RNAi) is employed to destroy the KRAS protein before it fully forms. RNAi uses bits of synthetically engineered RNA to silence specific genes. These bits of RNA bind to specific genetic messages called mRNA in the cell and direct enzymes to recognize the messages as enemies. In this context, the enzymes destroyed the genetic messages of KRAS mRNA so that KRAS can’t be made. As a result, the cells don’t grow, replicate, or move nearly as well.

RNAi has shown great promise in the treatment of liver diseases, viral infections, and cancers. To see if this approach could thwart the KRAS oncogene, researchers had to test different sequences of RNA to determine which one most effectively tagged KRAS for destruction. Of five RNA sequences, the researchers identified two candidates worthy to take into cancer models.

When they delivered these sequences into tissue culture cells, they found that the siRNAs destroyed over 90% of the KRAS gene messages, significantly impairing the growth of cancer cell lines. The siRNA sequences will have to be designed to specifically target the mutant form of KRAS without disrupting the normal form of the gene, which is necessary for maintaining normal growth in healthy cells.


Therapeutic Silencing of KRAS using Systemically Delivered siRNAs. Molecular Cancer Therapeutics, 2014

Effective potential drugs for the treatment of leukemia-PARP inhibitor

A new research indicated that the treatment with poly (ADP-ribose) polymerase (PARP) inhibitors, together with chemotherapy drugs, could be applied for RUNX leukemia. This study was published in Cell journal Reports.


Unlike other cancer is more common in the elderly, leukemia has a high incidence among young people. In recent years, the breakthrough treatment of the leukemia is few. According to the previous study, RUNX1 is one of the most frequent mutations of genes in leukemia. And RUNX3 is associated with the development of the disease.

The result showed that ablation of both Runx1 and Runx3 led to defective DNA repair. Recent technological advances have shown frequent deletions of chromosome 21q, including the RUNX1 locus, in patients with congenital syndromic thrombocytopenia with leukemia predisposition.

It is clearly demonstrated that human leukemia cell lines expressing the RUNX1-ETO fusion gene are sensitive to MMC, at least partially in a fusion gene-dependent manner. This sensitivity was further enhanced in the presence of PARP inhibitor. The treatment with PARP inhibitors, together with DNA ICL and/or standard chemotherapy drugs, could be applied for RUNX leukemia. Because deregulation in RUNX family genes is now found in a wide spectrum of cancers, this combined therapy can potentially be extended to common cancers.

PARP is found in the cell’s nucleus. The main role is to detect and signal single-strand DNA breaks (SSB) to the enzymatic machinery involved in the SSB repair. In this study, PARP play the imported role in the treatment of the leukemia, and it is the breakthrough treatment of the leukemia.


CQ Wang, V Krishnan, et al. Disruption of Runx1 and Runx3 Leads to Bone Marrow Failure and Leukemia Predisposition due to Transcriptional and DNA Repair Defects [J].Cell reports 2014, 8(3): 767–782.

New Device Monitoring Real-time Cancer Metastasis

Researchers from Johns Hopkins University have developed a new device which could monitor the metastasis of breast cancer cells. This finding allows scientists to watch and record the behaviour of cancer cells as they burrow through tissue, infiltrate blood vessels, and enter the blood stream to travel quickly and easily through the body. The study was published in Cancer Research.


More than 90 percent of cancer-related deaths are caused by metastatic cancer cells spreading around the body, however until now, scientists haven’t been able to get a good, clear look at this complicated process.

In this study, A special nutrient-rich solution was injected into the chip and made to flow through the artificial blood vessel. Then, the researchers inserted individual and clustered human breast cancer cells into the artificial tissue. The breast cancer cells were labelled with fluorescent tags so they could be easily tracked and recorded. In the tests, the artificial tissues acted like human tissue does in an actual cancer patient, which could be monitored.

The device offered such a detailed view for the scientists to observe a single cancer cell as it located a weak spot in the lining of the blood vessel, exerted enough pressure on it to break through, and then squeezed itself in far enough to be taken up by the bloodstream. Another advantage is that the cancer migration process can be viewed countless times without invasive procedures being carried out on actual cancer patients.

Generally, this device allows researchers to look at the major steps of metastasis as well as to test different treatment strategies at relatively fast pace. If one way to stop one of these steps in the metastatic is cascaded, a new strategy may be found to slow down or even the spread of cancer.

New Tactic against Cancer Matastasis

Metastasis is thought to be the main cause of cancer death. However, it has been slow in the process of preventing and treating migratory cancer cells.  A research team from Harvard Medical School has identified that an overabundance of a cell receptor named Frizzled-2, along with its activator, Wnt5, appears to raise a tumor’s likelihood of metastasizing. It could trigger the process known as the epithelial-mesenchymal transition(EMT). Their study may help researchers better understand how metastasis begins and inform the design of new treatments to combat it. This finding was published in Cell.


EMT generally plays a role in human development, allowing specific cells to become mobile and invasive. Then, they would move around and form new structures in the growing embryo. Previous researches have linked EMT to cancer metastasis, where tumor cells acquire those properties to disastrous effect. Nevertheless, the mechanism of this progress is still unknown.

In this study, scientists focus on the question “what makes one type of tumor metastasize and another type not?” and discovered a brand-new cell signaling pathway on the basic biology level.

After learning the importance of Frizzled-2, they also developed an antibody to block it . The antibody could curb metastasis in mice with certain type of tumors. In addition, frizzled-2 provides a promising new therapeutic target to prevent or delay metastasis, and both Frizzled-2 and Wnt5 are potential biomarkers that can be used to identify which patients are most at risk of metastasis and could benefit from frizzled-2-directed therapy.

They also found that Wnt and its receptor, Frizzled-2, were present at higher than normal levels in metastatic liver, breast, lung and colon cancer cell lines. In tissue samples from 48 cancer patients, Frizzled-2 was higher in late-stage cancers than in early-stage cancers. The team then painstakingly pieced together the players linking Wnt5 with the onset of metastatic behavior and discovered a previously unknown Wnt pathway. Frizzled-2 it turned out , could activate STAT3, which is known to drive cancer through.

The researchers are confident that their discovery can be translated into a novel therapeutic option for patients in the future.


Gujral T S, Chan M, Peshkin L, et al. A Noncanonical Frizzled2 Pathway Regulates Epithelial-Mesenchymal Transition and Metastasis[J]. Cell, 2014, 159(4): 844-856.

The comprehensive genomic characterization of squamous cell lung cancers

A resent research reported the comprehensive genomic characterization of squamous cell lung cancers.

Targeted kinase inhibitors have been successfully used for the treatment of lung adeno carcinoma but minimally so in lung SQCC. The observations reported here suggest that a detailed understanding of the possible targets in lung SQCCs may identify targeted therapeutic approaches. Whereas EGFR and KRAS mutations, the two most common oncogenic aberrations in lung adenocarcinoma, are extremely rare in lung SQCC, alterations in the FGFR kinase family are common. Lung SQCCs also share many alterations in common with head and neck squamous cell carcinomas without evidence of human papilloma virus infection, including mutation in PIK3CA,PTENTP53CDKN2ANOTCH1 and HRAS, suggesting that the biology of these two diseases may be similar.


The current study has identified a potentially targetable gene or pathway alteration in most lung SQCC samples studied. The data presented here can help to organize efforts to analyse lung SQCC clinical tumour specimens for a panel of specific, actionable mutations to select patients for appropriately targeted clinical trials. These data could thereby help to facilitate effective personalized therapy for this deadly disease.

Cancer cells can infect normal neighbours?

In a study published online on 23 October inCancer Cell, researchers show that when human breast-cancer exosomes can cause tumours when mixed with normal cells then injected into mice. The results could pave the way to finding markers to monitor the progression of cancer, and possibly even point to targets for therapies.


The team also collected exosomes from the blood of 8 healthy individuals and 11 people with breast cancer. Five of the 11 exosome samples from the patients induced tumour growth when mixed with normal cells and injected into mice; none of the exosome samples from healthy people did so.

It is unclear how far exosomes can travel in the body, says Kalluri, but the fact that the team could isolate them from blood suggests that they could be quite mobile. And even if their effect is only local, they could still make nearby cancer cells more aggressive, or transform healthy cells into cancerous ones, he says.

But trying to slow cancer by blocking exosomes is a difficult proposition, says Al-Nedawii. It is unclear how that would affect normal cells, he notes, and some exosomes from healthy cells have been shown to contain proteins that prevent cancer.

A more imminent application might be to use exosomes as a way to detect and monitor cancer, he adds. Kalluri notes that exosomes are more abundant and easier to isolate than tumour cells floating in the blood, which have also been used to track disease. “There are millions of exosomes being made by each cell,” he says. “That’s very powerful.”


Cancer cells can ‘infect’ normal neighbours, Nature ︱ doi:10.1038/nature.2014.1621

Cancer related signaling pathway, e.g. Wnt signaling,stat3,NF-KB