Bio Screening Industry News

Walter and Eliza Hall Institute scientist Dr Guillaume Lessene has won this year’s Biota Award for Medicinal Chemistry, awarded by the Royal Australian Chemical Institute.

Dr Lessene, who runs a laboratory in the institute’s Structural Biology Division, won the award for his role in the discovery of several compounds that interact with a protein that has been implicated in the poor response of many cancers to anti-cancer treatments.

The protein is a member of the Bcl-2 family of proteins. This protein family has a role in tumour development, anti-cancer-drug resistance and cancer spread. Dr Lessene’s drug target, in particular, is thought to be involved in the drug resistance of many tumours.

The Biota Award is presented annually to the chemist judged to be responsible for the best drug design and development paper published, patent taken out, or commercial-in-confidence report concerning small molecules as potential therapeutic agents.

Together with eight co-inventors Dr Lessene has made a patent application that describes how his compounds could be used to restore the cell death process that is important in combating the growth of cancers.

Since 2001 Dr Lessene has focused his research on developing small molecules that inhibit the Bcl-2 family of proteins.

“It is expected that drugs targeting Bcl-2-like proteins will have a major impact in cancer treatment,” he said.

Usually, when a cell’s DNA is damaged the cell tries to repair itself and, if it can’t, undergoes a process of programmed cell death.

Cancer develops when, despite cells having DNA damage, they don’t die but continue to divide, leading to tumour formation. This happens when the signal that tells the cell to die is inhibited by Bcl-2 proteins, which allows the cell to keep dividing.

Through high throughput screening, medicinal chemistry, and structure-guided drug design, Dr Lessene and the institute’s drug discovery team have been identifying and refining compounds that inhibit the Bcl-2 proteins.

“From a drug discovery point of view the Bcl-2 proteins are challenging targets because of the size and shape of their binding sites,” Dr Lessene said. “Our successful work therefore represents a considerable achievement, particularly in the field of protein-protein interactions.”

The research leading to the discovery of these compounds is the basis of a collaboration and licensing agreement between the Walter and Eliza Hall Institute, Genentech Inc and Abbott, the leader in Bcl-2 inhibitor development.

Dr Lessene is the second person from the Walter and Eliza Hall Institute to win the Biota Award. Dr Jonathan Baell, also from the Structural Biology Division, received the award in 2004.

Source: Walter and Eliza Hall Institute

The last decade has seen a major expansion in the cancer drug pipeline and studies are continually underway to advance the arsenal of drugs and create more effective treatments and targeted therapies for patients.

To highlight results of more recent research, the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International Conference will host a press briefing on “Drugs in the Pipeline.” Sara A. Courtneidge, Ph.D., D.Sc., professor and director of the Tumor Microenvironment Program, and director of academic affairs at the Burnham Institute for Medical Research, will moderate this press briefing.

“Conferences such as the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International Conference play a very important role in advancing translational cancer research. Here, one can learn about the newest breakthroughs across the continuum of cancer research,” said Courtneidge.

Breakthroughs to date have been made in the development of anti-angiogenesis inhibitors that target the tumor vasculature and of modulators of gene expression and protein stability, according to Courtneidge. Many more agents have been added to the pipeline of cancer drugs, including inhibitors that target the BCR-ABL fusion protein and other kinases. Cytotoxic agents remain a mainstay of cancer therapy, and inhibitors of DNA repair and cancer stem cells show great promise.

The press briefing will take place on Monday, Nov. 16, 2009, from 1:00 p.m. to 2:00 p.m. ET, in Room 202 of the Hynes Convention Center in Boston, Mass.

Reporters who cannot attend in person may call using the following information:

U.S./Canada: (888) 282-7404
International: (706) 679-5207
Access Code: 36170264
Topic: AACR

Leading researchers will present new and exciting data on the role of hsp70 as a novel therapy for breast cancer; various drug compounds that kill leukemia stem cells and yet spare normal stem cells; tolerability results of cediranib for use in children with recurrent or refractory solid tumors; and sensitivity study results of olaparib for colorectal cancer cells containing a specific DNA repair defect.

“This research spans studies on the genetic makeup of cancer cells, validation studies on the roles of key signaling proteins and pathways, the development of novel agents, and the testing of those agents in a variety of pre-clinical and clinical settings,” Courtneidge added.

The following abstracts will be presented during this press briefing:

# B21. Targeting autophagy induced by pan-HDAC inhibitor panobinostat and promoted by acetylated hsp70: A novel therapy for breast cancer

Targeting heat shock response protein with panobinostat, combined with an autophagy inhibitor, is an effective treatment strategy against growing stress cells in breast cancer.

“Clearly this points to a very new approach of targeting heat shock response in combination treatment,” said Kapil Bhalla, M.D., director of the Medical College of Georgia Cancer Center, professor of medicine in the Department of Medicine, Division of Hematology-Oncology at the Medical College of Georgia, and vice president for cancer research at the Medical College of Georgia.

Panobinostat is a potent histone deacetylase (HDAC) inhibitor that has been shown to induce cell death of tumor cell lines, but not the normal cells. In breast cancer cells where programmed cell death is inhibited, pan-HDAC inhibitor treatment induces autophagy, which allows the breast cancer cells to escape elimination.

Bhalla and colleagues evaluated the stress phenotype of breast cancer cells in the mammary fat pad of mice when mediated by two heat shock proteins — hsp90 and hsp70, which help to promote cancer survival. The researchers wanted to determine how these inhibitors that deacetylate proteins and histones affect the cell’s function.

“Basically we forced the cancer cell to have autophagy and then pulled the rug from under it by having an autophagy inhibitor take that away,” said Bhalla.

Treatment with panobinostat induced acetylation of amino acid lysine in the hsp70 protein. With growing tumor size they found an increase in hsp70, heat shock response and autophagy.

“Panobinostat accentuates stress, causes autophagy, and sets up the cell to be eliminated by autophagy inhibitors,” Bhalla said.

Panobinostat is not FDA approved for use in breast cancer.
# A51. Identification of compounds targeting human leukemia stem cells

Researchers at the University of Michigan, Ann Arbor, and the University Health Network, Toronto, have found a new paradigm for screening against leukemia stem cells that can target them and spare blood-forming stem cells at the same time.

The researchers identified small molecules, potentially novel or those currently known, that kill leukemia stem cells, but not normal blood-forming hematopoietic stem cells, which are multipotent stem cells that give rise to all blood types. Three of the 10 compounds they studied targeted leukemia stem cells: ciclopirox olamine, etoposide and kinetin riboside.

“Treatment with these compounds, at the appropriate doses, would kill the leukemia cells and potentially minimize blood system side effects, such as anemia,” said Sean McDermott, Ph.D., research investigator in the Department of Internal Medicine, Hematology-Oncology at the University of Michigan Medical School.

In total, the researchers screened a collection of 4,000 small molecules using two novel leukemia cell lines that have properties of leukemia stem cells. Compounds that killed these leukemia cells were further tested on normal hematopoietic stem cells to remove toxic compounds.

“Overall, to find three compounds that target the leukemia stem cell, all with vastly different mechanisms, is extremely surprising and bodes well for future drug discovery efforts,” said McDermott.

Cells from 51 patients with acute myeloid leukemia (AML) and 12 patients with chronic myelogenuous leukemia (CML) were screened with one of the drugs, etoposide. The researchers were surprised by the etoposide results, which showed that the drug may target the leukemia stem cell in 30 percent of patients with AML and 67 percent of those with CML. These patients might benefit from treatment with this chemotherapeutic drug.

“Screening of larger libraries hopefully will identify even more agents for the cancer pipeline,” he added.

Follow-up studies are currently planned for ciclopirox olamine and it would be beneficial in evaluating low-dose etoposide as a single agent. Kinetin riboside may be tested in a clinical setting in the future, according to McDermott.

# A5. Phase I trial and pharmacokinetic study of cediranib in children with recurrent or refractory solid tumors

Results of a new study show that cediranib can be administered safely to children and adolescents with cancer, and that the side effects are tolerable. Preliminary evidence further showed that the drug may have activity in childhood sarcomas.

“There are a number of antiangiogenic agents, like cediranib, in development for adult cancers,” said researcher Elizabeth Fox, M.D., M.S.C.R., staff clinician in the Pediatric Oncology Branch at the National Cancer Institute. “Encouraging results seen in this trial provide a rationale for future clinical trials of cediranib and other antiangiogenic agents in childhood cancer.”

Cediranib is an oral drug that inhibits vascular endothelial growth factor receptor. The recommended dose in adults is 20 mg to 30 mg administered daily every day for 28 days.

Fox and colleagues tested the toxicity and tolerance of this drug when given in 28-day cycles to patients 2 to 19 years old with malignant solid tumors to determine the appropriate dose of cediranib for this age group. Patients who participated in this phase I study had not responded to or recurred after conventional therapy.

Among the 13 patients enrolled, once daily dosing of 12 mg/m2 of cediranib was tolerable. Thus far, three patients have experienced partial shrinkage of their tumor while receiving the antiangiogenic agent. Side effects in children were similar to those seen in adults on cediranib: dose-limiting toxicities were diarrhea, nausea, vomiting, lethargy and high blood pressure.

“This outcome is encouraging and provides evidence that cediranib should be further studied in future clinical trials in young patients with these and other sarcomas to determine the activity of this new agent,” Fox said. “Hopefully, newer classes of anti-cancer drugs currently being developed will have fewer acute and long-term side effects than the chemotherapy that we currently use to treat childhood cancers.”

The researchers are currently evaluating the effects with 17 mg/m2 of cediranib and proposed to the Children’s Oncology Group that a phase II study be conducted in selected childhood solid tumors.

# A114. Preclinical evaluation of the PARP inhibitor olaparib in homologous recombination deficient (HRD) MRE11 mutant microsatellite instable (MSI) colorectal cancer

The investigational cancer therapy olaparib demonstrated activity against colorectal cancer cells, which suggests that microsatellite instable colorectal cancer represents a potential patient population that could benefit from treatment with this agent.

Researchers have already evaluated the use of the oral poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib and its antitumor activity pre-clinically and in patients with breast and ovarian cancer that contain a specific DNA repair defect in the form of BRCA1 and BRCA2 mutations. These gene mutations are associated with hereditary breast and ovarian cancer and play a major role in the repair of DNA by the homologous recombination repair pathway. PARPs also play a major role in DNA repair, by working in an alternative pathway.

Olaparib exploits the “Achilles’ heel” of homologous recombination deficient cancers by blocking another DNA repair pathway in these already compromised cancer cells, therefore leading to an overload of DNA damage and resulting in tumor cell death. The activity of one such homologous recombination gene, MRE11, is lost as a consequence of microsatellite instability in colorectal cancer cells.

“DNA damage is occurring all the time in our cells and a number of mechanisms have evolved to repair this damage that include the PARP and the homologous recombination repair pathways,” said Mark O’Connor, Ph.D., chief scientist at KuDOS Pharmaceuticals Ltd., United Kingdom.

The aim of this study was to determine if microsatellite instability and MRE11 status correlated with sensitivity to olaparib. Olaparib is an oral anti-cancer drug in early development for the treatment of certain types of breast and ovarian cancer.

The researchers found the majority of colorectal cancer cell lines sensitive to olaparib correlated with microsatellite instability status and had MRE11 mutations. Furthermore, all olaparib-sensitive colorectal cancer cell lines were homologous recombination deficient.

“These results reinforce the idea that PARP inhibition might have broader clinical utility than in BRCA-deficient tumors alone,” said O’Connor. “They support the idea of using targeted cancer therapies in defined molecular genetic backgrounds that exploit specific DNA repair deficiencies in the cancer to be treated.”

http://www.eortc.be/

Source: news-medical.net

The findings about this compound, published in the Nov. 3 issue of Biochemistry journal, might prove valuable to patients and clinicians, who may benefit if there is a demonstrated boost to chemotherapy. Researchers also can use the compound to manipulate the receptor to learn more about a common cell replenishing pathway, called the Wnt pathway, which requires the receptor for normal activities and can go wrong in cancer cases.

The researchers had a choice: to screen libraries of several hundred thousand biochemical compounds or to use a library of about 1,200 FDA approved or biologically active compounds.

“We decided to take the less expensive route of screening FDA approved drugs, and fortunately, we found 26 compounds that seemed to meet our goal, but only one that truly worked with the Frizzled receptor,”said Wei Chen, Ph.D., Assistant Professor of the Department of Medicine at Duke. “The goal was to drive the Frizzled 1 receptor from the outer membrane to the inside of the cell,” which effectively inactivated the receptor.

The effective compound, niclosamide, is currently approved for use against tapeworm infection. But some colon cancer patients, for example, have a Wnt pathway that is overactivated and may benefit from the “quieting” effects of niclosamide, which blocks the receptor in the Wnt pathway.

“The paper provides a rationale for clinicians to investigate using niclosamide for a new purpose,” Dr. Chen said. “Based on our findings, one oncologist at Duke is writing protocols for a phase 1 (safety) clinical trial to treat colon cancer patients with the intention of bringing our laboratory findings to the patient’s bedside.”

Chen says he is proud of the work, which is “truly translational science.”

“I am a basic scientist working with cell receptors, we have a medicinal chemist in our laboratory and one of our collaborators is Dr. H. Kim Lyerly, a professor of surgery, who is a researcher in gene- and immune-based therapies for cancer, as well as director of the Duke Comprehensive Cancer Center,” said Chen. “This type of diverse collaboration lets me shepherd a finding more rapidly from the laboratory to the clinic.”

Provided by Duke University Medical Center

physorg.com

Berlin, Germany, November 25, 2009 / b3c newswire / - Glycotope GmbH, a leading German Biotech company, has received regulatory approval by Germany and Italian regulatory authorities for a Phase I study of Glycotope´s lead antibody GT-MAB 2.5-GEX^TM for the treatment of various solid cancers. The approvals further underline the suitability of Glycotope´s proprietary GlycoExpress^TM technology for the improvement, glycooptimization and high yield production of therapeutic proteins for the use in humans.

“The approval of GT-MAB 2.5-GEX as well as the regulatory approval of the GlycoExpress production technology based on its glycoengineered human cell lines represents a significant milestone for the company” says Steffen Goletz, PhD, Founder, CEO and CSO of Glycotope. “After generating very encouraging data in pre-clinical studies, we are now looking forward to demonstrate the importance of glycosylation in the clinic by generating a substantial benefit to patients.”

The Phase I study will evaluate the safety and tolerability of GT-MAB 2.5-GEX^TM in a broad series of cancer indications.

Link to the news release
About GT-MAB 2.5-GEX
GT-MAB 2.5-GEX^TM is a novel, exceptionally potent monoclonal antibody for the treatment of a broad variety of cancer indications. The antibody is directed against a novel tumor-specific combined carbohydrate-protein epitope present in a large number of patients of various cancers. GT-MAB 2.5-GEX^TM shows three highly effective key modes of anti-tumor action: ADCC, phagocytosis and induction of apoptosis with an exceptionally high and specific tumor accumulation and tumor killing already at doses as low as 0.5 mg/kg.  

The antibody’s fully human glycosylation is optimized to yield a largely improved ADCC activity, bioavailability and no non-human immunogenic carbohydrate structures. This was achieved by Glycotope´s proprietary technology platform GlycoExpress ^TM, a screening and high yield production system of glycoengineered human cell-lines that allows significant enhancement of therapeutic potency by optimizing a protein’s glycosylation in various aspects.

About Glycotope GmbH
GLYCOTOPE was founded in 2001 and focuses on the improvement and humanization of glycosylation structures on proteins, a comparatively new field in biotechnology. GlycoExpress^TM, the company’s proprietary technology permits making existing and new drugs more effective and tolerable in the human body, which is of considerable medical as well as economic importance. The current product range currently includes both proprietary antibodies for cancer therapy (e.g. GT-MAB 2.5-GEX ^TM) and significantly improved versions (2nd generation) of antibodies and other therapeutic proteins already on the market.

OTTAWA, ONTARIO, Oct 27, 2009 (MARKETWIRE via COMTEX) —-PharmaGap Inc. (TSX VENTURE: GAP)(OTCBB: PHRGF) (”PharmaGap” or “the Company”) is pleased to announce highly positive results from the United States National Cancer Institute (”NCI”) 5-dose in vitro anti-cancer screen of PharmaGap drug GAP-107B8. These results confirm and extend results announced in August from the single-dose study and provide definitive independent validation of GAP-107B8 as an active pharmaceutical ingredient against a wide range of cancers.

GAP-107B8 is a novel peptide protein kinase inhibitor that was designed to specifically target molecular signaling pathways in cancer cells. Targeted therapies are designed to target cancer cells while sparing surrounding normal, healthy, cells, thus causing less toxic effects than many standard chemotherapeutic agents currently in use.

Within a dose concentration range of 10 to 100 micromolar (u M), GAP-107B8 caused 100% growth inhibition (measured against cancer cell growth in untreated groups) in 51 of 56 cancer cell lines and caused at least 50% cancer cell death (measured against the number of cancer cells at the beginning of the test period) in 29 of 56 cancer cell lines.

The standard NCI test methodology generates three values that are used to measure the drug compound’s activity against the cancer cell-line panel. These are: the GI50, the dose that causes an average 50% growth inhibition in the cell lines; the TGI, the dose that causes an average 100% growth inhibition in the cell lines; and the LC50, the dose that causes an average 50% cell death in the cell lines. For GAP-107B8, the GI50 was determined to be 23 u M, the TGI was 51 u M, and the LC50 was 89 u M. These data provide a very clear range of focus for all future studies.

These results provided a large amount of data, from the NCI testing which will be used by the Company to select specific cancer types and to determine an optimum dosing range for future animal studies and subsequent clinical trials. Based on these and prior results, the Company will be focusing its immediate development program on ovarian cancer and melanoma. The first of these animal studies is currently underway at the Ottawa Hospital Research Institute (”OHRI”) in ovarian cancer. Further testing of GAP-107B8 on melanoma is about to commence under the guidance of Dr. Gary Schwartz at Memorial Sloan Kettering Cancer Center in New York. GAP-107B8 showed a strong effect in both melanoma and ovarian cancers in both single-dose and 5-dose testing at the NCI. In addition, the Company and NCI staff will meet in late November to discuss these results and ways in which the NCI may participate in various aspects of the development program for GAP-107B8.

The results across such a wide range of cancer cell lines, including a number which are known to be resistant to standard chemotherapy, indicate that GAP-107B8 has the potential to become a new cancer drug with less toxic side effects than common chemotherapeutic regimens.

Robert McInnis, President of the Company, stated “We are very pleased with the extent of activity in the NCI panel, as this activity against all cell lines provides a wide range of development opportunities for us, and provides us with additional support for a focus on ovarian cancer and melanoma. Our objective of the testing at the NCI - independent and verifiable validation of activity - has been fully realized. Over the past 12 months we have made significant progress in moving our lead drug to clinical trials: generating quality- controlled gram-scale production of the compound; achieving verifiable independent validation of compound activity at both the NCI and here in Ottawa at the OHRI; and programs underway in the area of bioassay development, understanding of signalling pathways involved, and continued testing programs at Memorial Sloan Kettering. This progress is very encouraging to me and to our team. Most importantly, results so far indicate a potential for new hope for the future of patients suffering from several types of cancer”.

About The National Cancer Institute

The National Cancer Institute (NCI), located in Bethesda, MD is an institute of the National Institutes of Health, the primary U.S. Federal Agency for conducting and supporting medical research. The NCI has a mandate to select and screen novel drug compounds that could potentially make a material difference in the “war against cancer”. Selection to the NCI screening program is through a competitive application process. Details on the NCI’s compound screening program can be found at http://dtp.nci.nih.gov/. More general information on the NCI is found at www.cancer.gov.

About PharmaGap Inc.

PharmaGap Inc. (TSX VENTURE: GAP)(OTCBB: PHRGF), based in Ottawa, ON, is a biotechnology company with a core focus on developing novel peptide therapeutics for the treatment of cancer. PharmaGap’s GAP-107B8 is a novel peptide drug designed to inhibit the activity of protein kinase C (PKC), a cell signalling enzyme implicated in certain types and stages of cancer. Independent peer-reviewed research has demonstrated that over-expression of PKC plays a role in the development of many cancer types. For more information please visit www.pharmagap.com.

Note: Neither the TSX Venture Exchange nor its Regulation Services Provider (as that term is defined in the policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release. No Securities Commission or other regulatory authority having jurisdiction over PharmaGap has approved or disapproved of the information contained herein. This release contains forward looking statements that may not occur or may change materially.

Contacts:
PharmaGap Inc.
Robert McInnis
President & CEO
613-990-9551
bmcinnis@pharmagap.com
www.pharmagap.com

SOURCE: PharmaGap Inc.

OTTAWA, ONTARIO — 10/20/09 — PharmaGap Inc. (TSX VENTURE: GAP)(OTCBB: PHRGF) (”PharmaGap” or “the Company”) advises that the results of dose-range testing of the Company’s cancer drug GAP-107B8 at the United States National Cancer Institute (”NCI”) can be expected “shortly”. NCI staff has indicated to the Company that testing has been completed and the results can be expected to be received by the Company after analysis and review of these results by the NCI has been completed.The Company announced the results from single dose testing at the NCI on August 24, 2009, which showed significant inhibition of cancer cell growth at a low drug concentration across a wide range of human cancer cells. In this initial single dose test, GAP107B8 demonstrated greater than 50% inhibition in cancer cell growth in 26 of 57 cell lines tested, across all 9 cancer types included in the test panel. The full release can be found on the Company’s website.

Source: earthtimes.org

WASHINGTON - Researchers at Massachusetts General Hospital have developed a two-step process that uses a chemical reaction to make live cancer cells light up quickly and safely.

This attains significance because scientists generally label cells with coloured or glowing chemicals to observe how basic cellular activities differ between healthy and cancerous cells, but existing techniques are either too slow or too toxic to perform on live cells.

Under the novel process, chemically modified antibodies first home in on cancer cells, and then a chemical reaction called cycloaddition transfers a dye onto the antibody making the cancer cells glow when viewed through a microscope.

Philip Dawson, a member of Faculty of 1000 Biology and leading authority in chemistry and cell biology, reviewed a study and observed that the novel cycloaddition reaction is fast, very specific, and requires minimal manipulation of the cells.

He comments that, in combining antibody binding with the cycloaddition, “low signal-to-noise ratios are achieved”.

He points out that the new labelling technique could be used to track the location and activity of anti-cancer drugs, the location of cancer-specific proteins within the cell, or to visualize cancer cells inside a living organism.

Dawson concludes that cycloaddition will allow scientists to observe live cancer cells in the body, leading to a better understanding of cancer’s basic processes. (ANI)

Source: http://blog.taragana.com

A multi-institutional team of Boston-area researchers has discovered a chemical that works in mice to kill the rare but aggressive cells within breast cancers that have the ability to seed new tumors.

These cells, known as cancer stem cells, are thought to enable cancers to spread — and to reemerge after seemingly successful treatment. Although further work is needed to determine whether this specific chemical holds therapeutic promise for humans, the study shows that it is possible to find chemicals that selectively kill cancer stem cells. The scientists’ findings appear in the August 13 advance online issue of Cell.

“Evidence is accumulating rapidly that cancer stem cells are responsible for the aggressive powers of many tumors,” says Robert Weinberg, a Member of Whitehead Institute for Biomedical Research and one of the authors of the study. “The ability to generate such cells in the laboratory, together with the powerful techniques available at the Broad Institute, made it possible to identify this chemical. There surely will be dozens of others with similar properties found over the next several years.”

“Many therapies kill the bulk of a tumor only to see it regrow,” says Eric Lander, Director of the Broad Institute of MIT and Harvard, and an author of the Cell paper. “This raises the prospect of new kinds of anti-cancer therapies.”

An emerging idea in cancer biology is that tumors (breast, prostate, colon, lung, etc.) harbor a group of cells with the unique ability to regenerate cancers. In addition to promoting tumor growth, these so-called cancer stem cells are largely resistant to current cancer therapies. If it were possible to identify chemicals that selectively kill cancer stem cells, such chemicals might become critical candidates for future drug development.

However, researchers have struggled to study cancer stem cells directly in the laboratory. The cells’ relative scarcity compared to other tumor cells, combined with a tendency to lose their stem cell-like properties when grown outside of the body, have severely limited the amount of material available for analysis.

To overcome these hurdles, Broad and Whitehead Institute researchers drew upon recent findings from Weinberg and his colleagues that suggested a way to generate in the laboratory large numbers of cancer cells with stem cell-like qualities. The technique works by coaxing adult cells to undergo a critical change (known as an “epithelial-to-mesenchymal transition”) that alters their shape and motility. At the same time, the cells also adopt similar properties as stem cells.

“A critical aspect of our work was to generate relatively homogenous and stable populations of cancer stem-like cells that could then be used for screening,” says Tamer Onder, a former graduate student in Weinberg’s lab and co-first author of the study. (Onder is now a postdoctoral research fellow at Children’s Hospital in Boston.) “We were able to achieve this by inducing the cancer cells into an epithelial-to-mesenchymal transition using novel reagents that we had developed in the lab.”

With an ample number of stem cells in hand, the Broad-Whitehead team undertook a large-scale analysis of thousands of chemical compounds, applying automated methods to search for ones with activity against breast cancer stem cells. From a pool of more than 30 promising candidates, the researchers identified a compound with surprising potency.

The compound, called salinomycin, kills not only laboratory-created cancer stem cells, but also naturally occurring ones. Compared to a common chemotherapeutic drug prescribed for breast cancer (known as paclitaxel), salinomycin reduced the number of cancer stem cells by more than 100-fold. It also diminished breast tumor growth in mice.

To further dissect the function of salinomycin, the researchers also examined its genetic effects. Previous studies of tumors from breast cancer patients have revealed groups of genes that are highly active in cancer stem cells. Many of these same genes are linked with particularly aggressive tumors and poor patient prognoses. The researchers’ studies show that salinomycin (but not paclitaxel) treatment can decrease the activity of these genes, revealing a possible molecular basis for the chemical’s biological effects.

“Our work reveals the biological effects of targeting cancer stem cells,” says co-first author Piyush Gupta, a researcher at the Broad Institute. “Moreover, it suggests a general approach to finding novel anti-cancer therapies that can be applied to any solid tumor maintained by cancer stem cells.”

Although the new findings signal a noteworthy scientific milestone, it is still too early to know whether cancer patients will reap benefits from it. Additional research is needed to determine exactly how salinomycin works to kill cancer stem cells and if it can wield the same tumor-reducing power in humans as it does in mice. These types of analyses generally take several years to complete.

But even with such tempered enthusiasm, there is also cause for optimism. In the current study, just 16,000 chemical compounds were tested, of which a small subset showed toxicity against cancer stem cells. Therefore, deeper investigations of these compounds as well additional tests of broader collections of chemicals may yield other potential additions to the anti-cancer arsenal.

UT Southwestern Medical Center researchers are the first to design a large-scale, cell-based screening method that identifies which compounds activate immune-return cells that hold compact for prospective cancer-fighting vaccines.
The new screening technique can scan thousands and even millions of compounds to identify those that activate dendritic cells, which are on constant recon patrol throughout the body to scout out cancerous or infected cells and alert the immune system.
“Our assay is unique from other conventional ones in its sensitivity and cost- and time-efficiency,” said Dr. Akira Takashima, professor of dermatology and vice chairman for research and head of the project.
Dendritic cells (DCs) are considered key to developing future vaccines that can either mimic the body’s natural immune response or turn on immune responses that failed - due, for example, to cancer or an immune deficiency.
The team, which also included Dr. Norikatsu Mitzumoto, assistant professor of dermatology and the study’s lead author, and Drs. Hironori Matsushima and Hiroaki Tanaka, postdoctoral researchers in dermatology, created the cell-based biosensor system.
“We basically engineered DCs to express a fluorescent signal only when sensing activation signals so that you can identify immuno-stimulatory agents very easily,” said Dr. Takashima. Immuno-stimulatory agents launch the immune system.

Buy exelon

The research appears on Blood magazine’s online Web site and will appear in a future issue.
“We have optimized the high-throughput screening capability - an experienced scientist can now test one thousand chemicals a day almost single-handedly,” added Dr. Mizumoto. Previously, scientists would have to test each compound individually, a time-consuming process.
Their research already has led to the discovery of several compounds that turn on dendritic cells, which are found throughout the body from skin to blood. They continuously scan the body at the cellular level looking for antigens - foreign cells and materials invading the body - and for molecular signatures of tissue damage or infection.
“Their primary job is to present antigens to the immune system so that you develop protective immunity for infection and cancer,” said Dr. Takashima.
The DC biosensor system should help pharmaceutical and biotech companies sift through large numbers of chemicals for ones that tell the dendritic cells to launch the immune response. It may also prove useful in identifying biothreat agents because it detects infectious pathogens with high sensitivity.
Dr. Takashima said he hopes to garner additional funding to discover potent immuno-stimulatory drugs by screening high-quality libraries of compounds.
Doing so may be the first step toward developing a new class of vaccines that force or trick the natural immune system to kick on, or initiate an immune response that can be copied and initiated artificially.
Other UT Southwestern researchers from dermatology involved in the study were Dr. Yasushi Ogawa, postdoctoral researcher, and Dr. Jimin Gao, former instructor.
The research was funded by the National Institutes of Health, the Dermatology Foundation Career Development Award and the American Cancer Society Junior Investigator Award.
http://www.utsouthwestern.edu/