Tomatoes genetically modified to be rich in antioxidants called anthocyanins appeared to extend the life spans of cancer-prone mice, a European study finds.

The modified tomatoes were created by adding two genes (Delila and Rosea1) from the snapdragon flower. The anthocyanins, which belong to the flavonoid class of antioxidants, gave the tomatoes a peculiar purple color.

“The two genes we have isolated are responsible for flower pigmentation and, when introduced in other plants, turned out to be the perfect combination to produce anthocyanins, the same phytochemical found in blueberries,” study author Eugenio Butelli, of the FLORA project, said in a news release.

Chemical tests revealed that the “purple tomato has a very high antioxidant activity, almost tripled in comparison to the natural fruit,” making it very useful to study the effect of anthocyanins, Butelli said.

The researchers fed a powder obtained from the purple tomatoes to mice that lacked the p53 gene, which helps protect against cancer. These mice had an average life span of 182 days compared to 142 days for p53-deficient mice fed a standard diet.

The findings were published in the Oct. 26 issue of  Nature Biotechnology.

The study authors emphasized this is a preliminary study, and much more research needs to be done before there’s any possibility of human trials.

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A new anti-cancer compound that works by blocking a part of the cell’s machinery that is crucial for cell division has shown promising results in a phase I clinical trial in patients who have failed to respond to other treatments. Now it is going forward into a phase II clinical trial programme. In addition, the compound will also be tested in combination with other anti-cancer drugs to see whether combined therapies could be even more effective.

Professor Patrick Schöffski told the 20th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Geneva today (Wednesday 22 October) that after 50 patients had been given the compound BI 6727 in doses ranging from 12 to 450 mg, two patients with advanced bladder and ovarian cancers had shown confirmed partial responses and a further 32% of the patients had stable disease.

“The results so far indicate that BI 6727 is well tolerated by patients, with no serious side-effects detected. We have observed encouraging anti-tumour activity, which we would not necessarily expect to see in a phase I trial, and which warrants investigation in further clinical trials,” said Prof Schöffski, who is professor of medical oncology and head of the Department of General Medical Oncology at the University Hospitals Leuven (Belgium). [2]

BI 6727 is one in a series of compounds developed by Boehringer Ingelheim that work by inhibiting the action of a protein called Polo-like kinase 1 (Plk1), high levels of which are present in human tumours, but not in normal tissue. Plk1 is involved in cell growth; inhibiting it leads to abnormal mitotic spindles – the structures that separate the chromosomes into daughter cells during cell division – and this disrupts cell division, inhibiting the growth of tumour tissue.

“Plk1 inhibitors are targeted, cell cycle blockers that lead to spindle defects by inhibiting a key regulator of mitosis. They act on the mitotic spindle in a completely different manner compared to established anti-cancer agents such as vinca alkaloids or taxanes that directly bind to structural components of the mitotic spindle. Due to high levels of Plk1 in tumour cells compared to surrounding healthy tissue, compounds such as BI 6727 are effectively targeting dividing cancer cells,” said Prof Schöffski. “The results from this phase I trial suggest that BI 6727 potentially is a ‘first in class’ Plk1 inhibitor and the anti-tumour activity we have seen supports Plk1 as a therapeutic target.”

Preclinical data also presented at the meeting (abstract no: 430) show highly selective target inhibition and cellular activity at very low concentrations for this compound. BI 6727 shows excellent efficacy in multiple xenograft models of human cancer and its distinguishing features are its pharmacokinetic characteristics (what the body does to the drug) that allow for long-lasting tumour exposure.

The objectives of the phase I trial had been to assess the maximum tolerated dose of BI 6727 and its overall safety, the pharmacokinetics, and preliminary efficacy. Each treatment consisted of a single, one-hour infusion of the drug and it was given to sequential groups of three to six patients with advanced or metastatic solid tumours. If the cancer did not progress, further treatments were given at three-week intervals. The average number of treatments per patient was four, and at least 16 courses of treatment were given to two patients. The maximum tolerated dose was 400 mg.

The main adverse side effects of the drug were blood-related. Reduced white blood cells (neutropenia) or platelets (thrombocytopenia) were a result of Plk1 inhibition in normal cells and were both treatable and reversible events. About ten per cent of patients suffered from fatigue, mostly mild to moderate.

Speaking in September before the symposium started, Prof Schöffski said: “I will present the most up-to-date responses at the Geneva meeting, but, so far, one patient with urothelial [bladder] cancer has had clinical benefit for more than 16 cycles with BI 6727 and achieved confirmed partial response with the tumour shrinking by 42% within four cycles. Previously, this patient had failed other standard and experimental treatments. The cancer has not progressed since BI 6727 therapy started.

“A second patient with ovarian cancer had a confirmed partial response after two and four cycles, but her disease progressed at the sixth cycle. Previously, she had been treated with several courses of standard ovarian cancer treatments, including taxanes and cisplatinum.

“The initial part of the trial is completed, and now we have recruited a further 12 patients to compare different durations of infusion of the drug. We expect to have results from this soon.”

Prof Schöffski, who will be giving an invited “state of the science” lecture on Plk1 at the Geneva symposium, said the results for BI 6727 so far were promising. “This agent is among the few Polo-like kinase inhibitors in early clinical development. Boehringer Ingelheim has advanced this compound from its Plk1 inhibitor portfolio into phase II, due to favourable pharmacology and the promising safety and efficacy seen in this phase I trial.”

ECCO-the European CanCer Organisation

In the advance online edition of Nature Medicine, scientists from Sainte-Justine Hospital Research Center, the Université de Montréal and the Institut national de la santé et de la recherche médicale (INSERM) in France report how the GPR91 receptor contributes to activate unchecked vascular growth that causes vision loss in common blinding diseases. These findings could also have wide-ranging and positive implications for brain tissue regeneration.

While investigating the molecular mechanisms that lead to vision loss, the research team uncovered that the GPR91 receptor can mediate irregular vascular growth that is responsible for some of the main causes of blindness in the industrial world: retinopathy of prematurity in infants, diabetic retinopathy in adults (vision loss or blindness that affects up to 90 percent of diabetics) or age-related macular degeneration in seniors (central vision loss).

“We found that GPR91 is a master regulator of blood vessel growth, which upon enhanced activation leads to the unchecked and anarchic proliferation of vascular networks, which is the hallmark of retinopathies. This uncontrolled overgrowth can ultimately cause the retina to detach and a person to lose their sight,” says Dr. Mike Przemyslaw Sapieha, the study’s lead author and a scientist at the Sainte-Justine Hospital Reserch Center and the Université de Montréal.

“With the identification of GPR91 as a key player in this disease process, we can move forward in designing treatments that block the receptor and consequently stop vision loss,” adds Dr. Sapieha. “Inhibition of GPR91 has a great therapeutic potential to halt these blinding diseases.”

GPR91 to preserve neurons

The team’s study also provides promise that the GPR91 receptor could preserve neurons. “Neurons are key sensors in retina oxygenation and serve as key players in the repair process of the retina,” explains Dr. Sylvain Chemtob, director of the study and a neonatal researcher at the Sainte-Justine Hospital Research Center and professor at the Université de Montréal’s Department of Pediatrics, Ophthalmology, Pharmacology and the School of Optometry.

“Given the similarities between the retina and the brain, we can envisage applying our findings in retina to the brain,” says Dr. Chemtob. “Activation of the GPR91 receptor could be beneficial in helping salvage neurons in damaged brain tissue in stroke or head injury victims.”

GPR91 to stop cancer growth

This study is the first to examine the wide-ranging implications of GPR91 and to investigate how the receptor, which is present in neurons, responds to stresses and adjust when in its oxygenation state is compromised. “This is a new concept in vascular biology,” says Dr. Sapieha, noting it is conceivable that interfering with the GPR91 receptor could be used to stop cancer growth. “If you stop GPR91 from allowing blood vessels to expand and supply a tumour with nutrients and oxygen, one can significantly hamper growth of the cancer.”

While these promising investigations on GPR91 were conducted in animals, the receptor is also found in humans, and Dr. Chemtob surmises that extension of the research to human clinical investigations could be in three to fours years. “We expect these findings to have an enormous impact,” he says.

This study was funded through grants from the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Quebec, the Fonds de la recherche en santé du Québec, the Heart and Stroke Foundation of Canada, the March of Dimes Birth Defects Foundation, the Robert A. Welch Foundation and the Foundation Fighting Blindness.

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Researchers at the University of Toronto have shown that the EBNA1 protein of Epstein-Barr virus (EBV) disrupts structures in the nucleus of nasopharyngeal carcinoma (NPC) cells, thereby interfering with cellular processes that normally prevent cancer development. The study, published October 3rd in the open-access journal PLoS Pathogens, describes a novel mechanism by which viral proteins contribute to carcinogenesis.

EBV is a common herpesvirus whose latent infection is strongly associated with several types of cancer including NPC, a tumor that is endemic in several parts of the world. With NPC only a few EBV proteins are expressed, including EBNA1. EBNA1 is required for the persistence of the EBV genomes, however, whether or not EBNA1 directly contributes to the development of tumors has not been clear, until now.

In this study Frappier and her team examined PML nuclear bodies and proteins in EBV-positive and EBV-negative NPC cells. Manipulation of EBNA1 levels in each cell type clearly showed that EBNA1 expression induces the loss of PML proteins and PML nuclear bodies through an association of EBNA1 with the PML bodies. PML nuclear bodies are known to have tumor-suppressive effects due to their roles in regulating DNA repair and programmed cell death, and accordingly, EBNA1 was shown to interfere with these processes.

The researchers conclude that there is “an important role for EBNA1 in the development of NPC, in which EBNA1-mediated disruption of PML nuclear bodies promotes the survival of cells with DNA damage.” Since EBNA1 is expressed in all EBV-associated tumors, including B-cell lymphomas and gastric carcinoma, these findings raise the possibility that EBNA1 could play a similar role in the development of these cancers. The cellular effects of EBNA1 in other EBV-induced cancers will require further investigation.

http://www.plospathogens.org/doi/ppat.1000170

Demonstrating that despite the large number of cancer-causing genes already identified, many more remain to be found, scientists at Dana-Farber Cancer Institute have linked a previously unsuspected gene, CDK8, to colon cancer.

The discovery of CDK8’s role in cancer was made possible by new tools for assessing the activity of specific genes, say the authors of the new study. As these tools are further improved, the stream of newly discovered cancer genes is expected to increase, providing new avenues for therapy, the authors suggest. The findings are being published as an advanced online publication by the journal Nature on Sept. 14.

“This study provides confirmation that many of the genes involved in cancer have yet to be identified,” remarked the study’s senior author, William Hahn, MD, PhD, of Dana-Farber and the Broad Institute of Harvard and M.I.T. “When it comes to identifying gene targets for therapy, we’ve really only scratched the surface.”

The study is noteworthy in another respect, as well, the authors indicated. Many of the abnormal proteins linked to cancer are known as “transcription factors” because they’re able to “read″ cell DNA and use that information for producing other cell proteins. Although transcription factors are important regulators, this class of proteins has proven to be impossible to target with drugs. Genes that influence such transcription factors, however, make attractive targets for drugs, since they can potentially disrupt the cancer process and disable tumor cells. CDK8 is such a gene.

The new study began with a focus on a protein called beta-catenin, a transcription factor that is overactive in nearly all colorectal cancers. Although overactive beta-catenin plays a role in the initial formation of tumors, other genetic abnormalities must occur for tumors to become fully malignant.

To determine which genes control the production of beta-catenin and are involved in the proliferation of colon cancer cells, the research team ran three screening tests. In the first two, they used RNA interference to shut down more than a thousand genes one by one and recorded the instances where beta-catenin activity decreased and the cells stopped growing. They then analyzed colon cancers for genes that had extra copies. When they examined where the results of the three tests overlapped, one gene stood out — CDK8, explained Hahn, who is also an associate professor of medicine at Harvard Medical School

The protein produced from CDK8 is part of the “mediator complex,” a conglomeration of proteins that serves as a bridge for compounds involved in gene transcription. “This study demonstrates that blocking CDK8 interferes with the proliferation of colon cancer cells that have high levels of the CDK8 protein and overactive beta-catenin,” Hahn said. “Drugs that target CDK8 may be very useful against tumors whose growth is driven by beta-catenin.”

US scientists have unveiled the most complete genetic profile ever attempted of glioblastoma, a common and deadly form of the brain cancer that US Senator Edward Kennedy is battling.

The research uncovered a host of genetic alterations linked to the disease, including three previously unknown mutations found in at least three-quarters of tumour samples analysed.

It may also explain why, in some cases, standard chemotherapy treatment for brain tumours works at first but then loses its ability to beat back tumour growth.

The study, published in the British journal Nature, underscores a powerful new way to study cancer: harnessing powerful computers to analyse not just suspect genes in tissue samples, but entire genomes — each with tens of thousands of genes — across hundreds of samples.

“The ultimate aim is to achieve a complete atlas for the genomic changes in glioblastoma,” explained Lynda Chin, a researcher at the Dana-Farber Cancer Institute in Boston and a member of the Cancer Genome Atlas Research Network (TCGA), which collectively authored the study.

“It would be essentially like having a full parts list for cars so that you know everything that could go wrong,” she said in an interview.

The most aggressive and common of all brain tumours, glioblastoma strikes more than 20,000 people every year in the United States, and accounts for some 13,000 deaths.

Senator Kennedy, who spoke at the Democratic Party convention last month, was diagnosed with the disease this year.

Working with brain tumour samples donated by 206 patients from across the United States, the TCGA group sequenced 601 suspect genes and compared them to the same genes from healthy tissue.

Three new genes not previously linked to glioblastoma were found guilty by association: Nʽ, also implicated in an inherited disorder that causes runaway tissue growth along nerves; ERBB2, closely associated with breast cancer; and PI3, known to play a role in several cancers.

Besides checking for small mutations in genes, they looked for anomolies that can promote tumour growth: large strings of missing or duplicated genetic code, problems in the way information in the DNA is “transcribed” to produce proteins, and how certain molecules — called methyl groups — interact with DNA.

They also evaluated the impact of treatments, to see what kind of changes — intended or not — certain drugs trigger.

The most unexpected finding, said Chin, was that a commonly used chemotherapy treatment called temozolomide may provoke a “resistance mechanism” that compromises genes critical for DNA repair.

The result is new tumours with a large number of DNA mutations and a higher tolerance for chemotherapy.

“This type of comprehensive, coordinated analysis of unprecedented multi-dimensional data is made possible by advanced technologies” that simply did not exist a decade ago, said John Niederhuber, Director of the National Cancer Institute.

The TCGA study, which analysed many samples but relatively few genes, was released at the same time as another study, published in the US journal Science, that coded all the genes in 22 brain tumours.

“You can make important discoveries with either approach, but ideally you want to take the strength of both,” Chin told AFP.

A new generation of technologies known as single molecule sequencing is “an order of magnitude cheaper and faster” and should make that possible within several years, she said.

“We have the tumours in the bank — when this technology comes on line, we can go back and sequence not just 600 genes but all of them, and not in 20 samples but 200 or, better yet, 500 or 1000.”

The examples highlighted in what she called an interim study are “just the tip of the iceberg,” she added.

The TCGA consortium has already initiated the same sort of comprehensive approach to ovarian and lung cancer.

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Inhibitor turns ‘off’ receptors stops the growth of endometrial tumors and kills cancer cells

Researchers at the Translational Genomics Research Institute (TGen) today announced a new approach to treating endometrial cancer patients that not only stops the growth of tumors, but kills the cancer cells.

In a potentially major breakthrough, TGen scientists and collaborators at Washington University School of Medicine in St. Louis discovered that introducing a particular inhibitor drug can turn “off” receptors responsible for the growth of tumors in a significant number of patients with endometrial cancer.

And, they found that the inhibitor drug proved effective even in cancer tumors containing a commonly occurring mutant gene, PTEN, previously associated with resistance to drug treatment.

TGen’s findings appear today in a paper published as a priority report by Cancer Research, a Philadelphia-based peer-reviewed journal dedicated to original cancer research.

A clinical trial based on the TGen study will start within the next year.

Dr. Pamela Pollock, an associate investigator in TGen’s Cancer and Cell Biology Division and the paper’s senior author, led a team that used the latest genome-scanning technology to sequence 116 endometrioid endometrial tumor samples. This work was done in association with Dr. Paul Goodfellow, an expert in endometrial cancer and a professor in the departments of Surgery and of Obstetrics and Gynecology at Washington University.

Pollock and colleagues in May 2007 announced that they had discovered previously unrecognized alterations in the fibroblast growth factor receptor 2 (FGFR2) gene. The altered FGFR2 is present in the cancer cells of nearly 15 percent of women with endometrioid endometrial tumors. These kinds of tumors represent 80 percent of all endometrial cancers.

By introducing a commercially available inhibitor drug, PD173074, TGen researchers showed that they could stop the growth of tumors, and even kill cancer cells, in cases where the tumors contained the altered FGFR2 gene. The altered gene causes the receptors to get stuck in the “on” position and signal the endometrial cells to grow out of control.

“These findings could accelerate the development of new treatments for endometrial cancer because there are already drugs in clinical trials that inhibit FGFR2 function,” Pollock said.

Current treatment of endometrial cancer can involve surgical removal of the uterus, radiation and chemotherapy. While many women are successfully treated with these approaches, about 15 percent of those with endometrioid endometrial cancer have persistent or recurring tumors that are resistant to current drug therapies. Mutations in several genes previously have been identified in endometrial tumors, but they have not been suitable drug targets – until now.

“This targeted approach holds great promise for patients with uterine cancer (endometrioid endometrial) tumors that contain the FGFR2 mutation,” said TGen physician-in-chief, Dr. Daniel Von Hoff, “and offers yet another powerful example of how genomic medicine is changing the way we look at and treat cancer.”

Goodfellow agreed, “The discovery that endometrial cancer cells die when treated with an FGFR2 inhibitor - even when they carry other genetic abnormalities common in uterine cancers - suggests anti-FGFR2 therapies have great potential.”

The researchers’ already established ties with the National Cancer Institute, which will assist with the clinical trials, should speed the development of new therapies, Goodfellow said. “Our collaborative group’s strong ties with the NCI’s Gynecologic Oncology Group will allow us to rapidly take our findings from the lab to patients.”

Endometrial cancer, which invades the inner wall of the uterus, is the most common gynecological cancer in the United States. This year more than 40,000 women will be diagnosed and nearly 7,500 women will die of the disease, according to the American Cancer Society (ACS).

Among women, only breast, lung and colon cancers strike with more frequency. And while endometrial cancer is slow to develop, and often is not detected until after age 60, nearly one in eight women who are diagnosed die within five years, according to the ACS.

Pollock plans to start clinical trials with an FGFR inhibitor in endometrial cancer patients within a year. The trials will be conducted in collaboration with Dr. Matthew Powell, a gynecologic oncologist and assistant professor of Obstetrics and Gynecology at Washington University School of Medicine.

Targeted drug therapy is a relatively new approach to cancer treatment that is based on identifying the abnormalities in cancer cells that cause them to grow uncontrollably. It involves treating tumors with drugs that specifically inhibit the activity of these genetic abnormalities.

This approach of targeted therapy allows oncologists to match the therapy to the specific genetic signature of each patient’s tumor, a strategy that has been effective in multiple cancer types, including breast cancer, lung cancer and chronic myelogenous leukemia.

Tel Aviv University researchers are combatting cancer with a jasmine-based drug

Could a substance from the jasmine flower hold the key to an effective new therapy to treat cancer? Prof. Eliezer Flescher of The Sackler Faculty of Medicine, Tel Aviv University thinks so. He and his colleagues have developed an anti-cancer drug based on a decade of research into the commercial applications of the compound Jasmonate, a synthetic compound derived from the flower itself. Prof. Flescher began to research the compound about a decade ago, and with his recent development of the drug, his studies have now begun to bear meaningful fruit.

“Acetylsalicylic acid (aspirin) is based on a plant stress hormone,” says Prof. Flescher. “I asked myself, ‘Could there be other plant stress hormones that have clinical efficacy?’ While various studies have suggested that aspirin can prevent cancer, especially colon cancer, I realized that there could be a chance to find a potent plant hormone that could fight cancer even better. I pinpointed jasmonate.”

A Natural Leap to the Drugstore Shelf

Both blood cancers and solid tumors seem to be responsive to the jasmonate compound, known also as methyl jasmonate. Prof. Flescher refers to it as the “jasmonate scaffold,” a basis for developing a series of chemical derivatives. In terms of bioavailability and safety, early first-in-man studies have proven successful, and Prof. Flescher is hopeful that an anti-cancer drug based on jasmonate could be on the shelf in America within four years through the activity of Sepal-Pharma which licensed his research from Ramot, the technology transfer arm of Tel Aviv University.

Normally drug development takes much longer. “The jasmonate compound is used widely in agriculture and in cosmetics,” says Prof. Flescher. “Proven to be non-toxic, it has the same regulatory status as table salt. That and the fact we are working on a natural chemical gives us a good starting point for launching a new drug.”

Optimistic Responses from Peer Researchers

Other research groups are taking notice. Since Prof. Flescher started publishing papers on jasmonate (most recently in the academic journal Oncogene), six new research groups around the world have initiated research on the subject.

Peer commentary in Oncogene is positive about Prof. Flescher’s promising research. “Methyl jasmonate,” says the commentary, “has already been shown to have selective anticancer activity in preclinical studies, and this finding may stimulate the development of a novel class of small anticancer compounds.”

Prof. Flescher’s research is the foundation of a promising new biotech company, Sepal-Pharma, where Prof. Flescher serves on the scientific advisory board. Sepal-Pharma is developing new compounds based on the Jasmonate Scaffold. Sepal-Pharma has also been actively funding research done at Prof. Flescher’s lab.

University of Manchester scientists have uncovered the 3D structure of Mpѿ – a protein that regulates the number of chromosomes during cell division and thus has an essential role in the prevention of cancer – which will lead to the design of safer and more effective therapies.
Mpѿ belongs to the family of proteins called kinases. When subsets of these enzymes become deregulated, cancer can be one of the outcomes – making them a critical target for research by oncologists. Over 100 of the 500 or so kinases have been shown to be associated with cancer, but so far scientists only know the 3D structure of a handful. Knowing the structure is critical for the design of new kinase inhibitors as therapeutic agents, an area of enormous importance to the pharmaceutical industry. Over 100 kinase inhibitors are currently in clinical trials, and the revolutionary kinase inhibitor Glivec was approved for treating Leukaemia in the UK in 2001.

Mpѿ is particularly important as it controls a ‘checkpoint’ that cells use to encourage accurate chromosome sorting during mitosis. Mpѿ therefore prevents aneuploidy, the change in the number of chromosomes that is closely associated with cancer.

Dr Patrick Eyers and his team, including Hong Kong-born PhD student Matthew Chu, used the Diamond Light synchrotron, a “super-microscope” that works by speeding electrons around a huge doughnut-shaped chamber the size of five football pitches until they are travelling so fast they emit high energy particles. The X-rays were “fired” at a pure sample of the protein, allowing the researchers to “see” the protein’s atomic structure for the first time.

Their structure revealed the pocket where Mpѿ binds to ATP, the natural substrate from which Mpѿ transfers a phosphate group to its cellular target proteins. Further work showed the protein in complex with the ATP-competitive inhibitor SP600125, a well-known but non-specific inhibitor of many kinases, which revealed a secondary pocket not utilised by this compound. If a next-generation drug can be designed to specifically block this secondary pocket, it is hoped that Mpѿ will be specifically disabled, killing rapidly dividing cells such as those found in tumours.

The team hopes its work will allow chemists to design an anti-cancer drug with fewer side effects, allowing scientists to assess the relative importance of Mpѿ inhibition in different disease indications, including those that are currently hard to treat such as lung and pancreatic cancers.

Dr Eyers, whose findings are published in the Journal of Biological Chemistry (August 2008), said: “The crystallalographic structures of only a few key “mitotic” kinases are currently known so we are very early in the game. The scientific community has high hopes for developing novel “anti-mitotic” cancer therapies using this method of structure-based drug design.

“Mpѿ is a rational target because of its critical role in preventing aneuploidy. We wanted to see what this protein looked like at the molecular level and, by revealing the active site “lock”, help design a new inhibitory “key” to physically block the ATP-binding site.

His colleague Dr Lydia Tabernero added: “This work presents the first crystallographic structure of human Mpѿ, an important regulator of chromosomal stability and a potential target in cancer therapy. Our research has revealed several important structural features and additional binding sites that could be exploited for the development of specific Mpѿ inhibitors.”

Cancer starts when key cellular signals run amok, driving uncontrolled cell growth. But scientists at the Stanford University School of Medicine report that lowering levels of one cancer signal under a specific threshold reverses this process in mice, returning tumor cells to their normal, healthy s…