Alteration of lipid metabolism is increasingly recognized as a signature of cancer cells. It’s  reported that accumulation of aberrant cholesteryl ester is found in advanced prostate cancers with PTEN loss and PI3K/AKT activation. And inhibition of cholesterol esterification impairs cancer aggressiveness.

Additionally , the scientists from The University of Manchester combine prostate cancer cells in the lab with arachidonic acid (AA), an omega-6 fatty acid that has been shown to attract prostate cancer cells to the bone marrow, and uncover a link between cholesterol and prostate cancer’s ability to spread to the bones in a study published in the British Journal of Cancer.

They ascertain how naturally occurring fatty acids in the bone marrow directly interact with the body’s system of manufacturing cholesterol to enhance prostate cancer cells’ ability to spread. These findings give clues to prostate cancer migration and help explain why taking statins – commonly used cholesterol-lowering drugs – is thought to slow the progress of the disease in some cases.

“Prostate cancer spreading to the bones is a major challenge for doctors and unfortunately it’s very difficult to treat. ” said Nell Barrie, senior science information manager at Cancer Research , “Altering cholesterol metabolism or blocking the ways in which prostate cancer cells are able to change their shape, and thereby their ability to spread, could lead to major advances in treating men with aggressive forms of the disease.”

Reference:

Arachidonic acid induction of Rho mediated transendothelial migration in prostate cancer British Journal of Cancer. Br J Cancer. 2014 Apr 15;110(8):2099-108.

Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness. Cell Metabolism, 2014, 3(19):393-406

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*

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.

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.

Breast cancer is the most common malignant tumour among women in the western world, affecting 8-12 % of the female population. In the Netherlands, breast cancer occurs yearly in 1,000 per 100,000 women with an absolute incidence of 9,000 new cases per year.

Tamoxifen is effective for endocrine treatment of estrogen receptor(ER)-positive breast cancers but ultimately fails due to the development of resistance. A functional screen in human breast cancer cells identified two BCAR genes causing estrogen-independent proliferation. The BCAR1 and BCAR3 genes both encode components of intracellular signal transduction, and thereby mediate the cell growth control .

Conspiracy against drug resistance

Scientists at Sanford-Burnham Medical Research Institute provide conclusive evidence that antiestrogen resistance in breast cancer cells requires the interaction between BCAR1 and BCAR3 proteins. This interaction is responsible for resistance to antiestrogen drugs, paving the way for improved diagnostic and treatment strategies.

“Drug resistance is one of the most serious obstacles to breast cancer eradication,” said the senior study author Elena Pasquale, Ph.D., professor. “Our findings suggest that strategies to disrupt the BCAR1-BCAR3 complex and associated signaling networks could potentially overcome this obstacle and ultimately lead to more-effective breast cancer therapies.”

Parkinson’s Drug Shows Promise of prevention

One drug, called benserazide, is currently used for Parkinson’s disease, and in studies it reduced the formation of breast tumors in mice that had been implanted with cancer cells containing the BRCA1 gene mutation. All of the mice that did not receive the drug developed breast tumors, but 40 percent of mice given the drug were tumor-free, said study researcher Elizabeth Alli, of Stanford University School of Medicine.

A prominent role for BRCA1 gene in alternative growth pathways may reflect therapeutic effectiveness of benserazide. As a result describes, high levels of BCAR1/pl30Cas protein in ER-positive primary breast tumours are associated with intrinsic resistance to tamoxifen treatment. Thus, deciphering the expression variance of  BRCA genes is essential for understanding development of resistance of breast cancer.

References:

1. Kuenen-Boumeester V, Hop WCJ, Blonk Dl, Boon ME. Prognostic scoring using cytomorphometry and lymplmode status of patients with breast carcinoma. Ellr J Canw· Cl Oncology, 20(3): 337-345, 1984.

2. Association of the BCAR1 and BCAR3 Scaffolding Proteins in Cell Signaling and Antiestrogen Resistance.  J Biol Chem. 2014 Apr 11;289(15):10431-44.

3. Tamoxifen resistance in breast cancer: elucidating mechanisms. Drugs. 2001;61(12):1721-33.

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.

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

When we injured ourselves , our body’s mechanisms turns damaged muscle into bone. It is not a science fiction rather than an unusual genetic disorder known as fibrodysplasia ossificans progressiva (FOP) that locks people in a second skeleton as they age.

A finding in the article of the journal Nature Genetics refer to a conspicuous genetic association between FOP and a metastatic childhood brain tumor, and this discovery may offer novel approaches to treat children with the incurable disease.

A famous case is that Harry Eastlack in five year old broke his leg. During his recovery , Harry’s knee and hip became hardened as bone start to form on his thigh muscles. As he grew up this condition spread around his body, freezing up his muscles. Exposure of the rare disease from the perspective of genes may benefit children with a brain tumor called diffuse intrinsic pontine glioma(DIPG). When Dr Chris Jones attempted to find the driving gene faults of DIPG, more striking was the discovery that the same few spelling mistakes matched those responsible for FOP.

A surprising genetic crossover as clues for treatments

The identified gene is known as ACVR1 encoding a key protein ALk2. A child carrying the faulty gene in all cells at birth would predispose to develop FOP. Also, if the faulty gene is present only in the precursor cells of the specialised glials then child could suffer from DIPG.

The variant of ACVR1 produces a hyperactive form of ALK2 that permanently switches on a set of signals in cells. The precise role these signals play in DIPG is not yet known, but thanks to research into FOP there are potential drugs already being developed that target the faults in ACVR1. These are hoped to be repurposed as a new treatment for children with DIPG in the future.

A selection of DIPG cells with the faulty ACVR1 gene in the lab were treated with one of these promising compounds, and the result showed that it was effective at killing the cells. However, It’s big challenge to turn these compound suitable for treating DIPG patients.

This study is a fascinating example of how two drastically different, but equally devastating, diseases can be brought together by the genetic events.

Reference : Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nature Genetics 2014, DOI: 10.1038/ng.2925

Marian R.Glancy

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.

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

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.

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

According to statistics, dealmaking partnerships shrank to 301 deals in 2013, down one-fifth from 2012. However, oncology persists as a dominant area with 84 deals, in which biotech startups cooperates with academic institute focusing on technology platform rather than a single compound.

 As data shown, it is the big-ticket deals in oncology, and deal making covers extensively broad spectrum, although top ten records the megadeals and the EP Vantage data focuses on deals around products in Phase 1 to Phase 3.

Deals by business area, 2013(Source: SciBx: Science-Business eXchange)

 Commercial returns in Cancer immunotherapy

Since FDA approved Dendreon’s Provenge for treating prostate cancer and Bristol-Myers’s Yervoy for melanoma treatment. Immunotherapy are increasingly seen as a fourth category of oncology treatment, added to surgery, radiotherapy and chemotherapy.

In a cancer immunotherapy deal announced in March 2013, Celgene established tie-up with the gene-therapy bluebird bio,. In the US$225 million-plus deal, bluebird will be applying its technology to genetically modify a patient’s own T cells, priming them to target and destroy tumor cells.

In another cancer immunotherapy deal that closed in 2012, Colby Pharmaceutical, a privately owned company based in San Jose, California, acquired the immunotherapy assets of MannKind, including a Phase 1 melanoma vaccine that uses intra–lymph node injection to target cancer antigens directly at T cells.

Insight into academic-private partnerships 2013

Harvard University was one of the most active deal makers without focusing on oncology in 2013 (shown by below table). By contrast, University of Texas System processed 3 deals, belonging entirely to oncology. In the 25 deals listed, 8 deals were engaged in oncology. Additionally, both Johns Hopkins University and KU Leuven broke into the top 5 in 2013. Correspondingly, University College London and Broad Institute of MIT and Harvard dropped out of the top 5.

Academic-private partnerships 2013

Reference:

1. Academic-industry partnerships 2013. Nature Biotechnology 2014. doi:10.1038/nbt.2861

Marian R.Glancy

Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin disease. Half of melanoma patients with the BRAF mutation have a positive response to treatment with BRAF inhibitors, but nearly all of those patients develop resistance to the drugs and experience disease progression. To overcome this disease, many investigators attempted to solve the problem of BRAF-inhibitor resistance leading to medically ineffective treatment.

A research indicates that the root of resistance to BRAF inhibitors may lie in a never-before-seen autophagy mechanism induced by the BRAF inhibitors in many cases. Autophagy is a process by which cancer cells recycle essential building blocks to fuel further growth. Block this pathway with the antimalarial drug hydroxycholoroquine (HCQ), and the BRAF inhibitors will be able to do their job better.

Another research interprets why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a ‘drug holiday’. According to analysis, 6 out of 16 melanoma tumours acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Suppression of sex determining region Y-box 10 (SOX10) in melanoma is found to cause activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. Additionally, investigators find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples.

With the application of value, Moffitt researchers found that using two inhibitors (Mekinist [trametinib] and Tafinlar[dabrafenib]) to block different growth pathways during treatment prevented resistance in patients with BRAF mutation. The combination of these two inhibitors, as a newly FDA-approved therapy, is one of the biggest advancements in melanoma treatment in the past 30 years. From a clinical perspective, 76 percent of patients achieve success in the treatment of the Mekinist and Tafinlar combination, and this therapy reduces the incidence and severity of some of the toxic effects patients experience when the drugs is used alone.

Reference:

1. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014 Apr 3;508(7494):118-22.

2. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. New England Journal of Medicine, 2012; 367 (18): 1694 DOI: 10.1056/NEJMoa1210093

3. Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI70454

Marian R.Glancy

An oncogene is a kind of abnormal gene that predisposes cells to develop into cancers. Unlike normal genes, oncogenes are altered in a way that keeps them stuck in a state of constant activity. That uninterrupted action helps drive the uncontrolled growth that underlies tumors. One measure scientists take to inhibit this process is that small inhibitory RNAs are designated for silencing oncogenes.

The activation of oncogenes involves genetic changes to cellular proto-oncogenes. The consequence of these genetic alterations is to confer a growth advantage to the cell. Three genetic mechanisms activate oncogenes in human neoplasms: mutation, gene amplification, and chromosome rearrangements. These mechanisms result in either an alteration of proto-oncogene structure or an increase in proto-oncogene expression. Because neoplasia is a multistep process, more than one of these mechanisms often contribute to the genesis of human tumors by altering a number of cancer-associated genes.

Against potential Achilles’ heel in the oncogene

A XBP1 gene implicated in progression and relapse of deadly breast cancer finding points to potential Achilles’ heel in triple negative breast cancer(TNBC), and targeting this gene may be a new approach to treating the disease. Investigators find that interactions between XBP1 and another transcriptional regulator, HIF1-alpha, spurs the cancer-driving proteins. Silencing XBP1 in the TNBC cell lines reduces the tumor cells’ growth and other behaviors typical of metastasis.

Another study shows that a critical gene called oncogene is turned off by RNA interference, and it increases survival rates in mice suffering from glioblastoma. The therapeutic, based on nanotechnology, is nimble enough to cross the blood-brain barrier and get to the brain tumor. Once there, it flips the switch of the oncogene to “off,” silencing the gene.

Reference:

1.  Mechanisms of oncogene activation. Holland-Frei Cancer Medicine. 6th edition.

2. XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature, March 2014 DOI: 10.1038/nature13119

3. Spherical Nucleic Acid Nanoparticle Conjugates as an RNAi-Based Therapy for Glioblastoma. Science Translational Medicine, 2013; 5 (209): 209ra152 DOI: 10.1126/scitranslmed.3006839

Marian R.Glancy