Category Archives: Highlight

China tackle soaring cancer rates

It’s ten o’clock in the morning at the largest cancer hospital in Asia, a sprawling complex of buildings in Tianjin, a polluted city on China’s eastern coast.

Dr Zhang Jing is already scrubbing up for her fourth operation of the day. She has the tired resignation of someone who knows she’s in for a long shift at work. Ten years ago, surgeons here removed tumours once or twice daily. Now they perform at least seven operations every shift.

The cancer hospital recently doubled in size but is still struggling to cope with demand. “Even if we diagnose 50 patients every day, we cannot keep up,” Dr Zhang says. “No matter where you go in this hospital, you will never find an empty bed.” Cancer rates may be falling in many Western countries but they are steadily rising in China.

Blame the effects of pollution and unhealthy habits on the country’s aging citizens. In the lobby of the Tianjin Cancer Hospital, the tension is palpable. Patients and their families jostle with one another in line as they push to make appointments. It is a situation that is echoed in busy cancer hospitals across the country. There are no obvious national campaigns to educate citizens on the avoidable causes of cancer, like smoking.

The country’s National Cancer Centre, which was supposed to open in 2012, doesn’t even have a website. Reliable cancer statistics are also hard to find. In 2008, the Chinese Academy of Medical Science launched the China Cancer Registration Project, with 219 registration spots across China documenting cancer data. However, it has yielded little new information.

The project’s last report was released in 2013, using data from 2010. To date, China lacks a single database tracking national cancer rates. Cancer screening programs are virtually non-existent. The country’s fragile healthcare system also means that many aren’t diagnosed until it is too late. Around 130 million people in China are believed to be carrying the hepatitis B virus and 30 million have developed a chronic hepatitis B virus.

This is a serious problem because, without regular health checks, the virus can easily morph into liver cancer. China now accounts for half of the world’s cases of the disease. In a single morning, one of the hospital’s most respected doctors, Song Jing, meets 10 new patients. All of them are found to have late stage liver cancer. When asked if it is stressful telling so many people a day that they have less than a year to live, Dr Song nodded.

Genomics Melting into Cancer Biology and Medicine

Advances in genomics have brought convenience of genetically stratified cancer patients which would affect the tailored therapy. Additionally, genomics in the combination of molecular biology, engineering, and bioinformatics has revolutionized understanding of predisposed genes inducing the occurrence of cancer development , as well as of potential treatment responses.

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Genomics has remarkably influenced cancer research. Investigating the molecular characteristics in terms of gene expression, structural shifts of the genome , and mutations, as well as their influence in metastatic behavior and therapeutic responses will revolutionize cancer treatment.

Key characteristics of individual cancers are hoped to be identified and then support to establish tailored therapeutics. Thus investigators have been attempting to find out sets of genes associated with cancer and novel drug development targets. For instance, Roche’s antibody MPDL3280A (RG7446) in clinical development acts against an immune checkpoint blockade expressed in tumors.

Cancer Diagnostics for treatment 

Genetic tests have already changed medical practice. Patient’s genetic information obtained from genetic tests is often employed for differentiating their vital genotypes, and physicians thereby offer optimal medical decisions, practices and drugs. Decipher Prostate Cancer Classifier from GenomeDx, analyzing the activity of 22 genetic markers expressed in the prostate cancer, classifies the patient’s tumor independently of Prostate-Specific Antigen (PSA) rise. Scientists developed genome-wide search algorithms of more than a million markers, and discovered  these 22 markers related to aggressive disease.

Myriad’s Prolaris is a risk-stratification tool for patients with prostate cancer. Designed to measure the aggressiveness of a patient’s cancers to better predict an individual’s relative risk of disease progression within ten years, it can enable physicians to better define a treatment/monitoring strategy for their patients.

Oncogenic mutations of driver Genes

Adding to the complexity of data is the discovery of “driver” genes and their role in cancer biology. Elli Papaemmunuil and colleague recently described their analysis of oncogenic mutations in large, well-characterized patient cohorts of myelodysplastic syndromes (MDS), characterized by dysplasia, ineffective hematopoiesis, and a variable risk of progression to acute myeloid leukemia.

Using previously identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling, the investigators sequenced 111 genes across 738 patients with MDS or closely related neoplasms to explore the role of acquired mutations in MDS biology and clinical phenotype.

The scientists reported that 78% of patients had one or more oncogenic mutations and that they could identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers.

References:

1. Anti-programmed death-1 and anti-programmed death-ligand 1 antibodies in cancer therapy. Expert Opin Biol Ther. 2013 Jun;13(6):847-61.

2. Genetic testing comes of age in prostate cancer. Trends in Urology & Men’s Health.2014;5( 2): 9–13,

3. Academic medical centers: ripe for rapid-learning personalized health care. Sci Transl Med. 2011 Sep 21;3(101):101cm27.

Novel Drug: to Win Global battle against cancer

Scientists work together to attack caner by the means of chemotherapy and radiotherapy. However, to effectively kill cancer cells remains a challenging issue, reflected by poor overall survival of cancer patients. What a frightening thing is that, by the year 2020, 16.8 million annual new cancer cases are diagnosed worldwide. It’s particularly urgent for scientists to design and improve pharmaceutical strategies.

Estimated Number of New Cancer Cases by World Area, 2008*

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Source: GLOBOCAN 2008.

The occurrence of antibodies as immunotherapeutic agents has offered a tremendous novel  potential for the treatment of cancer patients. A range of monoclonal antibodies(mAbs),such as

erlotinib and gefitinib , have been approved by FDA with the support of positive clinical results . Some people can be grouped based on common genetic mutations, supporting mAB drugs to be an effective option matched to this group.

Difficulty and complexity in the drug development

Putting a new medicine in the hands of patients is vastly more complex. It requires academic institutions and pharmaceutical corporations to expend understanding of molecular mechanisms of tumor development and migration, and to develop specific antibodies targeted the process that lead to cancer. As Roche reports, researchers need to produce a large number of synthetic compounds and then find out one best suited for drug use. It will take about 12 years until a doctor can prescribe it .

What is the expenditure of a drug? We can know it from data Roche offers. To achieve a drug needs something listed as follows: 1 billion US $ investment, over 7 million hours of work, 6587 experiments, and 423 researchers.

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Strategies for novel drug

MAbs plus chemotherapy regimen are currently in clinical development and application, which can strengthen anti-cancer effectiveness of mAbs. For instance, bevacizumab plus mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin)as first-line treatment for metastatic colorectal cancer are superior in PFS.

Some patients using mAbs develop drug resistance over time , resulting in a relapse of the cancer within one year of starting therapy. Scientists and doctors should expand knowledge of drug resistance mechanisms, and thereby develop effective therapies for patients with cancer.

References:

1. Development of TGF-β signalling inhibitors for cancer therapy. Nat Rev Drug Discov. 2004 Dec;3(12):1011-22.

2. Drug interactions with solid tumour-targeted therapies. Crit Rev Oncol Hematol. 2014 Jan;89(1):179-96.

3. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1278-86.

A Milestone for Cancer treatment : Stratified Medicine from Genetic Variants

Since the discovery of the first cancer-causing genes in the 1970s, researchers have been attempting to map cancer-causing mutations in search of common genetic patterns that deviate from normal. Each mutated gene possesses the potential to deepen our understanding of what causes the disease and how to treat it.

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There are the latest progresses towards that goal. Investigators clearly describes how patterns of mutation can be used to track down the agent that caused cancer. For example, sunlight leaves a footprint that differs from a cancer-causing viral infection. Another team catalogue cancer-associated mutations in patients with advanced melanoma, hoping to use the information to tailor immune cells to destroy tumors. And promising initial results are unveiled on targeting the mutations of IDH2 protein in many different tumor types.

Genetic mutation in cancer

An article published in August 2013, initially reported a detailed map of genetic faults that cause cancers. It offers profound insights into the disease.

The map describes over 20 “genetic signatures”, or patterns of mutation, that alone or in combination drive 30 different types of cancer. Independent cancer specialists who have seen the research said it was “extremely important” and was likely to lead to new strategies to prevent and ultimately treat the disease.

To achieve the stratified medicine

As it’s known, stratified medicine identifies key molecular changes common to different people’s cancers. Patients can then be grouped based on these shared genetic faults, allowing some people to receive a targeted treatment matched to their group.

To realize this challenging goal, some scientists launched the Stratified Medicine Programme with the aim of establishing a network of labs and hospitals that in the future may enable individualized treatment. They expected it would become routine to consult patient stratification in cancer treatment .

Reference:

1. Metabolic quirks yield tumour hope. Nature 508, 158–159; 2014

2. Emerging patterns of somatic mutations in cancer. Nature Reviews Genetics 14, 703–718; 2013

3. The cancer genome.

Marian R.Glancy

Immune System: An Inside Attack on Cancer

Tumor metastasis leads to the overwhelming incidences of mortality in cancer patients and poses the great challenge for cancer therapy. Such diffuse tumor cell display usual antigens that can’t be recognized by body’s immune system . Therefore, to awaken immune cells to spontaneously reject metastatic tumors, many scientists make some progress in finding key molecular brakes in immune cells. In light of recent findings and future promises, immunotherapy has been chosen as scientific breakthrough of the year 2013 by the journal Science.

Some "Brake" molecules in the innate and adaptive immune system

Some “Brake” molecules in the innate and adaptive immune system

Researchers from the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (OeAW), in collaboration with researchers in Australia and Germany, demonstrated that a molecule called Cbl-b acts as a molecular brake for Natural Killer Cells to reject cancer. Deletion or targeted inactivation of Cbl-b efficiently enhanced the anti-tumor function of NK cells. As a result the progression of metastases in melanoma and breast cancer was significantly inhibited.

In the adaptive immune system, CTLA-4 functions as a molecular brake by preventing T-cell activation. Yervoy (ipilimumab) was developed to specifically binds to and blocks it. When Yervoy releases the brake , T cells are free to destroy tumors. Still, the promising aspects of Yervoy prompts researchers to look at other potential target molecules. For example, PD-1 as a brake protein gradually has became a research focus, by which some cancers use to deactivate the group of T cells that surrounds the tumor.

Immunotherapy against cancer types.

So far, researchers have focused on melanoma and kidney cancer because they responded best to immunotherapies in early trials, and are thought to be particularly visible to the immune system. However, some cancers such as liver cancer may still pose a challenge to immunotherapy approaches. Additionally , breast, colorectal, pancreatic and ovarian cancers are also particularly adept at suppressing immune cells says Lisa Butterfield, a cancer researcher at the University of Pittsburgh in Pennsylvania. Combination therapies, she thinks, may be applied to overcome these limitations.

Reference :

1. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature, 2014; DOI: 10.1038/nature12998

2. Cancer treatment: The killer within. Nature. 2014 Apr 3;508(7494):24-6.

Marian R.Glancy

Arming the Immune System to Fight Cancer

Cancerous tumors are formed when the immune system is unable to remove these diseased cells. Once immune cells capable of killing tumors are activated specifically, they can see tumors that were previously invisible to the immune system. When an immune system is working properly, diseased cells are captured and killed. To date, some researchers have unveiled the cancer’ evasion mechanism and recruited immune system to fight cancer.

Events in Cancer immunology

Events in Cancer immunology

Dr. Freeman’s lab In the Dana-Farber Cancer Institute develops an extensive body of knowledge regarding inhibitory signals conveyed by tumor cells via the programmed death 1 (PD-1) receptor and its ligand PD-L1. Interaction between PD-1 receptor and its ligand deactivates CD8 T cells and inhibits their capacity to kill tumor cells and make cytokines that recruit other immune cells.

Researchers in the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute eradicates solid tumors in laboratory mice using a novel combination of two targeted agents (a mTOR inhibitor and a CD4 antibody). These two synergistic therapies increase the immune system’s “memory” and ability to recognize tumors, ultimately allowing solid tumors to act as their own cancer-fighting vaccine.

Dr. Lee’s team at Roswell Park Cancer Institute explores two receptors (called CD80 and CD86) expressed on the surface of dendritic cells that trigger the cells to make either immune-stimulating factors or immune-suppressive factors. They defined the intracellular pathways by which the receptors triggered each response.

Fight against cancer

Deep insight into evasion mechanisms of solid tumors contributes to employing new therapeutic strategy to fight cancer. Actually, immune system is harnessed to specifically target tumour cells owing to tumour-specific immunological memory.

Åsa Lindgren, a researcher from the Department of Microbiology and Immunology ,finds that Activation of the NK cells can play a key role in stopping tumors from developing, and that reduced NK-cell activity can increase the risk of cancer developing. These findings are hoped to develop new ways of diagnosing and treating stomach cancer.

Researchers at the University of Calgary’s Hotchkiss Brain Institute (HBI) make a great discovery that amphotericin B (AmpB) as a drug is able to re-activate those immune cells and reduce brain tumor growth, thereby increasing the lifespan of mice two to three times.

Reference:

Foxp3 T cells inhibit antitumor immune memory modulated by mTOR inhibition. Cancer Research, 2014; DOI: 10.1158/0008-5472.CAN-13-2928

Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol. 2006 Jul;30(7):802-10.

Novel Regulation of CD80/CD86-induced Phosphatidylinositol 3-Kinase Signaling by NOTCH1 Protein in Interleukin-6 and Indoleamine 2,3-Dioxygenase Production by Dendritic Cells. Journal of Biological Chemistry, 2014; 289 (11): 7747

Marian R.Glancy