New class of compounds shrinks pancreatic cancer tumors, prevents regrowth .

A chemical compound that has reduced the growth of pancreatic cancer tumors by 80 percent in treated mice has been developed by researchers. The compound, called MM41, was designed to block faulty genes. It appears to do this by targeting little knots in their DNA, called quadruplexes, which are very different from normal DNA and which are especially found in faulty genes.

Pancreatic cancer is the most lethal of any common cancer. Only three in every 100 people diagnosed will live for five years or more and this survival rate has barely improved in the last 40 years.

Scientists from UCL (University College London) have designed a chemical compound that has reduced the growth of pancreatic cancer tumors by 80 percent in treated mice.

The compound, called MM41, was designed to block faulty genes. It appears to do this by targeting little knots in their DNA, called quadruplexes, which are very different from normal DNA and which are especially found in faulty genes.

The findings, published in Nature Scientific Reports, showed that MM41 had a strong inhibiting effect on two genes — k-RAS and BCL-2 — both of which are found in the majority of pancreatic cancers.

Funded by the UK charity, Pancreatic Cancer Research Fund, the UCL team, led by professor Stephen Neidle, conducted a small-scale trial, treating two groups of eight mice with pancreatic tumors with different doses of MM41 twice a week for 40 days (12 doses). A further control group received no treatment. The tumors in the group given the larger dose decreased by an average of 80 percent during the treatment period, and after 30 days, tumor regrowth stopped in all the mice. For two of the mice in this group, the tumor disappeared completely with no signs of regrowth after treatment ended for a further 239 days (the approximate equivalent to the rest of their natural life span).

Analysis of the mice tumors showed that the MM41 compound had been taken up into the nucleus of the cancer cells showing that it was able to effectively target the pancreatic cancer tumor.

The team also saw no significant side effects on the mice during the study: there was no damage to other tissue or organs, and none of the mice showed any significant weight loss.

Discussing the results, Neidle explained: “This research provides a potentially very powerful alternative approach to the way that conventional drugs tackle pancreatic cancer, by targeting a very specific area of the DNA of faulty genes. One of the genes that MM41 blocks — the BCL-2 gene — is involved in regulating apoptosis, the body’s natural process which forces cells to die if they become too damaged or unhealthy to be repaired. BCL-2 is present in high amounts in many tumors and helps cancer cells to survive, but when the BCL-2 gene is blocked by MM41 in mice, the cancer cells succumb to apoptosis and die.”

Neidle stressed that although these results are exciting, MM41 is not ideal for trialling in humans and further refinements are needed. “We are now working to optimise this class of compounds, but it’s clearly worthy of further investigation for potential use in treating pancreatic cancer in people,” he said.

Pancreatic cancer is the most lethal of any common cancer. Only three in every 100 people diagnosed will live for five years or more and this survival rate has barely improved in the last 40 years. The majority of patients are diagnosed too late for surgery — currently the only potentially curative treatment — and 80 per cent of those who have surgery will see the cancer return.

Maggie Blanks, Pancreatic Cancer Research Fund’s CEO, said: “It’s because of these bleak facts that our funding strategy focuses on finding and developing alternative, effective treatments for patients as well as finding a way to diagnose pancreatic cancer at an early stage. To find a potential new way to kill pancreatic cancer tumor cells is an exciting development.”

Russian Government Calls For International Investigation Into U.S. Moon Landings

Glioblastoma and Other Malignant Gliomas

Importance  Glioblastomas and malignant gliomas are the most common primary malignant brain tumors, with an annual incidence of 5.26 per 100 000 population or 17 000 new diagnoses per year. These tumors are typically associated with a dismal prognosis and poor quality of life.

Objective  To review the clinical management of malignant gliomas, including genetic and environmental risk factors such as cell phones, diagnostic pitfalls, symptom management, specific antitumor therapy, and common complications.

Evidence Review  Search of PubMed references from January 2000 to May 2013 using the termsglioblastoma, glioma, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,anaplastic oligoastrocytoma, and brain neoplasm. Articles were also identified through searches of the authors’ own files. Evidence was graded using the American Heart Association classification system.

Findings  Only radiation exposure and certain genetic syndromes are well-defined risk factors for malignant glioma. The treatment of newly diagnosed glioblastoma is based on radiotherapy combined with temozolomide. This approach doubles the 2-year survival rate to 27%, but overall prognosis remains poor. Bevacizumab is an emerging treatment alternative that deserves further study. Grade III tumors have been less well studied, and clinical trials to establish standards of care are ongoing. Patients with malignant gliomas experience frequent clinical complications, including thromboembolic events, seizures, fluctuations in neurologic symptoms, and adverse effects from corticosteroids and chemotherapies that require proper management and prophylaxis.

Conclusions and Relevance  Glioblastoma remains a difficult cancer to treat, although therapeutic options have been improving. Optimal management requires a multidisciplinary approach and knowledge of potential complications from both the disease and its treatment.

New Device Uses Patient Tumors as High-Throughput Screen Tool


Literature Review: Inpatient HTS?
  • Efforts to replace traditional cell culture–based testing of drug candidates with models that carry better predictive power, as relates to effect in human patients, have proliferated in recent years. These include 3D organotypic models, tissue printing platforms, and organs-on-chips. These two reports take the testing of new oncology drug candidates to the next level, that is, right into the human patient. In Klinghoffer et al., the team reports on a multi-needle-based device for injecting multiple drugs transcutaneously into discrete loci within the tumor in an actual patient (figure 1). Through extensive testing, the team demonstrated that up to eight drugs could be injected into mapped locations within the tumor, forming column-like tracks, and to remain acting locally, allowing the post-treatment analysis of drug efficacy and mechanism of action through the measurement of multiplebiomarkers. The biomarker analysis was performed after 24–72 h of treatment by obtaining 4 μm histological sections every 2 mm along the injection column. The authors evaluated three xenograft models either with several oncology drugs or with the same drug dosed at different concentrations. Post-treatment analyses showed that the different drugs acted distinctly based on their previously established molecular mechanisms and that their action exhibited a dose–response effect. Moreover, it was shown that the local responses to the microinjected drugs could be used to predict the corresponding response to the systemically delivered substance, and the system was demonstrated to support a pilot screen of 97 drugs. Last but not least, the authors tested the injection device in human lymphoma patients where the procedure was found to be generally well-tolerated. In a companion paper, the Robert Langer’s team provides an implantable microdevice containing a large number of drug-containing reservoirs that can be implanted inside the tumor. As a prototype, the team used a cylindrical device ∼0.8 mm thick for a delivery via biopsy needle (figure 2). By properly separating the drug-containing cavities along the cylindrical carrier, the team was able to control the crosstalk between adjacent drugs (either to eliminate it to study the individual agents or to retain it in order to test for advantageous drug–drug combinations). At this stage, the device contained 16 reservoirs, although the authors pointed out that further increase in the number would be possible. Further, changing the shape of the cavity, as well as manipulating the drug formulation, afforded control over the rate of delivery of drugs with different physicochemical properties. The two reports thus bring us one step closer to shifting the medium-to-high throughput testing of drug candidates from the laboratory to the patient.

  • Click Image To Enlarge +

    The CIVO tumor microinjection platform. (A) The CIVO platform consists of a handheld array of up to eight needles capable of simultaneously penetrating subcutaneous tumors and delivering microdoses of candidate therapeutics. (B) For preclinical studies, tumors were grown as flank xenografts in immunocompromised mice and injected while mice were anesthetized. A chemically inert ITD was co-injected through each needle. (C) A representative example of the ITD signal from a tumor injected using a five-needle array visualized with a Xenogen In Vivo Imaging System (IVIS). (D) A longitudinal IVIS scan demonstrating the column-like distribution of the tracking dye signal from a single needle spanning the z axis of the tumor. (E) Tumor responses were assessed after resection of the tumor via histological staining of cross sections (4 mm thick) sampled at 2-mm intervals perpendicular to the injection column. (F) High resolution whole-slide scanning captured images of every cell from each 4-mm-thick tissue section. (G) A representative tumor response to microinjected drug at a single injection site. Nuclei, DAPI (4′,6-diamidino-2-phenylindole) (blue); ITD (green); a drug-specific biomarker (orange). (H) The resulting images were processed by a custom image analysis platform called CIVO Analyzer, which classifies the cells within each region of interest as biomarker-positive (green dots) or biomarker-negative (red dots).

  • Click Image To Enlarge +

    In vivo drug sensitivity assay. (A) The device is implanted by needle directly into tissue, and drugs diffuse from device reservoirs into confined regions of tumor. Each region is assayed independently to assess the tumor-specific response to a given drug, such as apoptosis or growth arrest. A second biopsy needle selectively retrieves a small column of tissue that immediately surrounds and includes the device. This tissue contains the regions of drug diffusion and is used for determination of drug efficacy. (B) Three methods for precise control over the release profile of a given drug are demonstrated: reservoir opening size affects the rate of transport; the formulation of a drug in a polymer matrix (for example, PEG slows release of sunitinib versus free doxorubicin); and hydrophilic expansive hydrogels (to achieve rapid tissue uptake of highly insoluble drugs, such as lapatinib). Scale bars, 300 μm.

  • * Abstract from Science Translational Medicine 2015; Vol. 7, Issue 284, p. 284ra58

    A fundamental problem in cancer drug development is that antitumor efficacy in preclinical cancer models does not translate faithfully to patient outcomes. Much of early cancer drug discovery is performed under in vitro conditions in cell-based models that poorly represent actual malignancies. To address this inconsistency, we have developed a technology platform called CIVO, which enables simultaneous assessment of up to eight drugs or drug combinations within a single solid tumor in vivo. The platform is currently designed for use in animal models of cancer and patients with superficial tumors but can be modified for investigation deeper-seated malignancies. In xenograft lymphoma models, CIVO microinjection of well-characterized anticancer agents (vincristine, doxorubicin, mafosfamide, and prednisolone) induced spatially defined cellular changes around sites of drug exposure, specific to the known mechanisms of action of each drug. The observed localized responses predicted responses to systemically delivered drugs in animals. In pair-matched lymphoma models, CIVO correctly demonstrated tumor resistance to doxorubicin and vincristine and an unexpected enhanced sensitivity to mafosfamide in multidrug-resistant lymphomas compared withchemotherapy-naïve lymphomas. A CIVO-enabled in vivo screen of 97 approved oncology agents revealed a novel mTOR (mammalian target of rapamycin) pathway inhibitor that exhibits significantly increased tumor-killing activity in the drug-resistant setting compared with chemotherapy-naïve tumors. Finally, feasibility studies to assess the use of CIVO in human and canine patients demonstrated that microinjection of drugs is toxicity-sparing while inducing robust, easily tracked, drug-specific responses in autochthonous tumors, setting the stage for further application of this technology in clinical trials.

  • * Abstract from Science Translational Medicine 2015; Vol. 7, Issue 284, p. 284ra57

    Current anticancer chemotherapy relies on a limited set of in vitro or indirect prognostic markers of tumor response to available drugs. A more accurate analysis of drug sensitivity would involve studying tumor response in vivo. To this end, we have developed an implantable device that can perform drug sensitivity testing of several anticancer agents simultaneously inside the living tumor. The device contained reservoirs that released microdoses of single agents or drug combinations into spatially distinct regions of the tumor. The local drug concentrations were chosen to be representative of concentrations achieved during systemic treatment. Local efficacy and drug concentration profiles were evaluated for each drug or drug combination on the device, and the local efficacy was confirmed to be a predictor of systemic efficacy in vivo for multiple drugs and tumor models. Currently, up to 16 individual drugs or combinations can be assessed independently, without systemic drug exposure, through minimally invasive biopsy of a small region of a single tumor. This assay takes into consideration physiologic effects that contribute to drug response by allowing drugs to interact with the living tumor in its native microenvironment. Because these effects are crucial to predicting drug response, we envision that these devices will help identify optimal drug therapy before systemic treatment is initiated and could improve drug response prediction beyond the biomarkers and in vitroand ex vivo studies used today. These devices may also be used in clinical drug development to safely gather efficacy data on new compounds before pharmacological optimization.

Leading Scientists Believe Up to Half of Research-Based Literature Is Simply Untrue .


Corruption undermining science.

Leading Scientists Believe Up to Half of Research-Based Literature Is Simply Untrue

In a perfect world, science would have unlimited funding, free from corporations or special interest groups, where all studies would be truly objective and unbiased. Unfortunately, this is rarely the case. Financing by private companies, or those who have a vested interest in the outcome of the research, often leads to biased conclusions which favor the sponsor of the study.

Take for example a pharmaceutical company paying for a new drug to treat depression. When the track record of such research is examined, we find studies backed by the pharmaceutical industry tend to show partiality toward the drug under consideration, whereas research sponsored by government grants or charitable organizations is prone to draw more objective conclusions.¹

In a similar fashion, research financed by the food industry often favors the food under investigation compared to inquiries that are independently sponsored.²

Bad science

“Everyone should know that most cancer research is largely a fraud, and that the major cancer research organizations are derelict in their duties to the people who support them.”³ ~ Linus Pauling, PhD, and two-time Nobel Prize winner.

Dr. Marcia Angell, physician and longtime editor in chief of the New England Medical Journal, feels that objective research has taken a turn for the worse:

“It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of the New England Journal of Medicine.”

And John P.A. loannidis, a professor in disease prevention at Standford University School of Medicine, writes that most published research findings are false, due to several criteria — including “greater financial and other interest and prejudice.” He also states that “for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias.”

Another critique of our current scientific method is found with Richard Horton, editor in chief ofThe Lancet, who states, “much of scientific literature, perhaps half, may simply be untrue,” in the April 15th, 2015 edition of the journal. He lists a a variety of reasons for this failure: studies with small sample sizes, flagrant conflicts of interest and an obsession for pursuing fashionable trends of dubious importance. Horton adds, “as one participant put it, “poor methods get results.”’

Moreover, ScienceDaily reports that a study at the University of Michigan found that nearly one-third of cancer research published in high-profile journals have conflicts of interest. The research team examined 1,534 cancer studies published in well-respected journals.The most frequent type of conflict is with industry funding (17% of the papers). Twelve percent of the papers were in conflict because the author was an industry employee. And randomized trials were more likely to have positive findings when conflicts of interest were present.

Reshma Jagsi, M.D., D.Phil., and author of the University of Michigan study, feels that “merely disclosing conflicts is probably not enough. It’s becoming increasingly clear that we need to look more at how we can disentangle cancer research from industry ties.”

Leading Scientists Believe Up to Half of Research-Based Literature Is Simply Untrue 2

Jagsi believes that research has become corrupted by designing industry-funded studies in such a manner that’s likely to yield favorable results. Researchers may also be more inclined to publish positive outcomes while overlooking negative results.

“In light of these findings, we as a society may wish to rethink how we want our research efforts to be funded and directed. It has been very hard to secure research funding, especially in recent years, so it’s been only natural for researchers to turn to industry. If we wish to minimize the potential for bias, we need to increase other sources of support. Medical research is ultimately a common endeavor that benefits all of society, so it seems only appropriate that we should be funding it through general revenues rather than expecting the market to provide,” Jagsi says.

When all is said and done, we may question whether privately funded research should be dismissed altogether. Most likely, no. But we can consider the advice presented inUnderstanding Science by the University of California at Berkeley:

“Ultimately, misleading results will be corrected as science proceeds; however, this process takes time. Meanwhile, it pays to scrutinize studies funded by industry or special interest groups with extra care. So don’t, for example, brush off a study of cell phone safety just because it was funded by a cell phone manufacturer — but do ask some careful questions about the research before jumping on the bandwagon. Are the results consistent with other independently funded studies? Does the study seem fairly designed? What do other scientists have to say about this research? A little scrutiny can go a long way towards identifying bias associated with funding source.”

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