PARP Inhibitors Cancer Review
76.2K views | +15 today
Follow
 
Scooped by Krishan Maggon
onto PARP Inhibitors Cancer Review
Scoop.it!

Ixazomib (Takeda) Phase 2 Maintenance Data in Multiple Myeloma. ASH 2014

Ixazomib (Takeda)  Phase 2  Maintenance Data in Multiple Myeloma. ASH 2014 | PARP Inhibitors Cancer Review | Scoop.it

Takeda Pharmaceutical Company Limited (TSE:4502) today announced results from an open-label, Phase 2 study evaluating the safety and efficacy of oral, single-agent ixazomib (MLN9708) as maintenance therapy in patients with multiple myeloma (MM) who had received ixazomib, lenalidomide and dexamethasone as induction therapy. The data from this trial demonstrate the potential feasibility of single-agent ixazomib maintenance therapy following 12 cycles of ixazomib-lenalidomide-dexamethasone, with deepening responses and an acceptable tolerability profile. These data were presented today at the 56th American Society of Hematology (ASH) annual meeting in San Francisco, CA.


The primary objective of the Phase 2 component of the study was the percent of patients achieving a very good partial response [VGPR] or better (defined as complete response [CR] + VGPR). Fifty patients were enrolled in the Phase 2 cohort and received ixazomib, lenalidomide and dexamethasone as induction therapy for up to twelve 28-day cycles. Transplant-eligible patients could discontinue from the study for autologous stem cell transplant (ASCT) after six cycles. For those patients continuing on to receive ixazomib maintenance, treatment could continue until disease progression or unacceptable toxicity. All patients who received ixazomib maintenance therapy had responded to induction therapy. During induction (cycles 1–12), 29 patients discontinued study treatment, primarily to undergo autologous stem cell transplant (ASCT) (14/50). Other reasons included AEs (6/50), patient withdrawal (4/50), disease progression (2/50), and unsatisfactory response (1/50), among other factors (2/50). Twenty-one patients completed induction and progressed to the maintenance phase of the study, during which they received single-agent ixazomib for a median of 19 treatment cycles (range 3-23), with a median treatment duration of 29.0 months (range 14.3-33.3). Best overall confirmed/unconfirmed study response rates and additional results for patients who underwent any maintenance therapy were reported as follows:

CR or better was reached in 52 percent of patients (11/21) and VGPR or better was reached in 71 percent of patients (15/21).Forty-eight percent of patients improved their response during maintenance (10/21), including two VGPR to near-CR (2/10), five VGPR to CR (5/10), one VGPR to sCR (1/10), and two CR to sCR (2/10).Median PFS of patients entering maintenance has not been reached.Fifty-two percent of patients (11/21) remained on ixazomib maintenance after data cut-off.Median time to first response (≥PR) was 0.99 months (range 0.92–5.78) and median time to best response was 7.46 months (range 1.02–24.74). Mean ixazomib relative dose intensity was 95 percent and 89.5 percent in the induction and maintenance phases, respectively.All patients who received ixazomib maintenance were alive after follow-up of 25.1–33.9 months from study entry.




Krishan Maggon 's insight:

Ixazomib (MLN9708) is an investigational oral proteasome inhibitor, which is being studied in multiple myeloma (MM), systemic light-chain (AL) amyloidosis and other malignancies. Ixazomib was granted orphan drug designation in MM in both the U.S. and Europe in 2011, and for AL amyloidosis in both the U.S. and Europe in 2012. It is the first oral proteasome inhibitor to enter Phase 3 clinical trials. Four global Phase 3 trials are ongoing: TOURMALINE-MM1, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory MM; TOURMALINE-AL1, investigating ixazomib plus dexamethasone in patients with relapsed or refractory AL amyloidosis; TOURMALINE-MM2, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM; and TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant. For additional information on the ongoing Phase 3 studies please visit www.tourmalinetrials.com orwww.clinicaltrials.gov.

more...
No comment yet.
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.
Curated by Krishan Maggon
Your new post is loading...
Your new post is loading...
Scooped by Krishan Maggon
Scoop.it!

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...
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Biomarkers | The Colorectal Cancer Alliance

Biomarkers | The Colorectal Cancer Alliance | PARP Inhibitors Cancer Review | Scoop.it
​Learn more about biomarker testing for metastatic colorectal cancer patients to create individual treatment plans.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

A homing system targets therapeutic T cells to brain cancer

A homing system targets therapeutic T cells to brain cancer | PARP Inhibitors Cancer Review | Scoop.it
Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Molecular pathogenesis of disease progression in MLL -rearranged AML

Molecular pathogenesis of disease progression in MLL -rearranged AML | PARP Inhibitors Cancer Review | Scoop.it
Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N = 96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P < 0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P = 0.007) and associated with earlier leukemia onset (P = 0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P < 0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P < 0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

The next generation of PI3K-Akt-mTOR pathway inhibitors in breast cancer cohorts - ScienceDirect

The next generation of PI3K-Akt-mTOR pathway inhibitors in breast cancer cohorts - ScienceDirect | PARP Inhibitors Cancer Review | Scoop.it
The PI3K/Akt/mTOR pathway plays a role in various oncogenic processes in breast cancer and key pathway aberrations have been identified which drive the different molecular subtypes. Early drugs developed targeting this pathway produced some clinical success but were hampered by pharmacokinetics, tolerability and efficacy problems. This created a need for new PI3K pathway-inhibiting drugs, which would produce more robust results allowing incorporation into treatment regimens for breast cancer patients.

In this review, the most promising candidates from the new generation of PI3K-pathway inhibitors is explored, presenting evidence from preclinical and early clinical research, as well as ongoing trials utilising these drugs in breast cancer cohorts. The problems hindering the development of drugs targeting the PI3K pathway are examined, which have created problems for their use as monotherapies. PI3K pathway inhibitor combinations therefore remains a dynamic research area, and their role in combination with immunotherapies and epigenetic therapies is also inspected.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Prostate cancer

Prostate cancer | PARP Inhibitors Cancer Review | Scoop.it
PERSPECTIVES|CASE HISTORIES| VOLUME 392, ISSUE 10151, P908, SEPTEMBER 15, 2018 Prostate cancer DOI:https://doi.org/10.1016/S0140-6736(18)32123-8 Prostate cancer For much of human history men have not, typically, lived long enough to die from prostate cancer. Descriptions of terminal dribbling, urinary retention, and the signs of bony metastases can be found in case records from many times and places, but patients and practitioners seem to have regarded them as the price to be paid for surviving into middle age and beyond. Surgeons occasionally tried to ease their patients' suffering with catheterisation—one unnamed British patient in the early 19th century was catheterised almost 7000 times—or dilating the prostate with a probe. Both procedures were painful and potentially dangerous, and neither offered more than temporary relief. This article is available free of charge. Simply log in to access the full article, or register for free if you do not yet have a username and password. Already registered? Please log in. Forgot password? Not yet registered? Create a new account. Register for free Further reading Ablin RJ Soanes WA Bronson P Witebsky E Precipitating antigens of the normal human prostate. J Reprod Fertil. 1970; 22: 573-574 View in Article Ablin RJ The great prostate mistake. The New York Times. March 9, 2010; Ablin RJ Piana R The great prostate hoax: how big medicine hijacked the PSA test and caused a public health disaster. Palgrave Macmillan, London; 2014 Valier H Uncertain enthusiasm: PSA screening, proton therapy and prostate cancer. in: Timmermann C , Toon E (Eds.) Cancer patients, cancer pathways: historical and sociological perspectives. Palgrave Macmillan, London; 2012: 186-203 Article Info Publication History Published: 15 September 2018 IDENTIFICATION DOI: 10.1016/S0140-6736(18)32123-8 Copyright © 2018 Elsevier Ltd. All rights reserved. ScienceDirect Access this article on ScienceDirect Linked Article
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors

Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors | PARP Inhibitors Cancer Review | Scoop.it
Epigenetic crosstalk targeting together with MLL1-based stratification and inhibiting
feedback MAPK activation expand EZH2 inhibitors’ therapeutic utility and efficacy
in patient-derived solid tumor models.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Gene editing reveals the effect of thousands of variants in a key cancer gene

Gene editing reveals the effect of thousands of variants in a key cancer gene | PARP Inhibitors Cancer Review | Scoop.it
Gene editing has now been used to introduce every possible single-nucleotide mutation into key protein-coding regions in the cancer-predisposition gene BRCA1, to identify the variants that are linked to cancer risk.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Prospective study of brentuximab vedotin in relapsed/refractory Hodgkin lymphoma patients who are not suitable for stem cell transplant or multi‐agent chemotherapy - Walewski - - British Journal of...

Prospective study of brentuximab vedotin in relapsed/refractory Hodgkin lymphoma patients who are not suitable for stem cell transplant or multi‐agent chemotherapy - Walewski - - British Journal of... | PARP Inhibitors Cancer Review | Scoop.it
Some patients with relapsed/refractory Hodgkin lymphoma (HL) are not considered suitable for stem cell transplant (SCT) and have a poor prognosis. This phase IV study (NCT01990534) evaluated brentuximab vedotin (1·8 mg/kg intravenously once every 3 weeks) in 60 patients (aged ≥18 years) with CD30‐positive relapsed/refractory HL, a history of ≥1 prior systemic chemotherapy regimen, who were considered unsuitable for SCT/multi‐agent chemotherapy. Primary endpoint was overall response rate (ORR) per independent review facility (IRF). Secondary endpoints included duration of response (DOR), progression‐free survival (PFS) per IRF, overall survival (OS), proportion proceeding to SCT and safety. The ORR was 50%, with 12% CR; 47% proceeded to SCT. Median DOR was 4·6 months and median duration of CR was 6·1 months. After a median follow‐up of 6·9 and 16·6 months, median PFS and OS were 4·8 months (95% confidence interval, 3·0–5·3) and not reached, respectively; estimated OS rate was 86% at 12 months. Most common adverse events (≥10%) were peripheral neuropathy (35%), pyrexia (18%), diarrhoea and neutropenia (each 10%). Brentuximab vedotin showed notable activity with a safety profile consistent with known toxicities, and may act as a bridge to SCT, enabling high‐risk patients who achieve suboptimal response to frontline/salvage chemotherapy/radiotherapy to receive potentially curative SCT.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

CCR4-targeted therapy in cutaneous T-cell lymphoma

CCR4-targeted therapy in cutaneous T-cell lymphoma | PARP Inhibitors Cancer Review | Scoop.it
COMMENT| VOLUME 19, ISSUE 9, P1140-1141, SEPTEMBER 01, 2018 CCR4-targeted therapy in cutaneous T-cell lymphoma Published:August 09, 2018DOI:https://doi.org/10.1016/S1470-2045(18)30449-2 Various neoplasms, including T-cell lymphomas and solid tumours, have high C-C chemokine receptor 4 (CCR4) expression. In physiological conditions, CCR4 plays a part in the homing of memory T cells to peripheral tissues, such as the skin. 1 Importantly, cutaneous T-cell lymphomas, which arise from those skin resident memory lymphocytes, also express CCR4, opening avenues for therapeutic intervention. 2 To read this article in full you will need to make a payment Purchase one-time access Or purchase The Lancet Choice Access any 5 articles from the Lancet Family of journals Subscribe to The Lancet Oncology Already a print subscriber? Claim online access Already an online subscriber? Sign in Register: Create an account Institutional Access: Sign in to ScienceDirect References Farber DL Yudanin NA Restifo NP Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol. 2014; 14: 24-35 View in Article Campbell JJ Clark RA Watanabe R Kupper TS Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood. 2010; 116: 767-771 View in Article Prince HM Duvic M Martin A et al. Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2010; 28: 1870-1877 View in Article Prince HM Kim YH Horwitz SM et al. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017; 390: 555-566 View in Article Kim YH Bagot M Pinter-Brown L et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018; (published online Aug 9) (published online Aug 9) Duvic M Pinter-Brown LC Foss FM et al. Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood. 2015; 125: 1883-1889 View in Article Egawa G Kabashima K Skin as a peripheral lymphoid organ: revisiting the concept of skin-associated lymphoid tissues. J Invest Dermatol. 2011; 131: 2178-2185 View in Article Wang L Ni X Covington KR et al. Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat Genet. 2015; 47: 1426-1434 View in Article Sugiyama D Nishikawa H Maeda Y et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci. 2013; 110: 17945-17950 View in Article Berlato C Khan MN Schioppa T et al. A CCR4 antagonist reverses the tumor-promoting microenvironment of renal cancer. J Clin Invest. 2017; 127: 801-813 View in Article Article Info Publication History Published: August 09, 2018 IDENTIFICATION DOI: 10.1016/S1470-2045(18)30449-2 Copyright © 2018 Elsevier Ltd. All rights reserved. ScienceDirect Access this article on ScienceDirect Linked Article
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Offline: Why has global health forgotten cancer?

Offline: Why has global health forgotten cancer? | PARP Inhibitors Cancer Review | Scoop.it
COMMENT| VOLUME 392, ISSUE 10150, P806, SEPTEMBER 08, 2018 Offline: Why has global health forgotten cancer? DOI:https://doi.org/10.1016/S0140-6736(18)32162-7 Later this month (at the UN General Assembly) the global health community will likely witness an inflection point in the history of non-communicable disease (NCD) prevention and control. But one fact is certain. Whatever countries do to show they are taking NCDs more seriously, cancer treatment will be missing from their commitments. Cancer's undeserved neglect makes it the Cinderella of the emerging NCD movement. As health diplomats celebrate their political success, millions of people living with cancer will be consigned to early and painful deaths. Nothing illustrates the embedded irrationality of global health more than our attitudes to cancer. In 2016, according to the Global Burden of Disease, 8·9 million people died from cancer (23% of total worldwide deaths from NCDs, and 16% of deaths from all causes). The leading causes of cancer death are tumours of the trachea, bronchus, and lung (1·7 million deaths); gynaecological cancers (breast, cervix, ovary, and uterus: 1 million deaths); gastric cancer (834 000 deaths); colorectal cancer (829 600 deaths); and liver cancer (828 000 deaths). So why the indifference? The NCD community has become trapped in an ideology that privileges prevention over treatment. A similar mistake disfigured the early response to AIDS. I can recall senior WHO leaders two decades ago agreeing that a generation of people living with HIV would have to die before the pandemic could be controlled by prevention. Only anger and activism overturned the complacency of traditional public health practice. But the NCD community has no time for anger or activism. It prefers repeating and re-emphasising the old nostrums. We can all agree that tobacco control and vaccination against hepatitis B and human papillomavirus are indispensable interventions to curb cancer. But what about the treatment of breast cancer? Or surgery for resectable tumours? Or specialist services for cervical cancer? Or chemotherapy and radiotherapy facilities? Or treatment for childhood cancers? Or palliative care services? Silence. Two arguments will be mounted against the charge that global health has forgotten cancer treatment. First, if global health is about remedying inequity, and if those remedies are mainly concerned with resource-poor communities, then cancer treatment cannot be a priority. If, for example, one examines the top 20 causes of age-standardised disability-adjusted life-years (DALYs) in sub-Saharan Africa, you will see that cancer is absent. The global health community is therefore surely right to focus on AIDS, tuberculosis, malaria, and other infectious diseases. It should definitely accommodate ischaemic heart disease, stroke, diabetes, major depression, and chronic obstructive pulmonary disease. But cancer? No. A second argument is that even if we concede that cancer should be taken more seriously, the treatment gap will best be filled by focusing not on specific diseases but on strengthening health systems and achieving universal health coverage (UHC). Both claims are flawed. Take gynaecological cancers. The majority of women who die from breast and cervical cancer live in low-income and middle-income settings. Cancer should be a major health priority in the poorest countries. That is true today. It is even more true if one looks only a short distance into the future. As The Lancet's 2016 Series on Health, Equity, and Women's Cancers described, 1·7 million women are diagnosed with breast cancer annually. By 2030, the number of women diagnosed with breast cancer is projected to rise to 3·2 million. It is entirely wrong to suggest that cancer should only be a concern for richer nations. As to UHC filling the gap in cancer care, one mistake made by UHC advocates is that repeating the mantra of universal coverage is empty rhetoric without specifying the services that UHC should include. Too often, cancer treatment is absent from the debate about UHC. Some progress is being made. In its 2017 updated “Appendix 3”—a WHO-branded list of approved policy options to prevent and control NCDs—the agency does include treatment services for early cervical, breast, and colorectal cancers, together with palliative care, although none receive the coveted “bolding”. The Disease Control Priorities Project does not let countries off the hook so easily and goes further, including services to treat selected childhood cancers. The global health community has long let down those living with cancer. It is inexplicable that it continues to do so. Article Info Publication History Published: 08 September 2018 IDENTIFICATION DOI: 10.1016/S0140-6736(18)32162-7 Copyright © 2018 Elsevier Ltd. All rights reserved. ScienceDirect Access this article on ScienceDirect
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation

Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation | PARP Inhibitors Cancer Review | Scoop.it
Many tumors have mutations in the guanosine triphosphatases (GTPases) HRAS, NRAS, or KRAS. Pharmacologically targeting these proteins has so far been elusive; hence, targeting critical members of their signaling pathway(s) may be more successful. Sheffels et al . found that the guanine nucleotide exchange factor SOS2, in contrast to its family member SOS1, was dispensable for two-dimensional cell proliferation but mediated oncogenic and stem-like switches in the three-dimensional growth behavior of normal and tumor cells to varying degrees, most critically for cells expressing Gly12/13 mutants of KRAS. Further analysis of the differential downstream pathways suggested that SOS2 dependence and RAS mutant type may indicate whether individual inhibitors of the kinase PI3K, AKT, or MEK may be effective against the tumor.

About a third of tumors have activating mutations in HRAS , NRAS , or KRAS , genes encoding guanosine triphosphatases (GTPases) of the RAS family. In these tumors, wild-type RAS cooperates with mutant RAS to promote downstream effector activation and cell proliferation and transformation, suggesting that upstream activators of wild-type RAS are important modulators of mutant RAS-driven oncogenesis. The guanine nucleotide exchange factor (GEF) SOS1 mediates KRAS-driven proliferation, but little is understood about the role of SOS2. We found that RAS family members have a hierarchical requirement for the expression and activity of SOS2 to drive cellular transformation. In mouse embryonic fibroblasts (MEFs), SOS2 critically mediated mutant KRAS-driven, but not HRAS-driven, transformation. Sos2 deletion reduced epidermal growth factor (EGF)–dependent activation of wild-type HRAS and phosphorylation of the kinase AKT in cells expressing mutant RAS isoforms. Assays using pharmacological inhibitors revealed a hierarchical requirement for signaling by phosphoinositide 3-kinase (PI3K) in promoting RAS-driven cellular transformation that mirrored the requirement for SOS2. KRAS-driven transformation required the GEF activity of SOS2 and was restored in Sos2 −/− MEFs by expression of constitutively activated PI3K. Finally, CRISPR/Cas9-mediated deletion of SOS2 reduced EGF-stimulated AKT phosphorylation and synergized with MEK inhibition to revert the transformed phenotype of human KRAS mutant pancreatic and lung tumor cells. These results indicate that SOS2-dependent PI3K signaling mediates mutant KRAS-driven transformation, revealing therapeutic targets in KRAS-driven cancers. Our data also reveal the importance of three-dimensional culture systems in investigating the mediators of mutant KRAS.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Eliminating MRD — FDA approval of blinatumomab for B-ALL in complete remission

Eliminating MRD — FDA approval of blinatumomab for B-ALL in complete remission | PARP Inhibitors Cancer Review | Scoop.it
The approval of blinatumomab based on achievement of undetectable minimal residual disease (MRD) in patients with B cell acute lymphoblastic leukaemia in complete remission is the first of its kind and raises important considerations.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations

Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations | PARP Inhibitors Cancer Review | Scoop.it
RNA-seq analysis of CD34+ cells identifies novel aberrantly spliced genes and dysregulated pathways in splicing factor mutant MDS.

Aberrantly spliced isoforms predict MDS survival and implicate dysregulation of focal adhesion and exosomes as drivers of poor survival.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Androgen receptor expression reduces stemness characteristics of prostate cancer cells (PC3) by repression of CD44 and SOX2 - Srinivasan - - Journal of Cellular Biochemistry - Wiley Online Library

Abstract
Studies have shown that a subgroup of tumor cells possess stemness characteristics having self‐renewal capacity and the ability to form new tumors. We sought to identify the plausible stemness factor that determines the “molecular signature” of prostate cancer (PCa) cells derived from different metastases (PC3, PCa2b, LNCaP, and DU145) and whether androgen receptor (AR) influences the maintenance of stemness features. Here we show sex‐determining region Y (SRY)‐box 2 (SOX2) as a putative stem cell marker in PC3 PCa cells and not in DU145, PCa2b, or LNCaP cells. PCa2b and PC3 cells were derived from bone metastases. PCa2b cells which are positive for the AR failed to demonstrate the expression of either cluster of differentiation 44 (CD44) or SOX2. Knockdown (KD) of AR in these cells did not affect the expression of either CD44 or SOX2. Conversely, PC3 cells, which are negative for AR, expressed both CD44 and SOX2. However, the expression of AR downregulated the expression of both CD44 and SOX2 in PC3 cells. CD44 regulates SOX2 expression as KD of CD44 and reduces SOX2 levels considerably. SOX2 KD attenuated not only the expression of SNAIL and SLUG but also the migration and tumorsphere formation in PC3 cells. Collectively, our findings underscore a novel role of CD44 signaling in the maintenance of stemness and progression of cancer through SOX2 in AR‐independent PC3 cells. SOX2 has a role in the regulation of expression of SNAIL and SLUG. SOX2 could be a potential therapeutic target to thwart the progression of SOX2‐positive cancer cells or recurrence of androgen‐independent PCa.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Hmga2 is dispensable for pancreatic cancer development, metastasis, and therapy resistance

Hmga2 is dispensable for pancreatic cancer development, metastasis, and therapy resistance | PARP Inhibitors Cancer Review | Scoop.it
Expression of the chromatin-associated protein HMGA2 correlates with progression, metastasis and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Hmga2 has also been identified as a marker of a transient subpopulation of PDAC cells that has increased metastatic ability. Here, we characterize the requirement for Hmga2 during growth, dissemination, and metastasis of PDAC in vivo using conditional inactivation of Hmga2 in well-established autochthonous mouse models of PDAC. Overall survival, primary tumour burden, presence of disseminated tumour cells in the peritoneal cavity or circulating tumour cells in the blood, and presence and number of metastases were not significantly different between mice with Hmga2-wildtype or Hmga2-deficient tumours. Treatment of mice with Hmga2-wildtype and Hmga2-deficient tumours with gemcitabine did not uncover a significant impact of Hmga2-deficiency on gemcitabine sensitivity. Hmga1 and Hmga2 overlap in their expression in both human and murine PDAC, however knockdown of Hmga1 in Hmga2-deficient cancer cells also did not decrease metastatic ability. Thus, Hmga2 remains a prognostic marker which identifies a metastatic cancer cell state in primary PDAC, however Hmga2 has limited if any direct functional impact on PDAC progression and therapy resistance.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Development of a novel Hsp90 inhibitor NCT-50 as a potential anticancer agent for the treatment of non-small cell lung cancer

Development of a novel Hsp90 inhibitor NCT-50 as a potential anticancer agent for the treatment of non-small cell lung cancer | PARP Inhibitors Cancer Review | Scoop.it
Despite the development of advanced therapeutic regimens such as molecular targeted therapy and immunotherapy, the 5-year survival of patients with lung cancer is still less than 20%, suggesting the need to develop additional treatment strategies. The molecular chaperone heat shock protein 90 (Hsp90) plays important roles in the maturation of oncogenic proteins and thus has been considered as an anticancer therapeutic target. Here we show the efficacy and biological mechanism of a Hsp90 inhibitor NCT-50, a novobiocin-deguelin analog hybridizing the pharmacophores of these known Hsp90 inhibitors. NCT-50 exhibited significant inhibitory effects on the viability and colony formation of non-small cell lung cancer (NSCLC) cells and those carrying resistance to chemotherapy. In contrast, NCT-50 showed minimal effects on the viability of normal cells. NCT-50 induced apoptosis in NSCLC cells, inhibited the expression and activity of several Hsp90 clients including hypoxia-inducible factor (HIF)-1α, and suppressed pro-angiogenic effects of NSCLC cells. Further biochemical and in silico studies revealed that NCT-50 downregulated Hsp90 function by interacting with the C-terminal ATP-binding pocket of Hsp90, leading to decrease in the interaction with Hsp90 client proteins. These results suggest the potential of NCT-50 as an anticancer Hsp90 inhibitor.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Recent insights into the development of nucleic acid-based nanoparticles for tumor-targeted drug delivery - ScienceDirect

Recent insights into the development of nucleic acid-based nanoparticles for tumor-targeted drug delivery - ScienceDirect | PARP Inhibitors Cancer Review | Scoop.it
Highlights

Targeted therapies are currently focused on anticancer drug development.


Nucleic acid-based nanoparticles are playing important role in tumor targeted therapy.


Reviewed recent developments in the nucleic acid-based tumor-targeted drug delivery.


Importance of combinatorial tumor targeted therapy with nucleic acid-based therapeutic agents.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Inhibition of HER2 Increases JAGGED1-dependent Breast Cancer Stem Cells: Role for Membrane JAGGED1

Inhibition of HER2 Increases JAGGED1-dependent Breast Cancer Stem Cells: Role for Membrane JAGGED1 | PARP Inhibitors Cancer Review | Scoop.it
Purpose: HER2-positive breast cancer is driven by cells possessing stem-like properties of self-renewal and differentiation, referred to as cancer stem cells (CSC). CSCs are implicated in radiotherapy, chemotherapy resistance, and tumor recurrence.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma

Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma | PARP Inhibitors Cancer Review | Scoop.it
Medulloblastoma is an aggressive type of brain tumor that most often arises in children and lacks targeted therapeutic options. The subtypes driven by activity in the sonic hedgehog (SHH) pathway are particularly resistant to current drugs, such as those known as SMO inhibitors, which target this pathway. Purzner et al . used phosphoproteomics to track the development of mouse cells that give rise to medulloblastoma and identified the kinase CK2 as a likely target. CK2 inhibitors blocked the growth of SMO inhibitor–resistant, SHH-type human and mouse medulloblastoma cells and markedly extended the survival of tumor-bearing mice, in which the drug was well tolerated. One of the compounds also blocked the growth of tumors that had mutant CK2, suggesting that it is less susceptible to a common mode of drug resistance. A clinical trial is under way to test this inhibitor in pediatric patients.

A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Huge genetic-screening effort helps pinpoint roots of breast cancer

Huge genetic-screening effort helps pinpoint roots of breast cancer | PARP Inhibitors Cancer Review | Scoop.it
Scientists have sifted through thousands of genetic sequences in search of those that could foster tumours.

 

A massive study of nearly 4,000 variants in a gene associated with cancer could help to pinpoint people at risk for breast or ovarian tumours.

more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Olaparib, Cediranib Maleate, and Wee1 Inhibitor AZD1775 in Treating Patients With Recurrent, Refractory, or Metastatic Endometrial Cancer - Full Text View - ClinicalTrials.gov

Olaparib, Cediranib Maleate, and Wee1 Inhibitor AZD1775 in Treating Patients With Recurrent, Refractory, or Metastatic Endometrial Cancer - Full Text View - ClinicalTrials.gov | PARP Inhibitors Cancer Review | Scoop.it
Olaparib, Cediranib Maleate, and Wee1 Inhibitor AZD1775 in Treating Patients With Recurrent, Refractory, or Metastatic Endometrial Cancer - Full Text View.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

A machine learning approach for somatic mutation discovery

A machine learning approach for somatic mutation discovery | PARP Inhibitors Cancer Review | Scoop.it
Somatic mutation calling is essential for the proper diagnosis and treatment of most cancer patients. Wood et al . developed a machine learning approach called Cerebro that increased the accuracy of calling validated somatic mutations in tumor samples from cancer patients. Cerebro outperformed six other mutation detection methods by better distinguishing technical sequencing artifacts. An analysis of non–small cell lung cancer and melanoma patient samples revealed that Cerebro more accurately classified patients according to their immunotherapy response, suggesting that the authors’ mutation calling approach could favorably affect patient care.

Variability in the accuracy of somatic mutation detection may affect the discovery of alterations and the therapeutic management of cancer patients. To address this issue, we developed a somatic mutation discovery approach based on machine learning that outperformed existing methods in identifying experimentally validated tumor alterations (sensitivity of 97% versus 90 to 99%; positive predictive value of 98% versus 34 to 92%). Analysis of paired tumor-normal exome data from 1368 TCGA (The Cancer Genome Atlas) samples using this method revealed concordance for 74% of mutation calls but also identified likely false-positive and false-negative changes in TCGA data, including in clinically actionable genes. Determination of high-quality somatic mutation calls improved tumor mutation load–based predictions of clinical outcome for melanoma and lung cancer patients previously treated with immune checkpoint inhibitors. Integration of high-quality machine learning mutation detection in clinical next-generation sequencing (NGS) analyses increased the accuracy of test results compared to other clinical sequencing analyses. These analyses provide an approach for improved identification of tumor-specific mutations and have important implications for research and clinical management of cancer patients.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Route to cancer stem cell death ironed out | May 17, 2017 Issue - Vol. 95 Issue 21 | Chemical & Engineering News

Route to cancer stem cell death ironed out | May 17, 2017 Issue - Vol. 95 Issue 21 | Chemical & Engineering News | PARP Inhibitors Cancer Review | Scoop.it
[+]Enlarge Ironomycin or salinomycin (blue dots) works by sequestering iron, leading to cell death. Credit: Nature Chemistry Cancer stem cells are bad actors. They enable cancers to metastasize, or spread, and help revive cancers after the malignancies go dormant. One of the few agents that can effectively attack them is a small molecule called salinomycin. But scientists haven’t understood how the compound kills the cells. Now, researchers have discovered salinomycin’s mechanism (Nat. Chem. 2017, DOI: 10.1038/nchem.2778). The findings reveal a key weakness of cancer stem cells that could lead to the design of other drugs to help fight the cells. To discover the mechanism, Raphaël Rodriguez of Institut Curie and France’s National Center for Scientific Research, Maryam Mehrpour of Institut Necker Enfants Malades and INSERM, and coworkers first tried to create a more potent version of salinomycin by modifying it with groups of varying polarity and charge. The most potent was ironomycin, in which one of salinomycin’s hydroxyl groups was replaced by a short amine-alkyne chain. Ironomycin has an order of magnitude greater potency than salinomycin at killing breast cancer stem cells, both in culture and in mice. [+]Enlarge In ironomycin, a short amine-alkyne chain (red) replaces one of salinomycin’s hydroxyl groups. They then used in vivo click chemistry on ironomycin’s alkyne group to label the compound with a fluorescent dye, enabling them to track where the compound goes when in cancer stem cells. They had expected it to distribute evenly throughout the cells and were surprised when it instead localized in lysosomes, which are cellular compartments with enzymes that break down certain molecules. This led them to the mechanism: Salinomycin, or ironomycin, binds cellular iron and sequesters it in lysosomes. The high concentration of lysosomal iron then triggers a process called ferroptosis—in which iron catalyzes the so-called Fenton reaction, producing reactive oxygen species that break lysosomal membranes, oxidize cell lipids, and cause cell death. The mechanism is not specific to cancer stem cells, Rodriguez says, but these cells are more susceptible to salinomycin’s or ironomycin’s activity because they are more dependent on iron and may be less efficient at scavenging free radicals than conventional cells. The study “is the first to characterize salinomycin’s mechanism of action at a molecular level, which is in itself a major step forward and an impressive feat, given the structural complexity of this compound,” says Piyush Gupta of the Whitehead Institute and MIT, who discovered salinomycin’s activity against cancer stem cells. “It is also the first to convincingly show that iron plays an unusually important role in regulating the malignant properties of cancer stem cells. These are both important contributions that will guide the development of new therapies targeting the most malignant of cancer cells.” “Selective mechanisms for killing cancer stem cells have been a long-standing goal of cancer drug discovery, but few mechanisms have been identified,” says Brent R. Stockwell of Columbia University, who discovered ferroptosis. “This paper suggests that iron sequestration in lysosomes could be one such effective mechanism for targeting cancer stem cells.” One possible drawback to a cancer-stem-cell-targeting compound is that other cells in the tumor might still survive, he adds. “So you would likely need a combination of drugs targeting cancer stem cells and non-stem-cell tumor cells. And there might be toxicity to normal stem cells, so this would need to be evaluated” as research on stem-cell-targeted agents progresses. This article has been translated into Spanish by Divulgame.org and can be found here.   Chemical & Engineering News ISSN 0009-2347 Copyright © American Chemical Society
more...
No comment yet.