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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FDA grants marketing approval to scalp cooling system for breast cancer chemotherapy patients. ecancer - News

FDA grants marketing approval to scalp cooling system for breast cancer chemotherapy patients. ecancer - News | PARP Inhibitors Cancer Review | Scoop.it
FDA grants marketing approval to scalp cooling system for breast cancer chemotherapy patients. ecancer - News https://t.co/6iSDMmaYfx https://t.co/dlytswcMD7
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​Antibody Drug Conjugates in Cancer Drug Development - IQVIA

​Antibody Drug Conjugates in Cancer Drug Development - IQVIA | PARP Inhibitors Cancer Review | Scoop.it
This White Paper discusses the role of real-world data to generate evidence that enables development decisions to be made earlier and more efficiently.
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Effect of Targeted Therapies on Prognostic Factors, Patterns of Care, and Survival in Patients With Renal Cell Carcinoma and Brain Metastases.

Effect of Targeted Therapies on Prognostic Factors, Patterns of Care, and Survival in Patients With Renal Cell Carcinoma and Brain Metastases. | PARP Inhibitors Cancer Review | Scoop.it
To identify prognostic factors, define evolving patterns of care, and the effect of targeted therapies in a larger contemporary cohort of renal cell carcinoma (RCC) patients with new brain metastases (BM).
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Beyond maximum grade: modernising the assessment and reporting of adverse events in haematological malignancies

Beyond maximum grade: modernising the assessment and reporting of adverse events in haematological malignancies | PARP Inhibitors Cancer Review | Scoop.it

Executive Summary

Tremendous progress in treatment and outcomes has been achieved across the whole range of haematological malignancies in the past two decades. Although cure rates for aggressive malignancies have increased, nowhere has progress been more impactful than in the management of typically incurable forms of haematological cancer.

Several haematological malignancies are now chronic diseases that are treated with continuously administered therapies that have unique side-effects over time. In this Commission, an international panel of clinicians, clinical investigators, methodologists, regulators, and patient advocates representing a broad range of academic and clinical cancer expertise examine adverse events in haematological malignancies. The issues pertaining to assessment of adverse events examined here are relevant to a range of malignancies and have been, to date, underexplored in the context of haematology. The aim of this Commission is to improve toxicity assessment in clinical trials in haematological malignancies by critically examining the current process of adverse event assessment, highlighting the need to incorporate patient-reported outcomes, addressing issues unique to stem-cell transplantation and survivorship, appraising challenges in regulatory approval, and evaluating toxicity in real-world patients. We have identified a range of priority issues in these areas and defined potential solutions to challenges associated with adverse event assessment in the existing treatment landscape of haematological malignancies.

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Tallying a cancer’s vast array of genetic changes : Research Highlights

Tallying a cancer’s vast array of genetic changes : Research Highlights | PARP Inhibitors Cancer Review | Scoop.it
Advanced sequencing method yields a complex portrait of breast-cancer cell line.
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Superfast DNA replication causes damage in cancer cells

Superfast DNA replication causes damage in cancer cells | PARP Inhibitors Cancer Review | Scoop.it
Inhibitors of PARP proteins are used in cancer treatment. It emerges that PARP inhibitors exert their effect by accelerating DNA replication to a speed at which DNA damage occurs.
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Control of triple-negative breast cancer using ex vivo self-enriched, costimulated NKG2D CAR T cells | Journal of Hematology & Oncology | Full Text

Control of triple-negative breast cancer using ex vivo self-enriched, costimulated NKG2D CAR T cells | Journal of Hematology & Oncology | Full Text | PARP Inhibitors Cancer Review | Scoop.it
Triple-negative breast cancer (TNBC) is an aggressive disease that currently lacks effective targeted therapy. NKG2D ligands (NKG2DLs) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy.
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Emerging therapeutic modalities of PARP inhibitors in breast cancer - ScienceDirect

Emerging therapeutic modalities of PARP inhibitors in breast cancer - ScienceDirect | PARP Inhibitors Cancer Review | Scoop.it
Highlights

Platinum-PARPi combination use is promising in metastatic BRCA mutated breast cancer or TNBC.


Such combination use was demonstrated with no superiority in neoadjuvant setting of TNBC.


We provided promising prospects of PARPi as maintenance therapy in breast cancer.
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Unsupervised machine learning of radiomic features for predicting treatment response and overall survival of early stage non-small cell lung cancer patients treated with stereotactic body radiation...

Unsupervised machine learning of radiomic features for predicting treatment response and overall survival of early stage non-small cell lung cancer patients treated with stereotactic body radiation... | PARP Inhibitors Cancer Review | Scoop.it
To predict treatment response and survival of NSCLC patients receiving stereotactic
body radiation therapy (SBRT), we develop an unsupervised machine learning method
for stratifying patients and extracting meta-features simultaneously based on imaging
data.
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Heterogeneity in tumor chromatin-doxorubicin binding revealed by in vivo fluorescence lifetime imaging confocal endomicroscopy

Heterogeneity in tumor chromatin-doxorubicin binding revealed by in vivo fluorescence lifetime imaging confocal endomicroscopy | PARP Inhibitors Cancer Review | Scoop.it
The engagement of DNA-binding drugs to their target is difficult to study, particularly in vivo. Here the authors develop an in vivo fluorescence lifetime imaging confocal laparo/endomicroscope to show intra- and inter-tumor heterogeneity in doxorubicin binding to peritoneal metastases, which...
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BCL3 expression promotes resistance to alkylating chemotherapy in gliomas

BCL3 expression promotes resistance to alkylating chemotherapy in gliomas | PARP Inhibitors Cancer Review | Scoop.it
Chemotherapy with alkylating agents, including temozolomide (TMZ), is the most effective treatment for gliomas, but many patients do not respond to the treatment. Wu et al . now report that high B cell CLL/lymphoma 3 (BCL3) expression promoted resistance to TMZ by activating carbonic anhydrase II. Patients with high BCL3-expressing gliomas showed a poorer response to TMZ and shorter survival than did patients with low BCL3-expressing gliomas. In mice injected with high BCL3-expressing human gliomas, the carbonic anhydrase II inhibitor acetazolamide increased sensitivity to TMZ and survival in the mouse xenograft model. The results suggest that analysis of BCL3 expression might be useful in determining the best therapy for treating gliomas.
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Loss of tuberous sclerosis complex 2 sensitizes tumors to nelfinavir−bortezomib therapy to intensify endoplasmic reticulum stress-induced cell death

Loss of tuberous sclerosis complex 2 sensitizes tumors to nelfinavir−bortezomib therapy to intensify endoplasmic reticulum stress-induced cell death | PARP Inhibitors Cancer Review | Scoop.it

The TSC1 and TSC2 tumor suppressors are required for proper ER stress response and protect cells from ER stress-induced apoptosis. Cell Death Differ [...] Targeting protein homeostasis with nelfinavir/salinomycin dual therapy effectively induces death of mTORC1 hyperactive 

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Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma

Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma | PARP Inhibitors Cancer Review | Scoop.it

Epigenetic activation of WNT5A drives glioblastoma stemCell Differ Invasive Growth Cell. 2016;167:e18. Google Scholar 10. Shyr CR, Tsai MY, Yeh S, Kang HY, Chang YC, Wong PL, et al. Tumor suppressor PAX6 functions as androgen receptor co-repressor to inhibit prostate cancer growth 

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Relationships between tumour response and primary tumour location, and predictors of long-term survival, in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab...

Relationships between tumour response and primary tumour location, and predictors of long-term survival, in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab... | PARP Inhibitors Cancer Review | Scoop.it
Abstract
Background
Data from two trials of panitumumab in metastatic colorectal cancer (mCRC) were retrospectively analysed to investigate the effects of primary tumour location on early-tumour shrinkage (ETS) and depth of response (DpR), and identify factors predicting long-term survival.

Methods
Patients with RAS wild-type mCRC from PRIME (NCT00364013) and PEAK (NCT00819780) were included. ETS was defined as a ≥30% reduction in the sum-of-the-longest-diameters of measurable target lesions at eight weeks. DpR was the maximum percentage change from baseline to nadir in patients with shrinkage. Univariate and multivariate logistic analyses of short- versus long-term survivor data were performed.

Results
A total of 435/559 (78%) patients had left-sided disease. Of these, a higher proportion of patients treated with panitumumab versus comparator achieved ETS (PRIME: 62% vs. 36%; PEAK: 58% vs. 41%); median DpR was also higher with panitumumab (PRIME: 59% vs. 49%; PEAK: 70% vs. 48%). In pooled analyses of the studies, more patients with right-sided disease achieved ETS if treated with panitumumab than comparator (39% vs. 29%). Panitumumab treatment consistently predicted long-term survival.

Conclusions
First-line panitumumab was associated with improved ETS and DpR vs. comparator in patients with left-sided mCRC. ETS may identify a subgroup of patients with right-sided disease who might respond to panitumumab.
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Perspective: bidirectional exosomal transport between cancer stem cells and their fibroblast-rich microenvironment during metastasis formation

Perspective: bidirectional exosomal transport between cancer stem cells and their fibroblast-rich microenvironment during metastasis formation | PARP Inhibitors Cancer Review | Scoop.it
Carcinomas are complex structures composed of hierarchically organized distinct cell populations such as cancer stem cells and non-stem (bulk) cancer cells. Their genetic/epigenetic makeup and the dynamic interplay between the malignant cell populations and their stromal fibroblasts are important determinants of metastatic tumor invasion. Important mediators of these interactions are the small, membrane-enclosed extracellular vesicles, in particular exosomes. Both cancer cell and fibroblast-derived exosomes carry a set of regulatory molecules, including proteins and different species of RNA, which cooperatively support metastatic tumor spread. Here, we briefly overview potential links between cancer stem cells and the exosome-mediated fibroblast-enriched metastatic niche formation to discuss their role in the promotion of tumor growth and metastatic expansion in breast carcinoma models.
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Roche - Exploring cytokine fusion proteins in cancer treatment

Roche - Exploring cytokine fusion proteins in cancer treatment | PARP Inhibitors Cancer Review | Scoop.it
Cytokine fusion proteins are engineered to better use the powerful immune-stimulating properties of cytokines while minimising their known side effects....
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CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions

CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions | PARP Inhibitors Cancer Review | Scoop.it
Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by topoisomerase 1, resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. We conclude that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukaemia could provide an opportunity to exploit these findings therapeutically.
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Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial

Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial | PARP Inhibitors Cancer Review | Scoop.it
Summary
Background
Previous preclinical research has shown that extracorporeal devices can be used to enhance the delivery and distribution of systemically administered anticancer drugs, resulting in increased intratumoural concentrations. We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes triggered by mild hyperthermia, induced non-invasively by focused ultrasound.

Methods
We did an open-label, single-centre, phase 1 trial in a single UK hospital. Adult patients (aged ≥18 years) with unresectable and non-ablatable primary or secondary liver tumours of any histological subtype were considered for the study. Patients received a single intravenous infusion (50 mg/m2) of lyso-thermosensitive liposomal doxorubicin (LTLD), followed by extracorporeal focused ultrasound exposure of a single target liver tumour. The trial had two parts: in part I, patients had a real-time thermometry device implanted intratumourally, whereas patients in part II proceeded without thermometry and we used a patient-specific model to predict optimal exposure parameters. We assessed tumour biopsies obtained before and after focused ultrasound exposure for doxorubicin concentration and distribution. The primary endpoint was at least a doubling of total intratumoural doxorubicin concentration in at least half of the patients treated, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02181075, and is now closed to recruitment.

Findings
Between March 13, 2015, and March 27, 2017, ten patients were enrolled in the study (six patients in part I and four in part II), and received a dose of LTLD followed by focused ultrasound exposure. The treatment resulted in an average increase of 3·7 times in intratumoural biopsy doxorubicin concentrations, from an estimate of 2·34 μg/g (SD 0·93) immediately after drug infusion to 8·56 μg/g (5·69) after focused ultrasound. Increases of two to ten times were observed in seven (70%) of ten patients, satisfying the primary endpoint. Serious adverse events registered were expected grade 4 transient neutropenia in five patients and prolonged hospital stay due to unexpected grade 1 confusion in one patient. Grade 3–4 adverse events recorded were neutropenia (grade 3 in one patient and grade 4 in five patients), and grade 3 anaemia in one patient. No treatment-related deaths occurred.

Interpretation
The combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy.

Funding
Oxford Biomedical Research Centre, National Institute for Health Research.
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Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma | NEJM

Original Article from The New England Journal of Medicine — Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma...
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Interleukin 8 is a biomarker of telomerase inhibition in cancer cells | BMC Cancer | Full Text

Interleukin 8 is a biomarker of telomerase inhibition in cancer cells | BMC Cancer | Full Text | PARP Inhibitors Cancer Review | Scoop.it
We demonstrate that telomerase inhibition by telomerase inhibitor imetelstat results in decreased expression of interleukin 8 (IL8) in all telomerase responsive cancer cell lines. This phenomenon is of general occurrence because we find that multiple ovarian and colon cell lines show decrease in IL8 mRNA and protein levels after telomerase inhibition. Additionally, we find loss of IL8 phenocopy Telomerase inhibition mediated growth inhibitory effect in cancer cells.

Conclusion
Taken together, our results show that IL8 is a biomarker that predict telomerase inhibition mediated growth attenuation of cancer cells and its loss phenocopy telomerase inhibition. Therefore, IL8 expression can be utilized as a biomarker for telomerase targeted cancer therapies to potentially predict therapeutic response.

Keywords
TelomeraseInterleukinViabilityBiomarkerResponse
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Long-term outcomes of the GPOH NB97 trial for children with high-risk neuroblastoma comparing high-dose chemotherapy with autologous stem cell transplantation and oral chemotherapy as consolidation

Long-term outcomes of the GPOH NB97 trial for children with high-risk neuroblastoma comparing high-dose chemotherapy with autologous stem cell transplantation and oral chemotherapy as consolidation | PARP Inhibitors Cancer Review | Scoop.it

over 30 minutes given on days −8 to −5 before stem cell reinfusion, 40 mg/kg etoposide a day i.v. over 4 h given on day −4 before stem cell reinfusion, 500 mg/m² carboplatinum a day i.v. over 1 h on days −4 to −2 before stem cell reinf

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Microtubule minus-end aster organization is driven by processive HSET-tubulin clusters

Microtubule minus-end aster organization is driven by processive HSET-tubulin clusters | PARP Inhibitors Cancer Review | Scoop.it
Microtubules (MT) form higher-order structures such as asters, but the molecular pathway underlying aster formation remains unclear. Here authors demonstrate that the kinesin-14, HSET, clusters with soluble (nonMT) tubulin via its N-terminal tail domain and thereby promotes MT aster formation.
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Multidimensional communication in the microenvirons of glioblastoma

Multidimensional communication in the microenvirons of glioblastoma | PARP Inhibitors Cancer Review | Scoop.it
Glioblastomas remain one of the most aggressive and lethal tumours, with no effective treatments available. Here, Xandra Breakefield and colleagues examine the ways in which glioblastomas manipulate brain cells and immune cells in their environment to support tumour growth and the opportunities...
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lincROR influences the stemness and crizotinib resistance in EML-ALK+ | OTT

lincROR influences the stemness and crizotinib resistance in EML-ALK+ | OTT | PARP Inhibitors Cancer Review | Scoop.it
lincROR influences the stemness and crizotinib resistance in EML-ALK+ non-small-cell lung cancer cells Yonghua Yang,1,* Jingyu Huang,2,* Nianlin Xie,3,* Hu Huang,4,* Shaogan Xu,5 Jun Cai,1 Shuai Qi6 1Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei...
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Immune Driver of Castration-Resistant Prostate Cancer Identified | ESMO

A novel mechanistic insight on how prostate cancer can become insensitive to androgen deprivation and androgen receptor blockade...
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Seeking Convergence and Cure with New Myeloma Therapies - ScienceDirect

Seeking Convergence and Cure with New Myeloma Therapies - ScienceDirect | PARP Inhibitors Cancer Review | Scoop.it
For over a decade, the mainstay of multiple myeloma therapy has been small molecules that directly attack malignant plasma cell biology. However, pote…
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