Category Archives: Molecular Mechanism

Uncover a novel mechanism of acquired paclitaxel resistance

Paclitaxel has been extensively used as an antitumor drug to treat a broad range of epithelial cancers, including breast and cervical cancers. However, the efficacy of this drug is greatly limited by the development of acquired resistance. Identification of the underlying resistance mechanisms may inform the development of new therapies that elicit long-term response of tumors to paclitaxel treatment.


Y Zhu et al. reported that increased expression of TNFAIP1 (tumor necrosis factor alpha-induced protein 1) confers acquired resistance to paclitaxel. TNFAIP1 is shown to compete with paclitaxel for binding to β-tubulin, thereby preventing paclitaxel-induced tubulin polymerization, cell cycle arrest and ultimate cell death. We also show that expression of TNFAIP1 is regulated by the transcriptional factor Sp1. In a xenograft mouse model, increased expression of TNFAIP1 decreases, whereas knockdown of TNFAIP1 increases tumor response to paclitaxel. Therefore, these results reveal tnfaip1 as a novel paclitaxel-resistance associated gene and suggest that TNFAIP1 may represent a valuable therapeutic target for the treatment of cancer.

Taken together, their data uncover a novel mechanism of acquired paclitaxel resistance and suggest that TNFAIP1 may represent a valuable therapeutic target for the treatment of cancer with paclitaxel resistance. However, there are still other issues remaining to be addressed.


Role of tumor necrosis factor alpha-induced protein 1 in paclitaxel resistance. Oncogene.2014;33:3246-3255

Make Breast Cancer at Bay with Evolving Therapies

When it comes to a topic that individualized medicine walks into a reality, scientists would stress that the current challenge is identifying different subtypes of patients so that treatment can be truly tailored to the individual.

Clinical developments have enabled the classification of patients into various subtypes, based on anatomical and pathological findings. Currently, samples from cancer patients are routinely tested for relevant biomarkers in order to tailor the treatment. The ultimate goal is to get the right drug to the right patient, at the right time.

Genetic testing in breast cancer is becoming common practice to predict each patient’s therapeutic effect and risk of recurrence. Testing for ER positivity enables physicians to determine the likelihood of response to endocrine therapy and provides a variety of treatment options. HER2 presents in around 25% of cases, and is associated with an aggressive form of the disease. The monoclonal antibody trastuzumab targets HER2 and is active in patients expressing this receptor.


“Treatment today is getting much more individualized,” says Dr. Clifford A. Hudis, chief of breast cancer medicine service at Memorial Sloan Kettering Cancer Center in New York. “Depending on the molecular nature of a woman’s tumor, postoperative hormonal treatment or other drug treatments are routinely prescribed to prevent or delay a recurrence of disease.”

Cancer therapy and its environment

Gone is the simplistic notion that cancer is a disease of abnormal cell division, said Dr. Larry Norton, deputy physician-in-chief for breast cancer programs.”It’s a disease of abnormal relationships between the cancer cell and other cells in its environment.”

This new perspective is leading to changes in treatment. Bevacizumab, as the first FDA-approved angiogenesis Inhibitor, slows or blocks the formation of blood vessel to treat cancer. It is based on the discovery that tumour sends out signals to nearly blood vessel causing new capillaries to sprout towards the tumour, thereby effectively hijacking the blood supply. Therefore, this monoclonal antibody blocks cancer cell growth by cutting off supplies from its environment.

In light of this new perspective, current surgery for breast cancer involves removing only a few lymph nodes, rather than a whole, for testing. “We know that in many cases we’re leaving behind nodes that contain cancer cells, but it doesn’t hurt the patient to leave them there. Because cancer cells require other cells in their vicinity to help them grow, it’s not true that if there’s one cancer cell left it will definitely grow and cause trouble.”Dr. Norton said.

Cancer immunotherapy

Instead of waiting for cancer to recur in certain high-risk patients, scientists are now developing techniques to outwit the cancer cell’s aggressive tactics by recruiting the patient’s immune system to launch a continuous attack.

Knowing that the effectiveness of treatment is reduced once cancer has metastasized, researchers are now testing creative ways to prevent such recurrences. One, a specially designed vaccine called NeuVax, is in the final stage of multinational clinical tests.

The vaccine is made from a peptide, a small piece of a cancer protein, that is combined with an immune stimulant. Early results suggest that the vaccine can reduce the risk of recurrence by 50 percent among breast cancer patients whose tumors produce low levels of the protein HER2, a marker for more aggressive breast cancer.

Another approach under study involves destroying the tumor by freezing it with an ice probe, but leaving it in place so that the immune system can be trained to attack it, Dr. Hudis said. The patient then would be given an immune stimulant to help overcome the molecular obstacles that had kept the immune system from recognizing the cancer as foreign tissue.


1. The HER2 peptide nelipepimut-S (E75) vaccine (NeuVax™) in breast cancer patients at risk for recurrence: correlation of immunologic data with clinical response. Immunotherapy. 2014 May;6(5):519-31.

2. Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. Semin Oncol. 1999 Aug;26(4 Suppl 12):78-83

Dysregulation of target genes of SOX2 is very likely to contribute to tumorigenesis or cancer progression

Lung cancer is the leading cause of cancer-related death in many countries in the world. Among all subtypes of lung cancer, non-small cell lung carcinoma (NSCLC) is the most frequent one, which accounts for greater than 80% of lung cancers.The prognosis of NSCLC patients is poor, with the 5-year survival rate of only about 18%, and the high mortality of NSCLC is thought to be attributed to difficulties in early diagnosis and the lack of effective therapeutic methods in general. NSCLC can be further classified into three histological subtypes, i.e., squamous cell carcinoma (SQC), adenocarcinoma (ADC) and large cell carcinoma (LCC). Among these subtypes, SQC and ADC are the major ones, which together represent ∼70% of NSCLC. SQC was once the most common subtype of NSCLC during the past century. However, it was noted later that proportion of SQC relative to ADC declined gradually, most probably owing to change in smoking behavior and improved diagnostic methods. Today, ADC is the most common subtype in many countries, while SQC is estimated to account for 20–25% of NSCLCs.

Compared with ADC of the lung, in which many driver mutations have been identified and targeted therapies are applicable to a good proportion of patients especially in the Far Eastern countries, neoplasms of SQC of the lung were once regarded as tumors without readily targetable genetic abnormalities. However, recent studies have identified new lung SQC-associated genetic changes, including the amplification and overexpression of SOX2. SOX2 is located on chromosome 3q26, a region amplified in about 20% of lung SQC. At a much higher rate than gene amplification, overexpression of SOX2 mRNA was observed in about 90% of the lung SQC, indicating that SOX2 might play oncogenic role(s) in the tumorigenesis of lung SQC, which is supported by studies reporting that SOX2 is a lineage-survival oncogene of SQC of the lung.

As SOX2 functions upstream of the hierarchy of gene expression network, it is likely that its aberrant expression in lung epithelia could cause profound change in a wide variety of molecular pathways, which may contribute to growth and survival of the lung SQC cells. Although the oncogenic role of SOX2 in lung SQC has been identified, there is still a paucity in the understanding of the mechanisms regarding how SOX2-mediated signaling network affects the formation or progression of lung SQC cells.

In an initiative, using SOX2-abundant lung SQC cell lines, Wen-Tsen Fang et al. screened for genes whose expression was not only affected by silencing of SOX2 but can also account for the inhibition of cell growth upon SOX2 silencing. Among the other candidate genes, they found that BMP4, a member of the TGF-β superfamily genes, was significantly affected by silencing SOX2. As genes of TGF-β family are well known for their involvement in the regulation of cell proliferation and differentiation, they postulated that BMP4 is a plausible target of SOX2. In their study, several lines of evidence from in vitro and in vivo observation were provided showing that BMP4 expression may be transcriptionally suppressed by SOX2 to promote growth of lung SQC cells.


Downregulation of a putative tumor suppressor BMP4 by SOX2 promotes growth of lung squamous cell carcinoma. Cancer Cell Biology.2014;135:809-819

Combine immune response with radiation therapy

Radiation therapy is used in the treatment of around 50% of cancer patients and remains the most important nonsurgical treatment in the management of solid malignancies. Treatment with ionizing radiation (IR) induces lethal DNA damage leading to cellular death through mitotic catastrophe, necrosis and apoptosis. Recent evidence also suggests that treatment with IR can render the tumor cells immunogenic and potentially generate antitumor immune responses.

Exposure of cancer cells to IR leads to cellular stress and the expression of several damage-associated molecular patterns (DAMPs). These include High Mobility Group Box 1 (HMGB1) and the extracellular release of ATP, which can activate professional antigen presenting cells (APCs), such as the dendritic cell (DC), and engender tumor antigen-specific T-cell responses. In addition, the induction of DNA damage subsequent to treatment with IR can lead to the production of novel (and potentially immunogenic) proteins and has been shown to upregulate tumor cell expression of class I MHC. Taken together, these data demonstrate the immunogenic potential of radiation therapy for cancer. Data from preclinical studies, however, demonstrate that established tumors foster immunosuppressive microenvironments that favor angiogenesis and the production of cytokines such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), which attenuate TH−1 cytotoxic activity. Consequently, in both preclinical and clinical studies the use of IR alone is rarely capable of generating durable tumor antigen-specific immune responses. However, several preclinical studies have demonstrated the generation of systemic immune responses following combination therapy with IR and immuno-modulators such as monoclonal antibodies to CTLA4 and CD40, and small molecule agonists of the Toll-like receptor (TLR) family members TLR7 and TLR9.

Members of the TLR family are responsible for recognizing a diverse array of evolutionarily conserved pathogen-associated molecular patterns and are constitutively expressed by both professional APCs and effector immune cell populations. Activation of TLR7, which is localized intracellularly in endosomal membranes and recognizes viral guanosine and/or uridine-rich single-stranded RNA, leads to a MyD88-dependent signaling cascade ultimately resulting in interferon regulatory factor-7 (IRF-7), AP-1 or NFκB-mediated transcription of TH1 cytokines, predominantly Type I interferon (IFN).

Synthetic small molecule agonists of TLR7 have been developed such as imiquimod (Aldara 5% cream, 3M), which is FDA-approved for the treatment of genital warts and superficial basal cell carcinoma. However, delivery of topical TLR7 agonists to noncutaneous tumors is challenging and would require image-guided delivery such as ultrasound or computerized tomography. We have previously demonstrated that systemic delivery of a TLR7-selective small molecule agonist leads to the priming of systemic immune responses capable of reducing both primary and metastatic tumor burden. The TLR7 agonist 852A (Pfizer) is currently one of the most extensively studied compounds to be tested systemically in clinical trials. Amy L. Adlard et al. assessed the antitumor efficacy of a newly described systemically administered 8-oxoadenine derivative, DSR-6434, which has a higher water solubility and a 300-fold greater potency for human TLR7 than 852A. Their results demonstrate that systemic administration of DSR-6434 can enhance the effectiveness of radiotherapy in two syngeneic tumor models and that this occurs as a consequence of TLR7 activation and the generation of tumor-specific immune responses.


A novel systemically administered toll-like receptor 7 agonist potentiates the effect of ionizing radiation in murine solid tumor models. Tumor Immunology . 2014;135:820-829

Therapeutic Combination: The Blockage of Cancer Signaling Pathways

When cancer patients are initially diagnosed, they eagerly wonder if it’s curable. That’s because pharmacists and doctors are engaging in the development of novel treatment regimens that are expected to be more effective than traditional chemotherapies, and have fewer side effects. Indeed, they’re finding that therapeutic combinations have the potential to be more effective in slowing or even blocking cancer growth.


Biologic agents act against oncogenic proteins or enzymes in tumor cells that drive cancer development. However, considering complex signaling networks, including these proteins, interact through crosstalk and feedback loops to form drug resistance , clinical physicians would envision several trial designs to achieve the optimal drug combination.

“Cell signals operate in pathways, or networks, similar to interstate highways. When the interstate is clear, traffic runs smoothly. But an accident at one part, or a closed exit ramp, can lead to massive traffic snarls. That’s what happens in cancer, where an error in any signal along the pathway can bring the entire growth-regulating system to a halt.” explains Lebwohl, senior vice president and global head of Oncology Clinical Development at Novartis.

Biomarkers and therapeutic combination

Nearly all pharmaceutical companies are investigating oncogenic proteins, or biomarkers, which initiate the development of potential drugs. For instance, currently most of Roche’s anti-cancer drug candidates in clinical development are being developed with targeted biomarkers, by which doctors can distinguish the certain patients with potential pharmaceutical benefit.

Biomarker studies can help to understand disease biology and to identify patient subgroups in favour of genotyping. Moreover, biomarkers can help to understand the outcome of therapeutic combination and how to rationally design therapeutic combination. Finally, another goal of biomarker research is to understand the development of resistance against cancer therapies and overcome this issue.

A successful therapeutic Combination against cancer

A new study, published in the Lancet oncology, firstly demonstrate chemotherapy and a targeted therapy in combination work better than chemotherapy alone in treating lung cancer patients with KRAS mutation.

The 87 patients who participated in the phase II trial had advanced, KRAS-mutant NSCLC that had failed initial chemotherapy. They were randomly assigned to receive either selumetinib and the chemotherapy agent docetaxel or docetaxel alone. As investigators found, patients receiving selumetinib lived a median of 5.3 months before their cancer began to worsen, compared to 2.1 months for those receiving chemotherapy alone.

“Our findings suggest that selumetinib and docetaxel work synergistically – each enhancing the effect of the other,” says Dr. Pasi A. Jänne, HMS associate professor of medicine at Dana-Farber Cancer Institute. “This opens the possibility that there may finally be a therapeutic strategy using a targeted therapy which could be clinically effective in this population of KRAS-mutant lung cancer patients.”


1.  Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol. 2013;31(12):1592-605.

2. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14(1):38-47.

KRAS(G12C) Inhibitors: Shatter the myth about Undruggable Mutation Oncogene

For over 30 years, the protein KRAS is a major challenge in drug design. So far, there is no approved therapy for patients with KRAS mutations, which comprise around 25% of patients with lung cancer. It’s been on everyone’s “target” list as commonly mutated oncogene, while KRAS has earned a reputation in scientific circles as being “undruggable” because many pharmaceutical, biotech, and academic laboratories have failed to design a drug that successfully targets the mutant gene.

The KRAS Pathway and chemical compounds sitting inside a pocket in KRAS.

The KRAS Pathway and chemical compounds sitting inside a pocket in KRAS.

But recently , Dr. Kevan M. Shokat and his colleagues, in the Howard Hughes Medical Institute (HHMI) at the University of California, published an article entitled “KRAS(G12C) inhibitors allosterically control GTP affinity and effector interactions ” in the Nature journal, which aims for identifying and exploiting a novel “Achilles heel” in KRAs. They found “pocket”, or binding site, and designed a chemical compound that fits inside this pocket and inhibits the normal activity of mutant KRAS.

The above small molecules irreversibly bind to KRAS(G12C), subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Shokat said, “We report the discovery of a new pocket on KRAS that is druggable, and we believe this has real translational implications for patients.”

 Additionally, Dr. Nathanael S. Gray, in the Department of Cancer Biology at the Dana-Farber Cancer Institute, reported the synthesis of a GDP analogue(SML-8-73-1) and a prodrug derivative (SML-10-70-1), which were selective, direct-acting covalent inhibitors of the KRAS (G12C) mutant relative to wild-type Ras. Biochemical and biophysical measurements suggested that modification of KRAS with SML-8-73-1 renders the protein in an inactive state.

What is KRAS protein?

KRAS, a member of Ras protein family, acts as a molecular on/off switch. When turned on , it recruits and activates proteins necessary for the proliferation of growth factor and ther receptors’ signal such as c-Raf and PI 3-kinase. In Combination with GTP, KRAS possesses an intrinsic enzymatic activity which cleaves the terminal phosphate of the nucleotide, and finally make itself turn off.

KRAS is one of the most frequently mutated oncogenes in human cancer. According to a discovery nearly 30 years ago, KRAS is mutated in 30 percent of human tumors, including 90 percent of pancreatic cancers, 40 percent of colon cancers, and 20 percent of non-small cell lung cancers. Cancers with Ras mutations are aggressive and respond poorly to standard therapies.

How to test KRAS mutations

KRAS mutations (adapted from Heinemann et al.,2009)

KRAS mutations (adapted from Heinemann et al.,2009)

The usual testing detects the seven common mutations in exon 2, codons 12 and 13, which account for up to 90-95% of KRAS gene mutations. While scientists would use variant methods without standardized regulations. It is noteworthy that Mayo Clinic’s Molecular Genetics Laboratory has recently introduced a KRAS mutation analysis assay (#89378 KRAS Gene, 7 Mutation Panel, Tumor Tissue) that tests for the common mutations in codons 12 and 13. As shown in the assay, concordance between the presence or absence of KRAS mutations in a patient’s primary tumor and corresponding metastatic tumors is high.

KRAS mutation testing may be performed on the primary tumor or a metastasis, and both are equally acceptable. The pathologist should select a tissue sample that is predominantly tumor and estimate the percentage of tumor cells in the sample. After all, direct sequencing, generally considered as the “gold standard” for KRAS mutation detection, requires a higher percentage of tumor DNA to reliably detect the mutation.

 Treatment for cancer patients with KRAS Mutation

The Selected 4 Trials for KRAS Mutation

The Selected 4 Trials for KRAS Mutation

Some clinical trial data has suggested that patients with a KRAS mutation treated with chemotherapy and anti-EGFR therapy not only did not respond to the treatment, but had worse clinical outcomes than those treated with chemotherapy alone. There is currently no clear explanation for these findings.

Recent studies indicate that KRAS-normal tumors with a BRAF V600E mutation will also not respond to EGFR targeted therapy. This prompted National Comprehensive Cancer Network (NCCN) to update their guidelines to include optional BRAF mutation testing if KRAS results are normal.

EGFR is a therapeutic target for several other human tumors and Erbitux has been approved for use in certain head and neck cancers. However, KRAS mutation testing is not routinely recommended to guide treatment decisions for any other cancers.


1. KRAS(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature.  2013, 503, 548–551

2. Therapeutic Targeting of Oncogenic KRAS by a Covalent Catalytic Site Inhibitor. Angew Chem Int Ed Engl. 2014 Jan 3;53(1):199-204.

3. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treatment Reviews. 2009,


Unveil a Novel Mechanism for Bleomycin against Cancer

Approved by FDA in 1973, bleomycin– an kind of antibiotic produced by the bacterium, Streptomyces verticillus — has been employed for clinical treatment, especially for Hodgkin’s lymphoma, squamous cell carcinomas, and testicular cancer. However, its anti-cancer mechanism remain poorly known.


In a new research, investigators depict bleomycin’s property to cut through double-stranded DNA in cancerous cells, like a pair of scissors. Such DNA cleavage always cause some types of cancer to death. The study, lead by Basab Roy, firstly present alternative biochemical mechanisms for DNA cleavage by bleomycin.

Specifically bind DNA regions

Scientists keep on studying several forms of bleomycin and developing a scaled library of variants, with the purpose of designing the best bleomycin analog. Their interests focus on the subtle biochemistry of bleomycin, including the specificity of its binding sites along the DNA strand and the drug ‘s detailed mechanisms of DNA cleavage.

Beomycin A5 in the new study has similar DNA binding and cleaving properties, as well as bleomycin A2 and B2. Previous research has revealed that bleomycin binds with highly specific regions of the DNA strand, typically G-C sites, where a guanosine base pairs with a cytidine. Further, the strength of this binding is closely associated with the degree of double-strand DNA cleavage.

Cut cancer to pieces

As one of attractive feature, Bleomycin can be administered in relatively low doses in the treatment of some many other cancer. Previous research has shown that bleomycin can cause death in aberrant cells by migrating to the cell nucleus, binding with DNA and subsequently causing breaks in the DNA sequence.

Cleavage of DNA is regarded as a major mechanism by which bleomycin kills cancer cells, particularly through double-strand cleavages. It pose a great challenging for the cellular machine to repair. “There are several mechanisms for repairing both single-strand and double-strand breaks in DNA, but double-strand breaks are a more potent form of DNA lesion,” Roy says.

There is a great deal of work required to elucidate the biochemical causes of tight binding by bleomycin. The future discovery on drug-DNA binding aspect will guide improvement of the drug in property and alleviation of toxicity to healthy cells.


1. Hairpin DNA Sequences Bound Strongly by Bleomycin Exhibit Enhanced Double-Strand Cleavage. Journal of the American Chemical Society, 2014; 136 (11): 4382

2. Targeting DNA damage and repair: Embracing the pharmacological era for successful cancer therapy. Pharmacol Ther. 2012 Mar;133(3):334-50.

Drug Resistance: Conspiracy of Two Protein against Breast Cancer

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.


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.

Stone Man Syndrome Offer Hints for Treating Terrible Childhood Brain Tumors

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.

From bone to brain

From bone to brain

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

To target oncogenes: An Achilles’ heel of Cancer

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.


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