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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY



Sexta-feira, 26.06.15

Immunotherapies Shine at ASCO Annual Meeting

 

Immunotherapies Shine at ASCO Annual Meeting

 
FDA-approved immunotherapies are showing efficacy in different cancer types and combination therapies with new biologics are displaying increased efficacy.

The number of immunotherapy agents approved by the U.S. Food and Drug Administration for the treatment of patients with cancer has risen rapidly in recent years.

Naked monoclonal antibodies, such as bevacizumab, rituximab, and trastuzumab, are now approved for the treatment of various solid and hematologic cancers.

Chemolabeled antibodies, such as brentuximab vedotin, ado-trastuzumab emtansine, and the prostate cancer vaccine sipuleucel-T, add to the growing number of immunotherapies being used to combat cancer.

Positive results from various studies evaluating the use of  standard immunotherapies for different cancers and novel immunotherapies were announced at the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, IL.

The antiangiogenic drug bevacizumab (Avastin), which is already approved for the treatment of six cancer types, was shown to significantly increase progression-free survival (PFS) in combination with carboplatin and paclitaxel in recurrent endometrial cancer compared with carboplatin plus paclitaxel alone.

The phase 2 study showed that the addition of bevacizumab improved median  PFS by more than 4 months.1 A phase 3 trial evaluating the addition of bevacizumab to letrozole as first-line endocrine therapy found that bevacizumab improved PFS by 4 months in patients with hormone receptor-positive advanced breast cancer.2

In addition, BCD-021, a bevacizumab biosimilar candidate was found to be non-inferior to Avastin in patients with non-small cell lung cancer (NSCLC) in a phase 3 trial.3 Biosimilar drugs, unlike generic drugs, do not have identical active ingredients, but are similar.

Ramucirumab (Cyramza), which is now approved for the treatment of patients with gastric, colorectal, and NSCLC, was shown to provide clinical benefit in combination with docetaxel in advanced NSCLC in the phase 3 REVEL trial, but the study had a limited number of East Asian patients who received the docetaxel 75 mg/m2 dose.

A similar phase 2 study in Japanese patients demonstrated improved clinical benefit with ramucirumab plus docetaxel 60 mg/m2 compared with docetaxel plus placebo.4

The addition of obinutuzumab (Gazyva), a CD20-directed cytolytic antibody, to bendamustine was shown to significantly improve PFS compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma (NHL).5

RELATED: Pembrolizumab Immunotherapy Effective in Recurrent, Metastatic Head and Neck Cancer

“Obinutuzamab plus bendamustine followed by obinutuzumab maintenance represents an effective treatment option for patients with relapsed/refractory indolent NHL who are refractory to rituximab,” said Laurie Sehn, MD, MDCM, MPH, of the British Columbia Cancer Agency in Canada.

“The trial results are remarkable as this does represent the first randomized, controlled trial data that demonstrates the utility of a novel anti-CD20 monoclonal antibody in patients with rituximab-refractory lymphoma.”

FDA-approved immunotherapies are showing efficacy in different cancer types and combination therapies with new biologics are displaying increased efficacy.

The results of two trials evaluating combination immunotherapy in patients with advanced melanoma were announced at the conference. One trial included treatment with nivolumab plus ipilimumab and the other with pembrolizumab plus low-dose ipilimumab.

The first study found that nivolumab plus ipilimumab and nivolumab alone had superior clinical activity compared with ipilimumab alone in treatment-naïve patients.6

The second study demonstrated significantly improved PFS and objective response rate (ORR) with nivolumab plus ipilimumab versus ipilimumab alone.7

A small phase 1 study showed an acceptable safety profile with pembrolizumab plus low-dose ipilimumab in patients with advanced melanoma or renal cell carcinoma, as well.8

Immunotherapies for melanoma have multiplied in the last 5 years with the approval of ipilimumab (Yervoy), pembrolizumab (Keytruda), and nivolumab (Opdivo); however, these treatments can cost up to tens of thousands of dollars.

Two new immunotherapies currently under investigation were shown to have encouraging results in patients with relapsed/refractory hematologic cancers.

The first, polatuzumab vedotin, an anti-CD79b antibody-drug conjugate demonstrated high ORRs when used in combination with rituximab in patients with relapsed/refractory follicular lymphoma.9

The other, elotuzumab, was shown to significantly reduce the risk of progression and death when used in combination with lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone in patients with relapsed/refractory multiple myeloma.10.

“Elotuzumab now is the first monoclonal antibody demonstrating [PFS] benefit in combination with [lenalidomide/dexamethasone] in a large randomized phase 3 trial of relapsed/refractory multiple myeloma,” said Sagar Lonial, MD, Chief Medical Officer at Winship Cancer Institute of Emory University in Atlanta, GA.

While a number of studies evaluated the use of monoclonal antibodies, there were also various studies presented that tested vaccines and chimeric antigen receptor (CAR) modified T cells.

An autologous tumor-derived heat shock protein peptide vaccine improved survival compared with standard therapy in 46 patients with newly diagnosed glioblastoma multifome, a type of brain cancer that has limited treatment options and poor survival.11

 

RELATED: Older Adults with Head and Neck Cancers May Need More Cautious Treatment Strategies

Two studies assessing the impact of CAR T cells in patients with relapsed/refractory acute lymphocytic leukemia and two forms of NHL found that the immunotherapy induced a high complete response rate and durable response, respectively.12,13

It is clear that the use of immunotherapy for the treatment of cancer is expanding. As FDA-approved biologics demonstrate efficacy in other cancer types and new biologics are displaying efficacy in combination with other biologics and chemotherapy, the role of immunotherapeutic agents for patients with cancer continues to grow.

References

  1. Lorusso D, Ferrandina G, Colombo N, et al. Randomized phase II trial of carboplatin-paclitaxel (CP) compared to carboplatin-paclitaxel-bevacizumab (CP-B) in advanced (stage III-IV) or recurrent endometrial cancer: the MITO END-2 trial.  J Clin Oncol. 2015;33(suppl; abstr 5502).
  2. Dickler MN, Barry WT, Cirrincione CT, et al. Phase III trial evaluating the addition of bevacizumab to letrozole as first-line endocrine therapy for treatment of hormone-receptor positive advanced breast cancer: CALGB 40503 (Alliance).  J Clin Oncol. 2015;33(suppl; abstr 501).
  3. Filon O, Orlov S, Burdaeva O, et al. Efficacy and safety of BCD-021, bevacizumab biosimilar candidate, compared to Avastin: results of international multicenter randomized double blind phase III study in patients with advanced non-squamous NSCLC.  J Clin Oncol. 2015;33(suppl; abstr 8057).
  4. Hosomi Y, Yoh K, Kasahara K, et al. Docetaxel + ramucirumab (DR) versus docetaxel + placebo (D) as second-line treatment for advanced non-small cell lung cancer (NSCLC): a randomized, phase II, double-blind, multicenter trial in Japan. J Clin Oncol. 2015;33(suppl; abstr 8054).
  5. Sehn LH, Chua NS, Mayer J, et al. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2015;33(suppl; abstr LBA8502).
  6. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Efficacy and safety results from a phase III trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naïve patients with advanced melanoma (CheckMate 067). J Clin Oncol. 2015;33(suppl; abstr LBA1).
  7. Hodi FS, Postow MA, Chesney JA, et al. Clinical response, progression-free survival, and safety in patients with advanced melanoma receiving nivolumab combined with ipilimumab versus IPI monotherapy in CheckMate 069 study. J Clin Oncol. 2015;33(suppl; abstr 9004).
  8. Pembrolizumab (MK-3475) plus low-dose ipilimumab in patients with advanced melanoma or renal cell carcinoma: data from the KEYNOTE-029 phase I study. J Clin Oncol. 2015;33(suppl; abstr 3009).
  9. Advani RH, Flinn I, Sharman JP, et al. Two doses of polatuzumab vedotin in patients with relapsed/refractory follicular lymphoma: durable responses at lower dose level. J Clin Oncol. 2015;33(suppl; abstr 8503).
  10. Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide/dexamethasone with/without elotuzumab in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2015;33(suppl; abstr 8508).
  11. Bloch O, Raizer JJ, Lim M, et al. Newly diagnosed glioblastoma patients treated with an autologous heat shock protein peptide vaccine: PD-L1 expression and response to therapy. J Clin Oncol. 2015;33(suppl; abstr 2011).
  12. Park JH, Riviere I, Wang X, et al. Efficacy and safety of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed or refractory B-ALL. J Clin Oncol. 2015;33(suppl; abstr 7010).
  13. Schuster SJ, Svoboda J, Nasta S, et al. Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas.J Clin Oncol. 2015;33(suppl; abstr 8516).

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por cyto às 01:02

Sexta-feira, 26.06.15

Vaxon Biotech receives new patent in Japan for cancer vaccine candidates

Vaxon Biotech receives new patent in Japan for cancer vaccine candidates

Published on June 22, 2015 at 9:21 AM ·

The company’s worldwide cancer vaccines patent portfolio, made up of ten patent families, now comprises 24 issued patents

Vaxon Biotech, a company specialized in anti-tumor immunotherapy, today announces that it has been granted a new patent in Japan. This patent (JP application n°2012-502822) covers a series of optimized cryptic peptides to be used in the design of the Vbx-026, a new cancer vaccine for solid tumors.

This patent gives Vaxon exclusive rights in Japan and raises its worldwide portfolio to 24 issued patents.

The patent will support the development of Vbx-026, a vaccine dedicated to the treatment of cancer patients expressing the HLA-A24 molecule. This molecule is widely expressed in the Asian population, mainly in Japan, with more than 40% of the Japanese population expressing HLA-A24. The initiation of preclinical development of the Vbx-026 vaccine is planned for 2016.

“This new patent will strengthen our position in Japan, a promising market for the development of the Vbx-026 vaccine,” said Dr. Kostas Kosmatopoulos, CEO of Vaxon Biotech. “With four cancer vaccines under development, ranging from lead optimization to phase II, we have built a strong patent portfolio and we now cover the three major HLA molecules, corresponding to around 80% of cancer patients.”

Vaxon Biotech develops therapeutic vaccines against cancer, based on its proprietary technology of optimized cryptic peptides, which are protected by ten patent families. All vaccines developed by Vaxon target universal tumor antigens and therefore have wide-ranging applications in cancer treatment.

Vx-001 and Vx-006 are already in clinical trials (Vx-001 in an ongoing randomized phase II trial in eight European countries and Vx-006 in an ongoing phase I trial). Vbx-016 has successfully completed its preclinical development and is ready to enter clinical trials and Vbx-026 is at the final stage of lead optimization.

Vx-001 and Vx-006 can be used for the treatment of patients expressing HLA-A2, the most common HLA molecule in humans (40-45% of the world population). Vx-001 and Vx-006 are fully protected by a total of 17 patents granted in Europe, the US, Canada, China and Japan. These patents belong to four patent families and cover peptide optimization technology, the products derived from this technology and their use. Six of these patents belong to INSERM/IGR and have been licensed to Vaxon Biotech, while the remaining 11 are Vaxon’s own property.

Vbx-016 can be used for the treatment of patients expressing HLA-B7, a common HLA molecule (25% of the population). Vbx-016 is already protected by three patent families. Five patents are already granted in Europe, the US, China and South Korea. Additional patents are still under review. All these patents are Vaxon’s own property.

The global market for cancer vaccines is expected to grow to $4.3 billion (€3.8 billion) by 2019, with a five-year compound annual growth rate (CAGR) of 1.3%. Technological advancements, new product launches and unmet treatment needs are predicted to drive consistent growth in this market for the foreseeable future.

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por cyto às 00:58

Sexta-feira, 26.06.15

ImmunoCellular's ICT-107 phase 3 registrational clinical program in newly diagnosed glioblastoma, anticipated to begin in the second half of 2015.

ImmunoCellular, Pure MHC partner to develop new assay for ICT-107 phase 3 registrational clinical program

Published on June 22, 2015 at 7:32 AM ·

ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT: IMUC) announced an agreement with Pure MHC, an Emergent Technologies portfolio company, for development of a novel assay for quality control that will be an important component of ImmunoCellular's ICT-107 phase 3 registrational clinical program in newly diagnosed glioblastoma, anticipated to begin in the second half of 2015. Under the terms of the agreement, Pure MHC will develop and validate a new assay specifically created for ICT-107, a dendritic-cell based immunotherapy targeting six antigens found on glioblastoma cells, especially stem cells. The new assay will be used to validate the quality and confirm the activity of ICT-107 and allow it to be released for administration to patients in the phase 3 trial.

"The agreement with Pure MHC is another important milestone in ImmunoCellular's progress toward the phase 3 registration trial for ICT-107," said Andrew Gengos, ImmunoCellular Chief Executive Officer. "Designing a new release assay to support the specific requirements of the ICT-107 six-antigen complex requires special skill and expertise, and we are confident in Pure MHC's ability to deliver a validated release assay. We believe that the knowledge and know-how gained from developing this assay can be applied to our other dendritic cell-based immunotherapy programs, thus representing a meaningful return on investment for our Company. We look forward to continuing to advance toward beginning patient enrollment in the phase 3 trial of ICT-107 in the late third quarter or early fourth quarter of this year."

"Pure MHC has developed a suite of platform technologies in the field of immuno-oncology including the use of TCRm mAb to validate peptide vaccine delivery," said Tommy Harlan, Pure MHC Chief Executive Officer. "Pure MHC looks forward to using its patented TCRm potency assay to support the release of ImmunoCellular's ICT-107 dendritic cell-based immunotherapy for glioblastoma."

Source:

ImmunoCellular Therapeutics, Ltd.

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por cyto às 00:45

Sexta-feira, 26.06.15

Specific Protein Promotes Cancer Growth in Most Aggressive Breast Cancers

MD Anderson Study Finds That a Specific Protein Promotes Cancer Growth in Most Aggressive Breast Cancers

Researchers from The University of Texas MD Anderson Cancer Center (MD Anderson) have recently released study findings suggesting that the DAPK1 (death-associated protein kinase 1) protein is crucial for tumor growth in breast and other cancers with mutations in the TP53 gene and that it may be an efficacious therapeutic target for many of the most aggressive cancers. The study, entitled, “Death-associated protein kinase 1 promotes growth of p53-mutant cancers,” was published in the latest edition of the Journal of Clinical Investigation.

The current prognosis for Estrogen receptor–negative (ER-negative) breast cancers, a highly aggressive form of the disease, is extremely poor.  For patients who are diagnosed with triple receptor–negative breast cancer (TNBC), the survival outlook is bleak. In hopes of finding a way to increase survival rates in TNBC patients, scientists are looking for molecular targets that could lead to effective drug therapies for these patients.

In this Study

The researchers’ primary aim was to identify molecular targets that are capable of suppressing tumorigenesis in TNBCs.  To do this, they worked with breast cancer cell lines and mouse models to investigate the effect of inhibiting DAPK1, a protein associated with molecular pathways leading to cell death, in these experimental models.  What they found was that the when DAPK1 is blocked it significantly decreases the tumor growth rate in TP53-mutant cells, but had no impact on the normal TP53 cells.

In addition to the laboratory assessment of inhibiting DAPK1, the researchers also completed a medical records evaluation of numerous breast cancer patient data sets and found that high DAPK1 expression associates with worse outcomes in individuals with p53-mutant cancers.

In a University press release about the study, Dr. Powel Brown, MD, PhD, professor and chair, Clinical Cancer Prevention, MD Anderson CC, and senior study author, stated, “This is a little studied kinase that has not been previously focused on for the treatment of cancer. We discovered a yin and yang phenomenon in terms of DAPK1 function. In normal cells this protein functions as a death inducer, but in TP53 mutant cells DAPK1 acts a critical driver of cancer cell growth.”

Dr. Brown continued, “While a new treatment for triple-negative breast cancers would be a major advance, DAPK1 inhibitors have the potential to be used to treat many different kinds of cancers with TP53 mutations, which include the most lethal cancers without effective treatments.”

Dr. Brown’s lab is presently working on ways to translate these findings into potential therapies using DAPK1 inhibitors, as well as, testing DAPK1 inhibition in combination with various types of chemotherapy to assess if there are any additional benefits that may lead to greater treatment efficacy.

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por cyto às 00:42

Sexta-feira, 26.06.15

‘Double agent’ skin cells in fight against dengue

‘Double agent’ skin cells in fight against dengue

Scientists identify the skin immune cells targeted by the dengue virus when it infects a person

Published online 24 June 2015

A*STAR researchers have found that the dengue virus targets antigen-presenting cells in human skin.

© 2015 A*STAR Singapore Immunology Network

Cells in the skin immune system that act as ‘gateways’ enabling the dengue virus to spread through the body have been identified by A*STAR researchers1.

Dengue is a global health concern that is growing at an alarming rate. Approximately 390 million people are infected by the virus each year, and the World Health Organization now estimates that about half of the world’s population is at risk of infection. Although the virus generally causes relatively mild symptoms such as fever, headaches and rashes, in certain cases it can lead to potentially fatal organ failure.

Like malaria, dengue is transmitted by mosquitoes and enters the body via the skin. However, it had not been clear which components of the skin were involved in spreading the virus throughout the body — until now (see image).

By infecting skin from human donors and examining its response to infection, Katja Fink at the A*STAR Singapore Immunology Network and co-workers have discovered that the dengue virus targets certain immune cells in human skin. Specifically, they found that the main target of the virus is antigen-presenting cells — key players in initiating an immune response as they present microbes to immune cells. On further analysis, the scientists discovered that only certain antigen-presenting cells were susceptible to infection, namely macrophages and three of the four kinds ofdendritic cells.

There is a certain irony to these results as they indicate that these skin immune cells are simultaneously an entry point of the dengue virus into the body and leaders in the fight to rid the body of the virus.

The findings are critical to the fight against dengue. “It is vital to understand the initial steps that occur during a natural infection, as these are the basis of a subsequent immune response,” explains Fink. “By learning which cells will eventually present antigens to T cells, we can predict the type of response we need to trigger during immunization or vaccination in order to create an efficient and lasting memory against the virus.”

Fink is a strong advocate of the approach adopted in the study. “We believe that working with primary human cells and tissue, no matter how tedious and difficult it can be, provides very real insight into the biology of dengue disease,” she says.

In the future, the team intends to study the responses of dengue-virus-specific T cells activated by different subsets of infected dendritic cells.

 

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network and the Institute of Medical Biology.

 

Related Links

Strengthening the fight against dengue fever

Dengue fever: Keeping the dengue virus unmasked

Immunology: Targeting key cells for a dengue virus infection model

 

 

Reference

  1. Cerny, D., Haniffa, M., Shin, A., Bigliardi, P., Tan, B. K. et al. Selective susceptibility of human skin antigen presenting cells to productive dengue virus infection. PLoS Pathogens 10,e1004548 (2014). | article

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por cyto às 00:40

Sexta-feira, 26.06.15

A protein structure that went unsolved for 20 years has revealed how cells regulate their skeletons

Cell skeleton structure breakthrough

A protein structure that went unsolved for 20 years has revealed how cells regulate their skeletons

Published online 24 June 2015

An illustration of thymosin-β4 (colored) bound to actin (gray).

© 2015 A*STAR Institute of Molecular and Cell Biology

Insight into the regulation of cell skeleton structure has come from a study conducted by A*STAR researchers1. The work, which solved a protein structure that has eluded scientists for 20 years, should lead to further insights into many cellular processes and could even help to combat cancer.

The outer membrane of a cell is supported by a cytoskeleton that is built from actin, a globular protein that links together to make chains, which in turn form fibers that make up the skeleton. Lengthening and shortening of actin chains enables rapid changes in the cytoskeleton, a crucial adaptive process.

“Actin is essential in numerous cellular processes, including cell motility, cell division, cell signaling, establishment of cell junctions, and maintenance of cell shape,” explains lead author Bo Xue from the A*STAR Institute of Molecular and Cell Biology. “In addition, cancer cells often become invasive by increasing migratory signals to the cytoskeleton.”

A pool of unlinked actin is stored in cells to enable immediate changes to the cytoskeleton, but this pool requires tight regulation to prevent actin chains forming randomly. Two proteins involved in this regulation are thymosin-β4 (Tβ4) and profilin. The structure of profilin has been known for 20 years, but since then attempts to solve the structure of Tβ4 have failed. Xue and colleagues succeeded by fusing actin and Tβ4 so as to image the structure when the two proteins were bound together (see image).

The team saw two different structures of Tβ4, each bound differently to actin. One structure concealed the chain-forming regions of actin, explaining how Tβ4 blocks chain formation. The other allowed profilin to bind to actin at the same time. In this complex, Tβ4 and profilin each modulated the strength of the other’s interactions with actin.

“When combined with biochemical assays and molecular dynamics simulations, such details allow us to propose a mechanism of actin exchange between profilin and Tβ4, the two major players in maintaining the monomeric actin pool,” explains Xue.

The researchers suggest that the two proteins can pass actin between them without allowing it to freely move inside the cell, preventing it from adding to the cytoskeleton in a random way.

“This general mechanism of actin regulation is applicable to many cellular processes in cells that contain β-thymosins and profilins,” explains Xue, who says that such insights could have more specific applications. “A deeper understanding of actin regulation will enable researchers to find better ways to fight cancer,” he concludes.

 

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology.

 

Related Links

Structural biology: Many ways to form a filament

Structural biology: Unsheathing cellular construction

Infectious disease: Giving immune cells ‘indigestion’

 

 

Reference

  1. Xue, B., Leyrat, C., Grimes, J. M. & Robinson, R. C. Structural basis of thymosin-β4/profilin exchange leading to actin filament polymerization. Proceedings of the National Academy of Sciences of the USA 111, E4596–E4605 (2014). | article

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por cyto às 00:38

Sexta-feira, 26.06.15

Stem cell factories

Stem cell factories

Researchers at A*STAR are mass-producing stem cells to satisfy the demands of regenerative medicine

Published online 24 June 2015

Human embryonic stems cells (green) aggregate around spherical microcarriers (small black circle in center) floating in a nutritional brew, a technique that can be used to grow millions of stem cells.
© 2015 A*STAR Bioprocessing Technology Institute

Steve Oh had been growing stem cells by conventional means at the A*STAR Bioprocessing Technology Institute (BTI) for seven years, when in 2008 his colleague Shaul Reuveny proposed an idea for speeding up the process.

Instead of culturing the cells on round, flat Petri dishes, he could try growing them on tiny polystyrene beads known as microcarriers floating in a nutritional brew, suggested Reuveny, a visiting scientist at the BTI. This technique had been used for decades to mass-produce virus-infected cells for the vaccine industry, which Reuveny was very familiar with.

The average Petri dish fits fewer than 100,000 cells, a miniscule amount when stacked against the 2 billion muscle cells that make up the heart or the 100 billion red blood cells needed to fill a bag of blood. The approach Reuveny suggested potentially could produce cells in much vaster numbers to make them more practical for therapy.

“Why don’t I bring some of these microcarriers over to you?” Reuveny suggested to Oh. Eventually, Oh was convinced to try what could become the most scalable method for growing stem cells and differentiated cells worldwide.

“There is a trend now in industry to move away from this simple Petri-dish method to manufacturing stem cells in bioreactor processors,” Oh says. “We started this journey much earlier than everyone else in the world.”

Exponential growth

Oh’s Stem Cell Group first tried the approach on human embryonic stem cells. These are found in the early embryo and have the potential to mature into any type of cell in the body, a state known as pluripotency. For months, they struggled to develop a coating that would make the stem cells stick to the microcarriers, and to formulate a solution that contained the right mixture of nutrients for the cells to grow. “Without Reuveny’s know-how, we probably would have failed,” says Oh.

About a year into their experimentation, one line of human embryonic stem cells survived past the 20-week mark of stability. Not only were these cells viable, they were also two to four times more densely packed than those grown in Petri dishes.

The group has spent the last six years refining their processes to produce even more cells using cheaper materials and fewer steps. “We are easily achieving three times higher cell densities than the Petri dish approach,” says Oh. “In some cases, by modifying the feeding strategy, we can get six times more cell densities, and we could probably reach ten with a bit of work.”

The process can be scaled up exponentially in larger tanks. “If in one week we can go from a ten-milliliter culture volume to a hundred-milliliter bioreactor, then the next week we can go from a hundred milliliters to one liter; and ten liters the week after that,” explains Oh. The equivalent in Petri dishes — from 100 to 1,000 to 10,000 — would be practically impossible for a researcher to handle.

The team has also expanded their repertoire to two other types of stem cells — induced pluripotent stem cells and adult mesenchymal stem cells — as well as differentiated heart, neural, bone and red blood cells.

Healing hearts

The biggest advances for Oh’s team in recent years have been in the growth of differentiated heart muscle cells, called cardiomyocytes. “We beat the Petri dish method on all counts — purity, yield, cost of goods and simplicity of process,” he maintains.

But a lot of their success is thanks to protocols initially developed on Petri dishes. For a start, cardiomyocytes are the fastest cell type to differentiate, taking only two weeks. And researchers have developed a method to grow pure batches of cardiomyocytes without the addition of expensive growth factors. Instead, they use small molecules to first inhibit and then activate a key cell-differentiation pathway known as Wnt signaling. Oh’s team applied this small-molecule approach to grow and differentiate cardiomyocytes from embryonic stem cells directly on their microcarriers.

“We can hit 90 per cent cardiomyocyte purity with this activator–inhibitor protocol,” says Oh, and the process is five to ten times cheaper than the Petri dish approach. Other preliminary results from their bioreactors reveal densities of millions of cells per milliliter, nearing the dosage counts needed to use stem cells in regenerative medicine.

The ultimate goal of the research is to grow enough cells in an affordable way to patch up one square-centimeter of damaged heart muscle following a heart attack.

Oh’s team is now partnering with industry to further improve the process, as well as with clinicians to test the healing potential of their cells on animal models. “We always try to keep the end in mind, to translate our work into something that can eventually be used by companies and clinicians.”

Healing tissue


Heart cells are just one cell type being grown at the BTI. From embryonic stem cells, the team has also developed progenitor cells halfway to becoming mature neurons, as well as dopaminergic neurons that when progressively lost in the brain can cause Parkinson’s disease. And the team is in the early stages of differentiating red blood cells at speeds and scales sufficient for use in emergency blood transfusions.

From mesenchymal cells, for which there are currently more than 400 registered clinical trials worldwide, Oh’s group is growing bone and cartilage cells known as osteoblasts and chondrocytes that can be introduced to animal models to repair damaged tissue.

“There is a need for better clinical products to heal bone defects and fractures or to treat those in need of spinal fusions. Stem cell therapy shows promise in this area,” says Asha Shekaran, a biomaterials and cell therapy researcher at the BTI. Asha investigates the bone-forming and bone-healing potential of stem cells grown on biodegradable microcarriers by implanting the cells just under the fat in the back of mice and delivering them into skull defects in rats.

“One of the challenges with evaluating stem cell treatments in complex living systems is that there is often a large degree of variability,” says Asha. “The results don’t always translate very well fromin vitro to mineralization in a non-bone site to bone healing in a rat model. And it is even harder to say how it will fare in larger animal models and clinical trials.”

But her preliminary results on the ability of scalably grown stem cells to differentiate into osteoblasts and produce cell-signaling cytokine molecules have been encouraging, she says. “Over the next five years, there are going to be a lot of strides made in translating stem-cell-based products into commercial use, especially in the scaled-up manufacturing of these products.”

Thanks to their pioneering use of microcarriers for a wide variety of differentiated cells, Steve Oh and the Stem Cell Group are well-positioned to be part of that exciting new future.

 

About the Bioprocessing Technology Institute

The Bioprocessing Technology Institute (BTI) is a member of the Agency for Science, Technology and Research (A*STAR). Established in 1990 as the Bioprocessing Technology Unit, it was renamed the Bioprocessing Technology Institute (BTI) in 2003. The research institute’s mission is to develop manpower capabilities and establish cutting-edge technologies relevant to the bioprocessing community. Some of the key research areas include expression engineering, animal cell technology, stem cell research, microbial fermentation, downstream purification and analytics.

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por cyto às 00:07

Sexta-feira, 26.06.15

Discover Genetic Instability, Potential Cancer Hotspots Using Stampede and Lonestar Supercomputers

UT Austin Researchers Discover Genetic Instability, Potential Cancer Hotspots Using Stampede and Lonestar Supercomputers

The University of Texas at Austin’s Texas Advanced Computing Center (TACC) Stampede and Lonestar supercomputershave helped scientists find a surprising link between cross-shaped (or cruciform) pieces of DNA and human cancer, according to a study at The University of Texas at Austin (UT Austin).

In a podcast, Texas Advanced Computing Center Technology Writer and Editor Jorge Salazar explains that DNA naturally folds itself into cross-shaped structures called cruciforms that protrude along the sprawling length of its double helix, noting that there is an abundance of DNA cruciforms, with scientists estimating that as many as 500,000 cruciform-forming sequences may exist on average in a single normal human genome. Among these, over 80 percent of DNA cruciforms are considered small, meaning under 100 base pairs of DNA, and small cruciforms enable the DNA replication and gene expression that are essential for human life. However, Salazar says scientists also suspect these small cruciforms — an essential structure of DNA itself — may be linked to mutations that can elevate cancer risk.

The UT Vasquez lab Open Access study, entitled “Short Inverted Repeats Are Hotspots for Genetic Instability: Relevance to Cancer Genomes“ is published in the journal Cell Reports, coauthored by co-first authors Steve Lu and Guliang Wang, with Albino Bacolla, Junhua Zhao, Scott Spitser, and Karen M. Vasquez — all of the Dell Pediatric Research Institute and the Division of Pharmacology and Toxicology, College of Pharmacy, at The University of Texas at Austin.

High performance computing using UT Austin’s Texas Advanced Computing Center supercomputers Stampede and Lonestar helped the researchers to discover short inverted repeats of 30 base pairs and under in a reference database of mutations in human cancer that are somatic, meaning not inherited.

The research team found that small DNA cruciforms are mutagenic, altering DNA in a way that can increase risk of cancer in yeast, monkeys, and in humans, noting that analyses of chromosomal aberrations in human genetic disorders have revealed that inverted repeat sequences (IRs) often co-localize with endogenous chromosomal instability and breakage hotspots. They observe that with approximately 80 percent of all IRs in the human genome being short, DNA cruciforms are created by short inverted repeats of the nucleotides Adenine-Thymine-Cytosine-Guanine that form the bases of DNA structure. Inverted repeats are DNA nucleotide sequences are followed by their reverse compliment sort of like a palindrome — a word or phrase that spells the same forwards or backwards (e.g.,: “A man, a plan, a canal, Panama!” or “Never a foot too far, even”). The coauthors suggest that their discoveries implicate short IRs as endogenous sources of DNA breakage involved in disease etiology and suggest that these repeats represent a feature of genome plasticity that may contribute to the evolution of the human genome by providing a means for diversity within the population.

DNA strands commonly break in human cells, which have a built-in healing mechanism whereby repair proteins fuse the broken end of one DNA strand to the broken end of another. However, the UT scientists note that when formed in certain ways, these “gene fusions, or translocations” can lead to cancer development.

“We found that short inverted repeats are indeed enriched at translocation breakpoints in human cancer genomes,” supervising coauthor author Karen Vazquez told Jorge Salazar. Dr. Vasquez is a professor in the Division of Pharmacology and Toxicology at the UT Austin College of Pharmacy, and has been recognized for pioneering contributions concerning genome instability, particularly by demonstrating that noncanonical DNA structures can be mutagenic, and for discovering new roles for DNA repair factors. She is also the James T. Doluisio Regents Professor in the Division of Pharmacology and Toxicology at UT Austin.

“In many cases, translocations are what turn a normal cell into a cancer cell,” Vasquez Lab research associate and study co-author Albino Bacolla explains in the UTCC podcast. “What we found in our study was that the sites of chromosome breaks are not random along the DNA double helix; instead, they occur preferentially at specific locations. Cruciforms structures in the DNA, built by the short inverted repeats, mark the spots for chromosome breaks, mutations, and potentially initiate cancer development.”

The Vasquez Lab’s current research efforts are focused on an overall theme of genome instability, DNA damage and mechanisms of repair. A unique feature of our approach is an emphasis on the role of DNA structure, including non-canonical structures such as triplex DNA, as recognition sites for repair machinery, sources of genomic instability, and as a basis for technology to target DNA damage to specific genomic sites.

Dr. Vasquez adds that “DNA double-strand breaks can increase the risk of cancer because they can result in translocations, deletions, and other mutagenic events that disrupt the coding properties of genes [and] these modifications of the DNA can lead to cancer.”

“We have also studied the potential mechanisms that are involved in the interplays among alternative DNA structures and cancer development,” she continues. “Our team has discovered at least two different mechanistic pathways: one involving DNA replication, where these unusual structures cause a roadblock to DNA replication; the other pathway is independent of that, where DNA repair proteins, we think, recognize these alternative DNA structures as damage, even though there is no damage per se. The cells try to process the structures as damage, but they are really processing naturally occurring unusual DNA formations and not actual damage. An abortive error prone repair process can then cause DNA double-strand breaks and lead to serious problems including neoplastic transformation.”

geneticinstability

Image caption: Short inverted repgeneticinstabilityeat sequences of DNA nucleotides are enriched at human cancer breakpoints. Credit: Karen Vasquez, UT Austin.

Results of several studies are incorporated in the Cell Reports article, one of which used reporter gene assays to confirm that the short inverted repeat sequences from COS-7 cells, derived from monkey kidney tissue, were mutagenic. “We wanted to confirm that this was a biologically relevant finding,” Dr. Vasquez says. “That’s when we had to do some computational studies and insilico searching. We used the TACC supercomputers for that aspect of the work.”

“It would not have been possible to do this job without the TACC resources,” Albino Bacolla notes. “We have used both the Stampede and the Lonestar Linux clusters. The center is an incredible resource in terms of its capacity and support. We have been using the resources and staff support for some time now. It’s a wonderful opportunity for researchers at UT Austin.”

Stampede is a Dell PowerEdge C8220 Cluster with Intel Xeon Phi coprocessors, and as one of the largest computing systems in the world for open science research the system provides unprecedented computational capabilities to the national research community, enabling breakthrough science that has never before been possible. The scale of Stampede delivers opportunities in computational science and technology research, from highly parallel algorithms to high-throughput computing, and from scalable visualization to next generation programming languages.

Lonestar is a Dell Linux cluster containing 23,184 cores within 1,888 Dell PowerEdgeM610 compute blades (nodes), 16 PowerEdge R610 compute-I/Oserver-nodes, and 2 PowerEdge M610 (3.3GHz) login nodes. Each compute node has 24GB of memory, and the login/development nodes have 16GB. Lonestar also provides access to five large memory (1TB) nodes, and eight nodes containing two NVIDIA GPU’s, giving users access to high-throughput computing and remote visualization capabilities respectively. Lonestar is funded by The University of Texas at Austin, UT’s Institute of Computational Engineering and Sciences (ICES), UT System, Texas A&M, Texas Tech, and the National Science Foundation, and serves as a unique resource to researchers at all 15 UT System institutions.’

The broad strokes of the UT Austin study’s findings are that 1) short inverted repeat (IR) sequences are enriched at human cancer breakpoints; 2) short IRs stimulate DNA double-strand breaks and deletions in mammalian cells; 3) short IRs impede DNA replication forks in mammalian cells; and 4) ERCC1-XPF cleaves IRs and is required for IR-induced chromosome breakage.

Mr. Salazar also cites the program director at the Division of Cancer Biology of the National Cancer Institute, observing: “The focus of Dr. Vasquez’ research on the mechanisms of alternate DNA structure-induced mutations, DNA breaks, and chromosome translocations is a novel and significant aspect of NCI grant supported studies on mechanisms of genomic instability. Dr. Vasquez’ studies on the role of non-B DNA sequences in these mechanisms can contribute to our knowledge of the etiology of human cancer.”

“We wanted to confirm that this was a biologically relevant finding,” Dr. Vasquez notes. “That’s when we had to do some computational studies and insilico searching. We used the TACC supercomputers for that aspect of the work.”

“With TACC’s support, we were able to see that this is at least one plausible explanation in human cancer etiology, because these sequences are enriched at translocation breakpoints,” Dr. Vasquez tells Jorge Salazar. “That gives us hope, inspiration, and enthusiasm to move forward. “Our overarching interest is to understand how DNA structure can influence cancer development. With access to TACC, we are more confident that DNA sequences capable of forming particular unusual structures present a plausible explanation for how DNA breaks can lead to translocations in cancer. Our next steps are to go forward with a mouse model that can detect mutations and translocations in the mouse genome using human sequences from these cancer breakpoints.”

“The long term goal for these studies is to develop better prevention or treatment strategies for cancer patients,” Dr. Vasquez comments in the podcast. Questions that remain to be answered in further research include: are does this really occur now in the context of chromosomes in living organisms? Is it tissue specific? Does aging make a difference? “If we can help clinical scientists apply mechanistic information such as we hope will be gained from our research to better cancer treatment and a cancer prevention strategies, we are benefiting all of us, Dr. Vasquez concludes “I think the potential of the computational analysis is mind-blowing. Bioinformatics and computational centers like TACC are critical for the next steps in science. It’s an exciting time.”

The National Cancer Institute, part of the National Institutes of Health, funded this study.

Sources:
The University of Texas at Austin
Texas Advanced Computing Center

Image Credits:
The University of Texas at Austin
Karen Vasquez, UT Austin

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por cyto às 00:04

Sexta-feira, 26.06.15

UTHealth New Anticancer Antibody Research Core

CPRIT Awards $5.3M Grant to UTHealth New Anticancer Antibody Research Core

The Cancer Prevention and Research Institute of Texas (CPRIT) has awarded a $5.3 million grant to a professor at The University of Texas Health Science Center at Houston (UTHealth) to enable the creation of a facility to assist scientists advancing their research into anticancer antibodies.

The 5-year CPRIT grant is a Core Facilities Support Award awarded to investigator and Robert A. Welch Distinguished University Chair in Chemistry at UTHealth, Zhiqiang An, PhD. The grant to Dr. An will fund a new facility to be established at the Texas Therapeutics Institute (TTI), the academic drug discovery program at UTHealth directed by Dr. An, and will be called the Therapeutic Monoclonal Antibody Lead Optimization and Development Core.

The new core will be focused on the development of antibodies, which are important immune system components combating infections and cancers, and can be studied to search for and eliminate cancer cells with high specificity and fewer side effects. “We’re helping scientists translate their cancer discoveries into new treatments,” explained in a press release Dr. An. “A majority of the monoclonal antibodies generated in academic laboratories do not advance beyond basic discovery stage.”

The investigator believes that the poor success in advancing antibody-based therapeutics is related to the lack of access to highly specialized protein engineering technologies — an unmet need that he expects to fulfill at the new facility by providing Texas-based researchers state of the art antibody platform technologies. The core will be managed by An in collaboration with UTHealth’s associate professor Ningyan Zhang, PhD.

Dr. An explained that while there are already a series of antibody treatments for cancer available on the market, such as trastuzumab or rituximab, more research and the approval of treatments are both still needed. “We’re developing lots of treatments for the same types of cancer. We need treatments for other types,” he said.

One of An’s collaborators, Philipp Scherer, PhD, who is a researcher, professor and director of the Touchstone Center for Diabetes Research at UT Southwestern Medical Center, noted his enthusiasm about An’s leadership and working alongside with him. “Dr. An is a world leader in antibody drug discovery with previous experience in industry. This grant will enable him to take his efforts to the next level,” stated Scherer.

Kendra Carmon, PhD, who works with Dr. An at the TTI, was also awarded a $200,000 CPRIT grant in the same round of funding, totaling over $41 million given to scientists in The University of Texas System. Carmon’s grant was awarded for the development of antibodies expected to deliver anticancer toxins to cancer sites with fewer side effects. The investigator works in the laboratory of Qingyun (Jim) Liu, Ph.D., who holds the Janice Davis Gordon Chair for Bowel Cancer Research at UTHealth.

Another researcher whose work will benefit from the new facility is Rong Li, PhD, who serves as professor of molecular medicine and is co-leader of the Cancer Development and Progression Program at The University of Texas Health Science Center at San Antonio. “With the CPRIT funding and expertise from the UT anticancer antibody core, we hope to develop an antibody that can specifically inactivate this cell-surface protein and therefore block the tumor-fat cell communication, with the ultimate goal of relieving obesity-associated cancer burden,” Li said.

In addition to this grant to support the establishment of the Therapeutic Monoclonal Antibody Lead Optimization and Development Core, Dr. An had also recently been granted a $900,000 CPRIT grant to advance his research into the cause of why some tumors are able to evade targeted treatment, focusing on the most recent innovations regarding cancer treatment and targeted therapies. The results of the studies are expected to improve the effectiveness of health care and decrease damage caused to healthy tissue that is not affected by cancer.

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por cyto às 00:03

Quinta-feira, 25.06.15

Acute Lymphoblastic Leukemia, Blood, Blood Cancer, Blood Disorder, Bone, Bone Marrow, Cancer, Cardiology, Cell, DNA, Education, Gene, Genetic, Genetics, Hematology, Hospital, Leukemia, Neurology, Neurosurgery, Oncology, Pediatrics, Platelets, Thrombocytop

Researchers track down key gene mutation responsible for causing acute lymphoblastic leukemia

Published on June 18, 2015 at 8:52 AM ·

After collecting data on a leukemia-affected family for nearly a decade, Children's Hospital of Michigan, Detroit Medical Center (DMC), Hematologist and Wayne State University School of Medicine Professor of Pediatrics Madhvi Rajpurkar, M.D., joined an international team of genetic researchers in an effort to track down a mutation partly responsible for causing the disease. Their findings, recently published in one of the world's leading science journals, have "major implications" for better understanding the genetic basis of several types of cancer, including leukemia.

Says Children's Hospital of Michigan Hematology/Oncology Researcher and Wayne State University Assistant Professor of Pediatrics Michael Callaghan, M.D., an investigator who co-authored the recently published study in Nature Genetics: "This is a very exciting new finding in cancer research - and I think a lot of the credit has to go to Dr. Rajpurkar for identifying the family (with the genetic mutation). This is a great example of how an astute clinician can help accomplish a breakthrough in research by paying careful attention to patients and then thinking long and hard about what she is seeing in the treatment room."

Two medical researchers from the Children's Hospital of Michigan and the Wayne State University School of Medicine have published the results of a nearly 10-year investigation that identified a key gene mutation that can trigger acute lymphoblastic leukemia, or ALL, and several other types of cancer.

Recently published in Nature Genetics, the findings assembled by the Children's Hospital of Michigan and Wayne State University School of Medicine duo and a team of international investigators have for the first time pinpointed a mutation that allows a lymphoblastic leukemia "precursor" to set the biochemical stage for the blood disorder.

ALL is a blood cancer that attacks an early version of white blood cells manufactured in bone marrow. Investigators have long suspected that it is caused in part by a mutation in a gene that is supposed to "turn off" excessive blood-cell growth. When the mutation suppresses the controlling mechanism that regulates the runaway growth, leukemia is often the result.

The study, "Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia," began nearly a decade ago when Dr. Rajpurkar treated a child at the Children's Hospital of Michigan for low blood platelets, known medically as "congenital thrombocytopenia." When both the child and an aunt later developed ALL - even as several other family members were diagnosed with thrombocytopenia - Dr. Rajpurkar began to suspect that there might be a genetic mutation at work in the family.

What followed was a 10-year journey through the labyrinth of the Human Genome, as the researchers worked with a growing number of genetic investigators to isolate and identify the mutation in a gene (ETV6) that regulates growth rates in bone marrow.

A key breakthrough in the quest for the genetic culprit took place when a nationally recognized expert in gene mutation - University of Colorado physician-researcher Jorge DiPaola, M.D. - joined Drs. Rajpurkar and Callaghan, and other investigators from Italy and Canada, in the effort to solve the DNA puzzle by uncovering the flaw in ETV6. The mutation discovery occurred in a core facility where the gene-sequencing took place.

While noting that "our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition," the study's authors concluded that the mutation occurs through "aberrant cellular localization" of the gene, which can result in "decreased transcriptional repression" during white blood cell formation.

"What we think that means," Dr. Callaghan said, "is that ETV6's job is to 'turn off' growth, but when you have this mutation, it can't turn it off because it's in the wrong place. It's usually supposed to sit on the DNA and keep things (including cancer) from getting made, but when you have this mutation, instead of sitting on the DNA it's sitting in a different part of the cell.... And that predisposes you to getting a (blood) cancer."

Dr. Rajpurkar, who is also the division chief of Hematology at the Children's Hospital of Michigan and an associate professor of Pediatrics at the Wayne State University School of Medicine, said she was "greatly pleased" that her decade of treating the Detroit family with the mutation eventually led to the breakthrough. "I told them that I didn't know what the family had," she said, "but that I would do my best to find out. Sometimes one has to accept uncertainty in the field of medicine, but (persistence in clinical research) pays off!"

The Children's Hospital of Michigan Pediatrician-in-Chief and chair of the Wayne State University School of Medicine Department of Pediatrics Steven E. Lipshultz, M.D., said the breakthrough was "hugely important" because it resulted in "a new association (between a genetic mutation and leukemia) that can now be scanned for.

"Because of this finding," he added, "families will eventually be counseled regarding their risk for some kinds of cancer and targeted interventions will be devised and tested."

Dr. Lipshultz also noted that the new findings in "what many physicians and researchers regard as the leading journal in the world on the molecular genetic basis of human disease" also provide "an exciting and extremely encouraging example of how research that takes place in the clinical setting can greatly improve care for patients.

"Our goal at the Children's Hospital of Michigan is to do everything we can to help achieve better outcomes for the patients we serve. This latest publication by two CHM physician-researchers and their colleagues underlines the vitally important links between treatment and research, and to see them demonstrated so compellingly inNature Genetics is quite thrilling for all of us who spend our days trying to help kids at the Children's Hospital of Michigan!"

Source:

Wayne State University - Office of the Vice President for Research

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por cyto às 11:49

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