Their skills are literally in their DNA. Contrary to what we were told growing up as we trudged to music lessons and spent hours working on our piano fingerings or flute exercises, practice doesn’t make perfect. That is, unless you have the genetic profile for a star. Regardless of the hours spent practicing, two twins have about the same musical ability, according to a recent study published in the journal Psychological Sciences. Sorry Malcolm Gladwell fans, it appears 10,000 hours might not even cut it.

How do researchers know it’s genes, and not something else? Because they studied twins. Since they share their DNA, twins help scientists determine how factors outside the genes influence characteristics like music ability. Lead researcher Miriam Mosing looked at more than 1,000 pairs of identical twins (who share all their genes) and roughly the same number of fraternal twins (who share half). She then found the ones who sang or played a musical instrument and asked each to estimate how many hours a week they practiced at different ages. Mosing then used three tests to measure the person’s ability to detect differences in each of pitch, melody and rhythm. Unfortunately, for those putting in countless hours of practice, it seemed the real talent was mostly innate.

Here’s the craziest finding: In one pair of twins Mosing studied, the difference in total practice time over the course of both subjects’ lives was a whopping 20,228 hours of practice. Regardless, their musical ability was found to be the same. A previous study of identical twins not only had similar results, but it also found that the tendency to practice in the first place is also under genetic control. Sounds like an endless spiral, right? So here’s what we have: People with better genes will become better musicians, no matter how much they practice, and people with the genes to become better musicians are already programmed to practice more. It looks like that old joke might have to be altered: How do you get to Carnegie Hall? Genetics, genetics, genetics. 

In a recent study published in the journal PNAS, investigators have discovered a two-pronged therapeutic approach that shows great potential for weakening and then defeating cancer cells. The research team’s mix of genetic and biochemical experiments uncovered a avenue to enhance the presence of a tumor-suppressing protein, which stimulates cancer cells for self-destruction.

The finding holds the promise of increasing the effectiveness of radiation and chemotherapy in killing cancer if the research is supported by tests in animal models. The key is to increase p53-binding protein 1 (53BP1) so that it can weakens the cancer cells, leaving them more susceptible to existing cancer-fighting treatments.

New discovery for treating cancer

Researchers insisted on that the discovery could lead to a gene therapy where extra amount of 53BP1 will be generated to make cancer cells more susceptible to cancer measures. Alternatively, they could design other molecules to enhance levels of 53BP1 in cancer with the same cancer-killing effect.

The basis of the research involves DNA repair -more specifically, double-strand DNA repair. DNA damage is the consequence of an irregular change in the chemical structure of DNA, in which double-strand break in the chromosome is the most lethal irregularity to DNA.

There are two repair pathways operated in the body to fix these double strand breaks. One provides rapid, yet incomplete repair — namely, gluing the DNA strand ends back together. The second pathway uses information from intact, undamaged DNA to instruct damaged cells on how to mend broken double strands. During the study, investigators discovered a previously unidentified function of a known gene, UbcH7, in regulating DNA double-strand break repair. Specifically, they found that depleting UbcH7 led to a dramatic increase in the level of the 53BP1 protein.

The aim of the study is to increase the level of 53BP1 to force cancer cells into the error-prone pathway where they will die. Investigators expect to suppress deliberately the second repair pathway, the measure probably giving rise to enhanced effectiveness of cancer therapy drugs. To examine further, investigators would study the effects of introducing the protein 53BP1 in lab mice with cancer.

Reference:

UbcH7 regulates 53BP1 stability and DSB repair. Proceedings of the National Academy of Sciences, 2014; 111 (49): 17456

A new drug-Pictilisib can block the growth of cancer cells, this research was published on the Clinical Cancer Research.

PI3K pathway plays the key role in helping cancer cell growth, spreading to other parts of the body, maintaining the survival of cancer cell. Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue.

This experiment confirmed that the pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.

Reference:

Sarker D, Ang JE, et al. First-in-Human Phase I Study of Pictilisib (GDC-0941), a Potent Pan-Class I Phosphatidylinositol-3-Kinase (PI3K) Inhibitor, in Patients with Advanced Solid Tumors. [J].Clin Cancer Res, 2015 Jan 1;21(1):77-86.

According to the research from British Cancer Research Institute, when brain tumor-medulloblastoma relapses, there will be a unique genetic pathway.This study was published in Cancer Cell.

Relapse following conventional treatment is the single most adverse event in medulloblastoma. There are currently no effective therapies for children with relapsed medulloblastoma. Although clinical and biological features of the disease at diagnosis are increasingly well understood, biopsy is rarely performed at relapse, and few biological data are available to guide more effective treatments.

Moreover, disease features have been identified at diagnosis that are consistently associated with clinical outcomes. For high-risk disease, these are MYC gene family amplification, TP53 mutation, chromosome 17 defects, large-cell anaplastic pathology, metastatic disease, and subtotal surgical resection.

In this study, scientists show that medulloblastomas develop altered biology at relapse, which is predictive of disease course and cannot be detected at diagnosis. They have discovered the emergence of P53-MYC interactions at relapse, as biomarkers of clinically agressive relapsed disease, which can be modeled and routine clinical practice, to direct palliative care and the development of improved treatment strategies.

Reference:

Hill R M, Kuijper S, Lindsey J C, et al. Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease[J]. Cancer Cell, 2014.

Researchers from University of Dundee have identified an important function of one cancer suppressor gene, which may help scientists better understand how this gene confront the influences of oncogene mutation. This study was published in PNAS.

Dual-specificity phosphatase 5 (DUSP5) is one of four mammalian inducible, nuclear mitogen-activated protein kinase (MAPK) phosphatases (MKPs). However, DUSP5 is unique within this group in targeting only the classical extracellular signal-regulated kinases 1 and 2(ERK). Ras/ERK signaling is frequently deregulated in human cancers due to activating mutations in pathway.

Ras/extracelluar signal-regulated kinase (ERK) signaling is implicated in human cancer development and progression. ERK activation also results in the expression of MAP kinase phosphatases(MKPs) that inactivate ERK. However, it is currently unclear how MKPs regulate the oncogenic potential of the Ras/ERK pathway.

In this study, scientists identify the MKP encoded by dual-specificity phosphatase 5 (DUSP5) as both a key regulator of nuclear ERK activity and a tumor suppressor in the DMBA/TPA model of Harvey Ras (Hras)-induced skin carcinogenesis. DUSP5 loss results in increased HRas/ERK-inducible SerpinB2 expression, which causes increased skin cancer sensitivity.

Their results establish a key role for DUSP5 in the regulation of oncogenic ERK signaling and suggest that this enzyme may play a wider role in tumors containing activated Ras.

Reference:

Rushworth L K, Kidger A M, Delavaine L, et al. Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRasQ61L)-driven SerpinB2 expression[J]. Proceedings of the National Academy of Sciences, 2014, 111(51): 18267-18272.

A recent study from Steven Goossens and Enrico Radaelli shows that ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and ​IL-7 receptor signaling.

First, they observed increased ​ ZEB2 levels in the paediatric and adult immature/ETP-ALL subclass and identified a rare but recurrent t(2;14)(q22;q32) translocation in a few of these typical ETP-ALL cases. This novel translocation, results in juxtaposition of the promotor and proximal portion of the ​BCL11B locus to the ​ZEB2 locus, a finding reminiscent of previously described ​BCL11B-driven T-ALL oncogene activation. These data are strongly indicative for an oncogenic driver role for  ​ZEB2in T-ALL, and is consistent with previously reported retroviral mutagenesis screens  that have suggested ​Zeb2 involvement in leukaemogenesis. Whether or not loss/alternative functions of ​ BCL11B are involved in leukaemia initiation/progression specifically in these patients remains unknown. Importantly, other mechanisms are involved in ETP-ALL patients leading to ​ZEB2upregulated expression levels besides these rare recurrent translocations. One potential mechanism may be related to altered expression of  ​miR200c, which have previously been shown to negatively regulate Zeb family member expression and to be altered in cancer settings. Exactly how  ​miR200c levels are downregulated to begin with remains to be determined but may be related to changes in the promoter methylation status as has been previously shown in other tumour types.

Using a ​ROSA26-based overexpression of ​Zeb2 in the endothelium and throughout the entire haematopoietic system induces formation of precursor T-cell lymphoblastic leukaemia. Using the T-cell-restricted  ​CD4-Cre line to overexpress ​Zeb2 recapitulated the spontaneous thymoma formation and strongly suggests a cell autonomous role of ​Zeb2, however, given the paracrine effects associated with ​Zeb2 deletion in the central nervous system, they cannot exclude environmental involvement in the observed T-cell lymphoma formation phenotype. Intercrossing onto a ​p53-deficient background drastically accelerated tumour formation and shifted the tumour spectrum towards an immature precursor T-cell lymphoblastic leukaemia, with an expression profile similar to ETP-ALL patients. Mouse tumours showed prototypical activating mutations affecting ​Notch1 and loss of the tumour-suppressor genes ​Pten and ​Ikzf1, supporting the fact that the ​p53 null ​Zeb2 transgenic mouse model closely recapitulates human T-cell leukaemia, and is in keeping with the higher occurrence of ​IKZF1 mutations in ETP-ALLs.

In line with a presumed ETP-ALL phenotype for the mouse ​Zeb2-driven leukaemias, they also observed increased LSC properties. These enhanced LSC characteristics associated with ​Zeb2 overexpression are in line with previous observations that expression of the ZEB family members is correlated with poor prognosis of solid tumours, putatively in part through the acquisition of enhanced cancer stemness programmes.

Mechanistically, we demonstrate that ​ZEB2 leads to upregulated ​IL7R expression in immature/ETP-ALL cells. A strong positive correlation was observed between ​Zeb2 and ​Il7r mRNA levels in our mouse model and in the human LOUCY cell line, which exhibits an ETP-ALL-like phenotype. ​IL-7signalling is of key importance in normal thymocyte maturation and differentiation and constitutive activation of ​IL7R-driven signalling has been shown to lead to T-ALL oncogenesis. In approximately 10% of T-ALLs, including ETP-ALLs, activating mutations in the ​IL7R gene are present representing an interesting drugable target for novel treatment using ​IL7R-blocking antibodies or more novel compounds for the inhibition of downstream JAK/​STAT5 signalling27, like ​RUX. Previous studies have demonstrated that use of blocking ​IL-7 antibodies or use of ​IL-7-deficient mice could dramatically decrease human T-ALL formation in xenotransplantation settings using immunocompromised mice27, 42. Here we could see a clear ​IL-7-dependent survival effect of the derived ​Zeb2-overexpressing mouse T-ALL cell lines in vitro and an effect on their ability to initiate secondary tumours after transplantation. Whether the described ​ZEB2-​IL7R axis is also important in human ETP-ALL disease progression remains to be tested.

In conclusion, we have found that sustained overexpression of ​Zeb2 acts as a leukaemic driver for immature T-ALLs with increased leukaemic stem cell properties. ​ZEB2-mediated upregulation of Il7rexpression and activation of the JAK/STAT pathway represents a possible therapeutic target for this aggressive and chemoresistant subtype of human T-ALL.

Reference

ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and ​IL-7 receptor signaling, Nature Communications 6, Article number: 5794 ｜doi:10.1038/ncomms6794

Prevailing opinion holds that human cells accumulate DNA damage and that eventually this damage catches up with the body in a way that causes cancer. A recent study, lead by a team from a University of Colorado Cancer Center, shows that this prevailing opinion is incomplete. In addition to DNA damage, cancer depends on the slow degradation of tissue that surrounds cancer cells, something that naturally comes with aging.

A investigator interprets that when a person is young, healthy cells are optimized to the surrounding tissue. At that point, any mutation that influences function makes a cell less fit, so cells with mutations are not out-competed by the young, healthy cells. But in the aged landscape, mutations may actually make certain cells better, allowing them to out-compete the normal cells and form tumors.

To effectively monitor it, researchers created mathematical models of this kind of natural selection in hematopoietic or blood cells. The models are used to predict what it exists in the real world by combining several variables, like predicting the weather.

When scientists plugged only mutation variables into the model, the result appeared poor fit. Even if it is believed that mutations would play a role -even a big role , the model would not accurately predict stem cell changes overtime or leukemia development without other factors. So, investigators look not only inside cells, but also outside the cells for the causes of cancer.

They added more variables to the model to account for microenvironmental tissue decline. Suddenly, there was a much better fit. The new model, driven by age-related changes in stem cell fitness and behavior, accurately predicts the point at which a cancer cell might out-compete the normal cells and become a leukemia. Importantly, the model demonstrates that the systemic processes accompanying general tissue decline with age have a crucial power in governing cancer cell fates and the odds of developing cancer.

Scientists point out that natural selection only “cares” about the human body until it passes reproductive age. It means that there is programmed maintenance that takes care of human bodies and keeps them fit until around age 40. At that point, the maintenance program gets lazy. And tissue landscape then starts to change, and unfortunately it changes in ways that allow cancer cells to out-compete normal cells.

In summary, only mutations, although necessary, cannot promote blood cancer development without an age-altered tissue microenvironment. This implies that in addition to research and drug development aimed at the genetic mutations associated with cancer, scientists need to work on maintaining the fitness of  human tissue landscape in order to prevent cancer cells from taking over. Natural selection has provided human bodies with a very effective mechanism to accomplish this maintenance until middle ages.

Reference:

Stochastic modeling indicates that aging and somatic evolution in the hematopoietic system are driven by non-cell-autonomous processes. Aging, December 2014

New study from the wistar institute, published in the journal Cancer Cell, reported that a variation in a person’s DNA sequence called molecular polymorphism could lead to a chain of events, dictating how a tumor will progress in certain types of cancer, such as a form of breast cancer as well as ovarian cancer.

The study indicated that the interaction between the helpful bacteria in human body and immune cells at places situated away from tumors influence systematic responses in the host that alter how these tumors are able to progress.

Many of human cells are programmed to recognize pathogen-associated molecular patterns. Over 23% of the general public carries mutations in a group of pathogen recognition receptors called Toll-like receptor (TLR) genes. To be the most abundant polymorphisms is TLR5, which makes the people who do carry it susceptible to illnesses such as Legionnaires disease, and urinary tract infections.

Whether does TLR5 signaling influence cancer?

As shown from the research, TLR5 signaling influences certain types of cancer in different ways and is dependent upon the ability of the tumor to respond to interleukin 6 (IL-6), a small protein that can have both pro-inflammatory and anti-inflammatory properties.

In individuals with functional TLR5 expression, commensal bacteria are able to stimulate IL-6 production, as well as greater mobilization of myeloid-derived suppressor cells (MDSCs) , to produce high amounts of galectin-1, a protein that suppresses antitumor immune activity and hastens tumor progression.

While the researchers showed that TLR5 signaling does not always mean that tumors will grow faster. TLR5-deficient mice with tumors that produce low levels of IL-6 have faster tumor progression. In this instance, IL-17, another interleukin closely associated with autoimmune diseases and inflammation, is consistently found in higher levels in TLR5-deficient mice that have tumors, but IL-17 only accelerates cancer when the tumors are unresponsive to IL-6.

For ovarian cancer, which is associated with high levels of IL-6, researchers found a significantly higher number of TLR5-deficient patients alive six years after their initial diagnosis compared with patients with TLR5, indicating a correlation between the absence of TLR5 and improved survival. For luminal breast cancer, which is associated with low levels of IL-6, the long-term survival prospects were worse for patients without TLR5.

Reference:

Microbially Driven TLR5-Dependent Signaling Governs Distal Malignant Progression through Tumor-Promoting Inflammation. Cancer Cell, 2014

Recently, the researchers from Case Western Reserve University found that combining mTOR and Src inhibitors may provide a new approach for treating multiple breast cancer subtypes that may circumvent resistance to targeted RTK therapies.

Resistance to receptor tyrosine kinase (RTK) blockade in breast cancer is often mediated by activation of bypass pathways that sustain growth. Src and mammalian target of rapamycin (mTOR) are two intrinsic targets that are downstream of most RTKs. To date, limited clinical efficacy has been observed with either Src or mTOR inhibitors when used as single agents. Resistance to mTOR inhibitors is associated with loss of negative feedback regulation, resulting in phosphorylation and activation of AKT. Herein, the study describe a novel role for Src in contributing to rapalog-induced AKT activation. The research found that dual activation of Src and the mTOR pathway occurs in nearly half of all breast cancers, suggesting potential cross-talk. As expected, rapamycin inhibition of mTOR results in feedback activation of AKT in breast cancer cell lines. Addition of the Src/c-Abl inhibitor, dasatinib, completely blocks this feedback activation, confirming convergence between Src and the mTOR pathway. Analysis in vivo revealed that dual Src and mTOR inhibition is highly effective in two mouse models of breast cancer. In a luminal disease model, combined dasatinib and rapamycin is more effective at inducing regression than either single agent. Furthermore, the combination of dasatinib and rapamycin delays tumor recurrence following the cessation of treatment. In a model of human EGFR-2–positive (HER2+) disease, dasatinib alone is ineffective, but potentiates the efficacy of rapamycin. These data suggest that combining mTOR and Src inhibitors may provide a new approach for treating multiple breast cancer subtypes that may circumvent resistance to targeted RTK therapies.

Reference:

Jennifer L. Yori1, Kristen L. Lozada,et,al. Combined SFK/mTOR Inhibition Prevents Rapamycin-Induced Feedback Activation of AKT and Elicits Efficient Tumor Regression [J].Cancer Res., 2014 74; 4762.

Scientists from Baylor College of medicine have identified a new mechanism by which bladder cancer stem cells(CSCs) actively contribute to therapeutic resistance via an unexpected proliferative response to repopulate residual tumours between chemotherapy cycles. It may provide a potential new method to cure cancer. This study was published in Nature.

Bladder urothelial carcinomas contain cells that span various cellular differentiation stages, cytokeratin 14(CK14) marks the most primitive (or least differentiated) cells and patients with abundant Ck14 staining correlate with poor survival. On the other hand, cytotoxic chemotherapy remains the standard of care for many advanced carcinomas. Although chemotherapy is effective in debulking tumour mass, certain patients show initial response but progressively become unresponsive after multiple treatments.

In this study, researchers investigate the unexplored concept that CSCs may actively proliferate in response to chemotherapy-induced damages, similar to how tissue resident stem cells mobilized to wound sites during tissue repair. Further analyses demonstrate the recruitment of a quiescent label-retaining pool of CSCs into cell division in response to chemotherapy-induced damages, similar to mobilization of normal stem cells during wound repair. While chemotherapy effectively induces apoptosis, associated prostaglandin E₂ (PGE₂) release paradoxically promotes neighboring CSC repopulation.

This repopulation can be abrogated by a PGE₂ signaling. In vivo administration of the cycooxygenase-2(COX2) inhibitor celecoxib effectively abolishes a PGE₂- and COX2-mediated wound response gene signature, and attenuates progressive manifestation of chemoresistance in xenograf tumour, including primary xenografts derived from a patient who was resistant to chemotherapy.

These findings uncover a new underlying mechanism that models the progressive development of clinical chemoresistance, and implicate an adjunctive therapy to enhance chemotherapeutic response of bladder urothelial carcinomas by abrogating early tumour repopulation.

Reference:

Kurtova A V, Xiao J, Mo Q, et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance[J]. Nature, 2014.