PARP Inhibitors Cancer Review
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PARP Inhibitors Cancer Review
Poly ADP ribose polymerase (PARP) inhibitors for triple negative breast cancer (TNBC) The Phase III failure of Iniparib to extend OS or PFS in TNBC patients has cast a dark shadow on PARP inhibitors drug class and R&D in one of the most active area in industrial oncology. The most advanced product iniparib (BSI 201, Sanofi Aventis) has shown 30% response rates in Phase I trials and 62% in triple negative breast cancer patients in Phase II trials. Addition of Iniparib to chemotherapy increased overall survival to 12.2 months from 7.7 months on gemcitabine+ carboplatin. A global Phase III trial in squamous NSCLC was initiated in 2010. It has completed enrollment of TNBC patients in Phase III trials. The NDA and MAA is expected to be filed in 1-2 Q 2011. The second product olaparib has shown 40% response rates in extended Phase I trials and completed Phase II studies. Olaparib planned Phase III trials in BRCA1/BRCA2 positive breast cancer was cancelled by Astra Zeneca and focus shifted to Phase III in ovarian cancer patients. Olaparib extended PFS and time to progression by 4 and 4.6 months over placebo. Veliparib from Abbott is the third PARPi to complete Phase II trials in advanced metastatic breast cancer with 37% RR in BRCA positive patients. Tumor cells use PARP pathway to repair DNA damage to proliferate and replicate. A new test to identify defective genes RAD51 assay indicates that PARP inhibitors may benefit 60% of the ovarian cancer patients. Inhibition of PARP offers novel agents for treating tumors with DNA repair defects. PARP inhibitors have the market potential to generate 10-15 billion annual sales with each brand worth $3-5 billion in sales within 5 years after approval and marketing in major markets.
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Wendt Lab Metastatic Breast cancer

Wendt Lab Metastatic Breast cancer | PARP Inhibitors Cancer Review | Scoop.it
Metastatic breast cancer research. Bioluminesent imaging of drug resistant cancer. Wendt lab at the Purdue center for cancer research.Mouse models of breast cancer progression...
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Cancer patients face higher risk for shingles, new vaccines hold promise for prevention

Cancer patients face higher risk for shingles, new vaccines hold promise for prevention | PARP Inhibitors Cancer Review | Scoop.it
People newly diagnosed with cancer, particularly blood cancers, and those treated with chemotherapy have a greater risk of developing shingles, according to a new study in the Journal of Infectious Diseases.
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Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells - FullText - Cellular Physiology and Biochemistry 2018, V...

Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells - FullText - Cellular Physiology and Biochemistry 2018, V... | PARP Inhibitors Cancer Review | Scoop.it
<b><i>Background/Aims:</i></b> Blocking estrogen signaling with endocrine therapies (Tamoxifen or Fulverstrant) is an effective treatment for Estrogen Receptor-<i>α</i> positive (ER+) breast cancer tu...
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Clinical and biological characteristics of myeloma patients influence response to elotuzumab combination therapy

Clinical and biological characteristics of myeloma patients influence response to elotuzumab combination therapy | PARP Inhibitors Cancer Review | Scoop.it
Abstract
Based on ELOQUENT-2, combination therapy with the monoclonal antibody elotuzumab was approved for relapsed/refractory multiple myeloma in the US and Europe. However, outside clinical trials, the optimal integration of elotuzumab into the sequence of treatment lines remains to be determined. Therefore, we analyzed safety and efficacy of elotuzumab/immunomodulatory drug combinations in a real-life cohort of 33 patients from our institution. The most frequent grade 3/4 adverse event was lymphopenia which did not increase the incidence of viral reactivations. After a median of four prior treatment lines, an overall response rate of 60% and a median progression-free survival (PFS) of 8 months were observed. The presence of cytogenetic high-risk status had no impact on PFS while low disease burden and high numbers of natural killer (NK)-cells at treatment initiation were associated with longer PFS. We observed an extramedullary relapse in three patients, associated with reduced expression of the elotuzumab target antigen SLAMF7 on extramedullary myeloma cells in one patient. Thus, biomarkers like disease burden, NK-cell count and SLAMF7 expression on myeloma cells may help to define myeloma patients with high likelihood to respond to elotuzumab treatment. Prospective trials investigating these biomarkers in larger patient cohorts are highly warranted.

Keywords
Multiple myeloma SLAMF7 Immunotherapy Natural killer cells Extramedullary disease 
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A strategy using mesoporous polymer nanospheres as nanocarriers of Bcl-2 siRNA towards the therapy of breast cancer - Journal of Materials Chemistry B (RSC Publishing)

Small interference RNA (siRNA) has demonstrated unprecedented potential as a therapy for drug-resistant cancer. However, efficient cellular delivery is still a challenge due to hydrolytic sensitivity and poor cellular uptake of siRNA.
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Targeted drug – palbociclib – stops tumour growth in patients with early breast cancer - The Institute of Cancer Research, London

Targeted drug – palbociclib – stops tumour growth in patients with early breast cancer - The Institute of Cancer Research, London | PARP Inhibitors Cancer Review | Scoop.it
Adding a new targeted therapy to hormone therapy halts the growth of tumour cells in women with early-stage breast cancer, new research shows.
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Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker

Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker | PARP Inhibitors Cancer Review | Scoop.it
Epigenetic reprogramming in cancer genomes creates a distinct methylation landscape encompassing clustered methylation at regulatory regions separated by large intergenic tracks of hypomethylated regions. This methylation landscape that we referred to as Methylscape is displayed by most cancer types, thus may serve as a universal cancer biomarker. To-date most research has focused on the biological consequences of DNA Methylscape changes whereas its impact on DNA physicochemical properties remains unexplored. Herein, we examine the effect of levels and genomic distribution of methylcytosines on the physicochemical properties of DNA to detect the Methylscape biomarker. We find that DNA polymeric behaviour is strongly affected by differential patterning of methylcytosine, leading to fundamental differences in DNA solvation and DNA-gold affinity between cancerous and normal genomes. We exploit these Methylscape differences to develop simple, highly sensitive and selective electrochemical or colorimetric one-step assays for the detection of cancer. These assays are quick, i.e., analysis time ≤10 minutes, and require minimal sample preparation and small DNA input.
Krishan Maggon 's insight:

Universal 10 min cancer detection test.

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Olaparib Desensitization in a Patient with Recurrent Peritoneal Cancer | NEJM

Correspondence from The New England Journal of Medicine — Olaparib Desensitization in a Patient with Recurrent Peritoneal Cancer...
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Darzalex ®▼ (daratumumab) Phase 3 Study Shows Efficacy and Safety Data of Anti-CD38 Monoclonal Antibody in Patients with Newly Diagnosed Multiple Myeloma | Business Wire

Darzalex ®▼ (daratumumab) Phase 3 Study Shows Efficacy and Safety Data of Anti-CD38 Monoclonal Antibody in Patients with Newly Diagnosed Multiple Myeloma | Business Wire | PARP Inhibitors Cancer Review | Scoop.it

Phase 3 MAIA study results show daratumumab in combination with lenalidomide and dexamethasone reduced the risk of disease progression or death in newly diagnosed patients who are transplant ineligible

Data featured as a Late-Breaking Abstract at ASH 2018 (Abstract #LBA-2)

December 04, 2018 10:46 AM Eastern Standard Time

BEERSE, Belgium--(BUSINESS WIRE)--The Janssen Pharmaceutical Companies of Johnson & Johnson today announced results from the Phase 3 MAIA study demonstrating that the addition of daratumumab to lenalidomide and dexamethasone (Rd) significantly reduced the risk of disease progression or death in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT) (Abstract #LBA-2).1 These data were featured during the late-breaking abstract (LBA) oral session at the 60th American Society of Hematology (ASH) Annual Meeting in San Diego, CA.

 

The most common Grade 3/4 treatment-emergent adverse events (TEAEs) for daratumumab-Rd (≥10 percent) included neutropenia (50 percent), lymphopenia (15 percent), pneumonia (14 percent) and anaemia (12 percent).1 Infusion-related reactions (IRRs) occurred in 41 percent of patients, only 3 percent of which were Grade 3/4.1 Incidence of invasive second primary malignancy was 3 percent in the daratumumab-Rd arm compared to 4 percent with Rd alone.1 TEAEs with an outcome of death were 7 percent in the daratumumab-Rd arm compared to 6 percent in the Rd arm.1 The safety profile of daratumumab was consistent with that of previous studies.1

These data will support a future application for marketing authorisation for daratumumab in combination with Rd for this patient population.

Krishan Maggon 's insight:

About daratumumab

Daratumumab is a first-in-class biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.2 Daratumumab is believed to induce tumour cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.3 A subset of myeloid derived suppressor cells (CD38+ MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by daratumumab.3 Daratumumab is being evaluated in a comprehensive clinical development programme across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.4,5,6,7,8,9,10,11 Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant haematologic diseases in which CD38 is expressed, such as smouldering myeloma.12,13 For more information, please see www.clinicaltrials.gov.

In Europe, daratumumab is indicated for use in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant, as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy, and in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.3 For further information on daratumumab, please see the Summary of Product Characteristics at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004077/WC500207296.pdf.

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive licence to develop, manufacture and commercialise daratumumab.14

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Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer | NEJM

Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer | NEJM | PARP Inhibitors Cancer Review | Scoop.it
Phosphatidylinositol 3-kinase (PI3K) is involved in multiple cell processes, including insulin signaling, cell growth, immunity, and brain development. It is activated in a wide variety of cancers and is being targeted as a treatment, with notable success in lymphoma.
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Novel Tracer Developed for Precision Targeting of Non-Small Cell Lung Cancer - SNMMI

Novel Tracer Developed for Precision Targeting of Non-Small Cell Lung Cancer - SNMMI | PARP Inhibitors Cancer Review | Scoop.it
New research shows PET imaging with the 18F-FAC radiotracer can be used as a non-invasive substitute for liver biopsies. The study is featured in the October issue of The Journal of Nuclear Medicine.
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Single-cell multiomics sequencing and analyses of human colorectal cancer

Single-cell multiomics sequencing and analyses of human colorectal cancer | PARP Inhibitors Cancer Review | Scoop.it
To better design treatments for cancer, it is important to understand the heterogeneity in tumors and how this contributes to metastasis. To examine this process, Bian et al. used a single-cell triple omics sequencing (scTrio-seq) technique to examine the mutations, transcriptome, and methylome within colorectal cancer tumors and metastases from 10 individual patients. The analysis provided insights into tumor evolution, linked DNA methylation to genetic lineages, and showed that DNA methylation levels are consistent within lineages but can differ substantially among clones.

Science , this issue p. [1060][1]

Although genomic instability, epigenetic abnormality, and gene expression dysregulation are hallmarks of colorectal cancer, these features have not been simultaneously analyzed at single-cell resolution. Using optimized single-cell multiomics sequencing together with multiregional sampling of the primary tumor and lymphatic and distant metastases, we developed insights beyond intratumoral heterogeneity. Genome-wide DNA methylation levels were relatively consistent within a single genetic sublineage. The genome-wide DNA demethylation patterns of cancer cells were consistent in all 10 patients whose DNA we sequenced. The cancer cells’ DNA demethylation degrees clearly correlated with the densities of the heterochromatin-associated histone modification H3K9me3 of normal tissue and those of repetitive element long interspersed nuclear element 1. Our work demonstrates the feasibility of reconstructing genetic lineages and tracing their epigenomic and transcriptomic dynamics with single-cell multiomics sequencing.

[1]: /lookup/doi/10.1126/science.aao3791
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Differential Expression of MicroRNA-19b Promotes Proliferation of Cancer Stem Cells by Regulating the TSC1/mTOR Signaling Pathway in Multiple Myeloma.

Differential Expression of MicroRNA-19b Promotes Proliferation of Cancer Stem Cells by Regulating the TSC1/mTOR Signaling Pathway in Multiple Myeloma. | PARP Inhibitors Cancer Review | Scoop.it
A new interesting article has been published in Cell Physiol Biochem. 2018 Nov 5;50(5):1804-1814. doi: 10.1159/000494821.[Epub ahead of print] and titled: Differential Expression of MicroRNA-19b Promotes Proliferation of Cancer Stem Cells …...
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Replication Stress: An Achilles' Heel of Glioma Cancer Stem–like Cells

Replication Stress: An Achilles' Heel of Glioma Cancer Stem–like Cells | PARP Inhibitors Cancer Review | Scoop.it
Glioblastoma (GBM) is a highly aggressive form of cancer that is resistant to standard therapy with concurrent radiation and temozolomide, two agents that work by inducing DNA damage. An underlying cause of this resistance may be a subpopulation of cancer stem–like cells that display a heightened...
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c‐Met inhibition is required for the celecoxib‐attenuated stemness property of human colorectal cancer cells - Lin - - Journal of Cellular Physiology - Wiley Online Library

Cyclooxygenase‐2 (COX‐2) is frequently overexpressed and enhances colorectal cancer (CRC) tumorigenesis, including cancer stem cell (CSC) regulation. Accordingly, nonsteroidal anti‐inflammatory drugs (NSAIDs), inhibiting COX‐1/2 activity, are viewed as potential drugs for CRC treatment. Accumulated evidence indicates that celecoxib has the most potency for antitumor growth among NSAIDs and the underlying mechanism is only partly dependent on COX‐2 inhibition. However, the potency of these NSAIDs on CSC inhibition is still not known. In this study, we found that among these NSAIDs, celecoxib has the most potency for CSC inhibition of CRC cells, largely correlating to inhibition of c‐Met, not COX‐2. Further analysis reveals that c‐Met activity was required for basal CSC property. Silence of c‐Met blocked whereas overexpression of c‐Met enhanced the celecoxib‐inhibited CSC property. Collectively, these results not only first elucidate the mechanism underlying celecoxib‐inhibited CSC but also indicate c‐Met as a critical factor for the CSC property of CRC cells.
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IJMS | Monoclonal Antibodies for the Treatment of Multiple Myeloma: An Update

IJMS | Monoclonal Antibodies for the Treatment of Multiple Myeloma: An Update | PARP Inhibitors Cancer Review | Scoop.it
The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation.
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Anti-BCMA CAR T Cell Development Continues to Evolve for Multiple Myeloma

Anti-BCMA CAR T Cell Development Continues to Evolve for Multiple Myeloma | PARP Inhibitors Cancer Review | Scoop.it
Each of the many BCMA-targeted CAR T cells in development demonstrate a different efficacy and safety profile, and each have different constructs. None of the agents have reached the FDA yet, but data for many of the agents were presented at the 2018 ASH Annual Meeting.
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Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers

Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers | PARP Inhibitors Cancer Review | Scoop.it
Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites1. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer—two tumor types for which T cell infiltrates form a positive prognostic marker2,3. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.
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Towards a Predictable Combination Therapy for Multiple Cancer Types –

Towards a Predictable Combination Therapy for Multiple Cancer Types – | PARP Inhibitors Cancer Review | Scoop.it
TOWARDS A PREDICTABLE COMBINATION THERAPY FOR MULTIPLE CANCER TYPES Glycostem and ENPICOM receive MIT Zuid subsidy to support their R&D partnership project of over half a million euros Oss - ‘s-Hertogenbosch, The Netherlands, December 6, 2018– Today, two innovative Dutch SME's active in Life Sciences,...
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Coverage of Novel Therapeutic Agents by Medicare Prescription Drug Plans Following FDA Approval.

Coverage of Novel Therapeutic Agents by Medicare Prescription Drug Plans Following FDA Approval. | PARP Inhibitors Cancer Review | Scoop.it
A new interesting article has been published in J Manag Care Spec Pharm. 2018 Dec;24(12):1230-1238. doi: 10.18553/jmcp.2018.24.12.1230. and titled: Coverage of Novel Therapeutic Agents by Medicare Prescription Drug Plans Following FDA Approval.
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An avatar for precision cancer therapy. Screening patient-derived tumor cell cultures against a drug library is a promising adjunct to clinical decision-making https://go.nature.com/2Q9WaHI  #NBTNV...

An avatar for precision cancer therapy. Screening patient-derived tumor cell cultures against a drug library is a promising adjunct to clinical decision-making https://go.nature.com/2Q9WaHI  #NBTNV... | PARP Inhibitors Cancer Review | Scoop.it
From BioPortfolio: An avatar for precision cancer therapy. Screening patient-derived tumor cell cultures against a drug library is a promising adjunct to clinical decision-making ...
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GSK and J&J spend billions to boost their cancer drug pipelines

GSK and J&J spend billions to boost their cancer drug pipelines | PARP Inhibitors Cancer Review | Scoop.it
GSK will acquire Tesaro for its PARP inhibitor niraparib as J&amp;J partners with Argenx to develop a drug for blood cancers...
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Paper: Proteomic Landscape of De Novo Pediatric Acute Myeloid Leukemia

Paper: Proteomic Landscape of De Novo Pediatric Acute Myeloid Leukemia | PARP Inhibitors Cancer Review | Scoop.it
Background: Many genetic drivers that are implicated in disease pathology and risk stratification have been identified for pediatric acute myeloid leukemia (pedi-AML). However, only a minority have been exploited for therapeutic interventions and most of the identified genetic events currently lack targeted therapy to address the mutations. The combined consequences of genetic and epigenetic events culminate in a net effect manifested at the protein level and most of the chemotherapies target proteins. Yet little is known about the proteomic landscape of pedi-AML. Methods: Reverse Phase Protein Array (RPPA) was performed with 291 strictly validated antibodies to determine the protein expression levels of bulk leukemic cells from 505 pedi-AML patient samples that were collected prior to therapy. All patients participated on the COG AAML1031 Phase 3 clinical trial, that compared standard therapy (ADE) to ADE plus bortezomib (ADE+B). Proteins were allocated into 31 protein functional groups (PFG) (e.g. cell cycle, apoptosis) to analyze proteins in relation to related proteins. Progeny clustering was performed to identify patients with correlated protein expression patterns within each PFG (protein cluster). Block clustering searched for protein clusters that recurrently co-occurred (protein constellation), and for subgroups of patients that expressed similar combinations of protein constellations (protein signatures). Protein signatures were correlated with known cytogenetics and mutational state. Results: For each PFG, cluster analysis identified an optimal number of protein clusters, resulting in a total of 120. From this we constructed 11 protein constellations (PRCON) and 10 protein signatures (SIG) (Fig. 1A). A training set (n=334) and test set (n=171) showed high reproducibility (Pearson’s X2; p < 0.001). SIG were prognostic for event-free survival (EFS) (p = 0.029), with a favorable EFS for SIG 1, 2, 3, 5, 7 & 9, and an unfavorable EFS for SIG 4, 6, 8, 10. Notably, patients that formed SIG 3 had a significant better EFS after receiving ADE+B than patients that received ADE (p = 0.039) (Fig. 1B). This SIG was highly enriched for CEBPA mutated cases; 43% vs. 9% overall (p < 0.001). SIG were associated with cytogenetic aberrations (p < 0.001) and mutational state, as well as with the traditional risk groups (p < 0.001). For example, t(8;21) was overrepresented in SIG 9 (39% vs. 16% overall) and MLL-rearrangement in SIG 6 (61% vs. 19% overall). Multivariate analysis was performed using variables definable at time of diagnosis and known prognostic factors. This resulted in a final model including unfavorable protein SIG together with low risk cytogenetics and NPM1 mutation state as independent prognostic factors, suggesting that proteins add to known prognostic factors. Proteomics could also identify aberrantly expressed proteins within each SIG compared to normal CD34+ cells. This recognized 31 proteins as universally down regulated (e.g. CDKN1A, PPP2R2A) and 13 as universally up regulated (e.g. PIK3CA, NCL). Many other proteins were different between SIG, and thus potentially targetable in particular patient groups: high KIT (SIG 3, 4 & 5), high BCL2 (SIG 3, 4, 5, 6, 9 & 10) and high BRD4 (SIG 6). SIG 1 & 2 both had a very characteristic expression pattern and were most distinct from the others. IGFR1, IGFR1.pY1135, AKT3, SMAD5.pS463-7 and RICTOR.pT1135 were all high, whereas they were low in most other SIG. Conversely, STAT3 was normal in SIG 1&2, but changed in the other SIG. SIG 6, 7 & 8 also had relatively similar expression patterns, but had different outcomes. Compared to SIG 6 & 8, SIG 7 had higher GAB2 and MCL1 and lower RAD50, ERCC1. Conclusions: Pedi-AML is characterized by a finite number (n=10) of recurrent protein signatures. SIG were only partially correlated with cytogenetics and mutation state, indicating that protein expression could add to genetics in the process of risk stratification. We identified SIG that did well vs. SIG that did not, independent of known risk factors, and identified a group of patients that could potentially benefit from ADE+B. Recognition of differentially expressed proteins suggest potential targets for combinational treatment (Hoff et al. ASH HSF1 abstract). Figure 1. A. Identification of 11 PRCON (horizontally) and 10 SIG (vertically). B. SIG were prognostic for EFS. C. SIG 3 significantly benefitted from ADE+B (green) compared to ADE alone (blue).
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Metastases go with the flow

Metastases go with the flow | PARP Inhibitors Cancer Review | Scoop.it

To colonize distant organs and thus disseminate throughout the body, cancer cells and associated factors exploit several fluids for transport. Recently, circulating tumor cells (CTCs) were found to survive and exploit the inner biomechanics of the bloodstream to foster tumor metastasis ([ 1 ][1], [ 2 ][2]). Thus, in addition to using both the blood and lymphatic circulation as a means to travel throughout the body ([ 3 ][3]–[ 5 ][4]), the underlying forces allow CTCs to seed distant metastases. The contribution of fluids, particularly vascular flow mechanics, and physical constraints raises interesting questions about the biology of metastasis.

According to the “seed and soil” theory of metastasis, CTCs survive and establish growing colonies in distant organs within environments that are compatible with their growth. Successful metastatic outgrowth involves several steps, including organ infiltration, immune escape, growth, and survival in supportive niches ([ 6 ][5]). The metastatic potential of tumor cells is also tightly linked to body fluids that favor their journey to distant organs ([ 1 ][1], [ 2 ][2]). CTCs disseminate early through the lymphatic circulation to spread to tumor-draining lymph nodes, which often correlates with reduced survival. Although removal of these metastatic lymph nodes has shown no benefit on overall survival of patients with, for example, melanoma ([ 7 ][6]), as well as other types of cancer, lymph nodes were recently demonstrated to be intermediate steps for metastases in mice ([ 3 ][3]–[ 5 ][4]). Efficient CTC colonization of distant organs occurs mostly via the blood circulation ([ 6 ][5]) (see the figure).

On their way to blood vessels (intravasation), invading tumor cells encounter mechanical pressures imposed by architectural constraints of tissues. In particular, space constraints induce nuclear squeezing, which challenges the integrity of the nucleus and triggers genomic rearrangements that might foster metastatic potential ([ 8 ][7]). It is likely that such pressure also applies to CTCs during arrest in distant sites, extravasation (exiting vessels), and metastatic outgrowth.


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New stem cell therapy to improve fight against leukemia

New stem cell therapy to improve fight against leukemia | PARP Inhibitors Cancer Review | Scoop.it
Stem cell transplantation is effective against leukemia. In many cases, however, the transferred immune cells of the donor also attack the recipients' healthy tissue—often with fatal consequences. Researchers at the University ...
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