NTRC at Pivot Oncology conference Breakthroughs in Precision Cancer Treatment

Oss, November, 13th, 2017 – Pivot Park organizes the symposium Breakthroughs in Precision Cancer Treatment on Tuesday November 21st.  As part of the conference, NTRC has organized one of the scientific sessions, entitled ‘Drug discovery: from target to preclinical candidate’. In the session, scientists from NTRC and Lead Pharma will present different aspects of the discovery and development of new precision drug candidates for cancer. The challenges of the different phases of small molecule drug discovery will be described based on real case stories from the drug discovery programs of the two companies.

Program session ‘Drug discovery: from target to preclinical candidate’:

1.30 Opening

1.35 Hit identification and optimization (Lead Pharma)

2.10 Lead optimization and structure-based drug design (NTRC)

2.30 Patient stratification strategies (NTRC)

2.45 Q&A

3.00 End of session

NTRC will also exhibit at the symposium.

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, GeneNominator™, SynergyFinder™ and SynergyScreen™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact info@ntrc.nl

Target residence time-guided lead optimization at the European Pharma Summit in Berlin

Oss, November, 10th, 2017 – At GTC Bio’s European Pharma Summit to be held in Berlin on 16 and 17 November, Dr. Guido Zaman will present on NTRC’s TTK drug discovery program in a scientific session on “Target residence time in kinase drug development”.

Target residence time, that is the time a compound resides on it target, is thought to be a more important determinant of the biological activity of small molecule kinase inhibitors than their potency in enzyme assays, or their binding affinity at equilibrium. Dr. Zaman will present data on twelve TTK inhibitors from different chemical series, comprising NTRC proprietary compounds and compounds designed . Parallel testing showed that the cellular activity of these TTK inhibitors correlates with their binding affinity to TTK and, more strongly, with target residence time. X-ray structures and thermal stability experiments revealed that NTRC’s kinase inhibitor series induce a unique conformational shift in TTK that disrupts its catalytic machinery. This knowledge was applied to design a series of novel TTK inhibitors with unprecedented cellular potency. In addition, Dr. Zaman will present the discovery of a prospective drug sensitivity biomarker for TTK inhibitors using NTRC’s Oncolines™ cell line panel profiling.

Symposium: Kinase inhibitors in drug discovery

Title: Target residence-guided optimization of kinase

Presenter: Dr. Guido Zaman

Date and Time: Thursday, November 16th, 6:40 PM

Literature references:

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, SynergyFinder™ and SynergyScreen™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact info@ntrc.nl

Pharmacogenomic analysis at Molecular Targets and Cancer Therapeutics conference

Oss, October, 16th, 2017 – NTRC will present three scientific posters at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference to be held in Philadelphia (USA) from October 27th to 30th. Two of the posters concern pharmacogenomic analysis of cell proliferation data, one related to NTRC’s TTK kinase inhibitor program; the other on gene expression analysis by GeneNominator™.

 GeneNominator™

Screening of new drugs on large cell panels is an important tool to study the biological mechanism of drug response. NTRC scientists have previously shown that the workflow of Oncolines™ screening leads to highly reproducible IC50s which are necessary for genomic biomarker discovery [1,2]. The IC50 in Oncolines™ profiling experiment have been coupled to curated databases of somatic mutations and copy numbers [1]. However, these changes reflect only a small percentage of oncogenic transformations. A more comprehensive view of oncogenic signalling can be obtained from mRNA expression levels [3]. A workflow to investigate drug response in the 102 cell line Oncolines™ panel based on gene expression levels was developed at NTRC, and applied to determine correlations between cancer cell line sensitivity and gene expression levels of more than 18,000 genes. At the AACR-NCI-EORTC conference case studies will be presented on a protein – protein interaction inhibitor, irreversible EGFR and BTK kinase inhibitors, and drug transporter substrates.

Genomic drug sensitivity biomarker for TTK inhibitors

The spindle assembly checkpoint TTK, also known as Mps1, is a key regulator of chromosome segregation and a promising new drug target for the treatment of cancer. With the aim to identify a genomic biomarker to predict the response of tumour cells to TTK inhibitor therapy, a set of TTK inhibitors from different chemical series [4] was profiled on the Oncolines™ cell line panel [1]. Cell lines harbouring activating mutations in the CTNNB1 gene, encoding the Wnt pathway signalling regulator β-catenin, were up to five times more sensitive to TTK inhibitors than cell lines wild-type for CTNNB1 [2]. The association of CTNNB1-mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed with isogenic cell line pairs harbouring either mutant or wild-type CTNNB1. Treatment of a xenograft model of a CTNNB1-mutant cell line with NTRC 1501-0 resulted into tumour regression. Based on these results, mutant CTNNB1 has been proposed as a prognostic drug response biomarker, enabling the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-concept clinical trials

Posters

Combining cell panel screening with analysis of gene expression levels reveals features of drug response and resistance, by Dr. Joost Uitdehaag

Session: Therapeutic Agents: Small-Molecule Kinase Inhibitors; Sunday Oct 29, 2017 12:30 PM – 4:00 PM; Poster Board Number 155, Abstract Number B155

TTK inhibitors as a targeted therapy for CTNNB1 (β-catenin) mutant cancers, by Dr. Guido Zaman

Session: New Molecular Targets; Sunday Oct 29, 2017 12:30 PM – 4:00 PM; Poster Board Number 65, Abstract Number B065

Novel synergistic drug combinations of PARP, bromodomain, and spindle assembly checkpoint kinase inhibitors by large-scale screen of 150 anticancer agents, by Dr. Suzanne van Gerwen

Session: Drug Screening; Saturday Oct 28, 2017 12:30 PM – 4:00 PM; Poster Board Number 153, Abstract Number A153

Meet NTRC Services at booth #815 in the Exhibition Hall of the Pennsylvania Convention Center

Literature references:

[1] Uitdehaag et al. (2016) Cell panel profiling reveals conserved therapeutic clusters and differentiates the mechanism of action of different PI3K/mTOR, Aurora kinase and EZH2 inhibitors. Molecular Cancer Therapeutics 15, 3097-3109.

[2] Zaman et al. (2017) TTK inhibitors as a targeted therapy for CTNNB1 (β-catenin) mutant cancers. Molecular Cancer Therapeutics, advanced online, July 27, 2017.

[3] Rees et al. (2016) Correlating chemical sensitivity and basal gene expression reveals mechanism of action. Nature Chemical Biology 12: 109-116.

[4] Uitdehaag et al. (2017) Target residence time-guided optimization on TTK kinase results in inhibitors with potent anti-proliferative activity. Journal of Molecular Biology, 429, 2211-2230.

[5] de Roos et al. Prognostic biomarkers for TTK inhibitor chemotherapy. WO 2016/166255 A1.

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, SynergyFinder™ and SynergyScreen™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact info@ntrc.nl

 

Novel synergistic combinations identified by unbiased high-throughput screening

Oss, October, 11th, 2017 – A high-throughput screening approach to identify novel synergistic drug combinations has been launched by NTRC under the name SynergyScreen™. The new service product is available as an extension to NTRC’s cell line profiling on the 102 cancer cell line Oncolines™ panel.

SynergyScreen™

The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. The discovery of new effective drug combinations is constrained by the cost and effort of carrying out large unbiased screens. NTRC scientists have previously shown [1] that curve shift analysis by the approach developed by Straetemans et al. [2] is a more robust method of determining synergy than combination matrix screening using Bliss-scoring. In addition, it shown that NTRC’s workflow for single agent cellular IC50 determination is highly reproducible compared to other workflows [3]. To bring these advantages to bear, and to increase the throughput of identifying new synergistic drug combinations, a two-step approach consisting of screening and confirmation was developed at NTRC.

Combination of PARP inhibitor and topoisomerase inhibitor irinotecan studied by SynergyScreen™ (left) and SynergyFinder™ (right).

NTRC at Molecular Targets and Cancer Therapeutics conference

The screening approach will be presented at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference, to be held in Philadelphia (USA) from October 27th to 30th. Results will be presented of a SynergyScreen™ with a poly-ADP ribose polymerase (PARP) inhibitor, the BET bromodomain inhibitor JQ1 and inhibitors of the spindle assembly checkpoint.

The poster on SynergyScreen™ will be presented by Dr. Suzanne van Gerwen on Saturday, October 28th, p.m.

Title: Novel synergistic drug combinations of PARP, bromodomain, and spindle assembly checkpoint kinase inhibitors by large-scale screen of 150 anticancer agents

Session Title:                                   Poster Session A

Session Category:                           Drug Screening

Session Date and Time:                  Saturday Oct 28, 2017 12:30 PM – 4:00 PM

Location:                                          Hall E, Pennsylvania Convention Center

Poster Board Number:                    153

Permanent Abstract Number:          A153

Meet NTRC Services at booth #815 in the Exhibition Hall of the Pennsylvania Convention Center

Literature references:

[1] Uitdehaag et al. (2015) Selective targeting of CTNNB1-, KRAS- or MYC-driven tumor cell growth by combinations of existing drugs. PLoS ONE 10(5): e0125021.

[2] Straetemans et al. (2005) Design and analysis of drug combination experiments. Biometrical Journal 47, 299-308.

[3] Uitdehaag et al. (2016) Cell panel profiling reveals conserved therapeutic clusters and differentiates the mechanism of action of different PI3K/mTOR, Aurora kinase and EZH2 inhibitors. Molecular Cancer Therapeutics 15, 3097-3109.

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, SynergyFinder™ and SynergyScreen™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact info@ntrc.nl

 

NTRC’s key TTK kinase inhibitor patent granted in US

Oss, September, 19th , 2017 – NTRC, a biopharmaceutical company focused on the discovery and development of innovative precision medicines for the treatment of cancer, today announced that the United States Patent and Trademarks Office (USPTO) has granted patent protection for a key patent for its TTK kinase inhibitor programme.

The spindle assembly checkpoint TTK, also known as Mps1, is a key regulator of chromosome segregation and a promising new drug target for the treatment of cancer. Scientists at NTRC, based in Oss, The Netherlands, designed and optimized the novel TTK inhibitors, which exhibit high biochemical and cellular potency. The TTK inhibitors are based on a (5,6-dihydro)pyrimido[4,5-e]indolizine scaffold. This is a completely novel class of synthetic chemical molecules, which are described for the first time in the NTRC patent (WO 2015/155042 A1). The NTRC TTK inhibitors demonstrate very potent anti-proliferative activity in cell-based assays, in the same range as classic cytotoxic agents, but show preference for tumour cells with activated Wnt signalling. In several in vivo cancer models, lead compounds from the series have shown strong reduction of tumour growth or even tumour regression, without toxicity.

Efficacy study NTRC 1501-0, a lead compound from the NTRC TTK inhibitor series, in a xenograft model of the human A427 lung cancer cell line. A427 is mutant for the CTNNB1 gene, coding the Wnt pathway regulator β-catenin. As disclosed by NTRC scientists in another patent application (WO 2016/166255 A1) and in a recent article in Molecular Cancer Therapeutics, tumour cells with activating mutations in the CTNNB1 oncogene show increased sensitivity for TTK inhibitors. In the A427 xenograft model, treatment with NTRC 1501-0 at a dose of 3.75 mg/kg bi-daily, results in tumour regression.

Publications on NTRC’s TTK inhibitor series:

NTRC patents on TTK:

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, and SynergyFinder™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact info@ntrc.nl

Meet NTRC at Discovery on Target conference in Boston 25 – 29 September, 2017

Oss, September, 19th , 2017 – At the 15th Annual Discovery on Target (DOT) conference to be held in Boston (USA) on 25 – 29 September, Dr. Guido Zaman will present on NTRC’s TTK drug discovery program and its ResidenceTimer™ platform.

Title: Targeted residence time-guided optimization of TTK inhibitors

Kinase Inhibitor symposium, Thursday September 28th, 9:05 – 9:35 a.m.

The interactive breakout discussion on the topic of: New kinase inhibitor targets in cancer immunotherapy will be chaired by Dr. Zaman.

Kinase Inhibitor symposium, Thursday September 28th, 8 to 9 a.m.

NTRC’s high-througput SynergyScreen™ platform for identification of novel synergistic drug combinations will be presented during the poster session by Dr. Suzanne van Gerwen.

Title: Novel synergistic drug combinations of PARP, bromodomain and TTK inhibitors by large scale screen of 150 anti-cancer agents

Exhibition area, Wednesday September 27th p.m. and Thursday September 28th a.m. and p.m.

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, and SynergyFinder™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. For more information please visit www.ntrc.nl or contact info@ntrc.nl

NTRC publishes an association of CTNNB1 mutant status and increased cancer cell line sensitivity to TTK inhibitors

Oss, July, 27th, 2017 – In a new publication, NTRC scientists propose mutations in the cancer hot spot region of the β-catenin gene (CTNNB1) as prognostic drug sensitivity biomarkers for TTK inhibitors. The paper appeared online today in the journal Molecular Cancer Therapeutics, a leading journal on cancer research from the American Association of Cancer Research (AACR).

The protein kinase TTK, also known as Mps1, is a promising new drug target. Inhibition of TTK activity with small molecule inhibitors effectively kills tumor cells, and several TTK inhibitors have been shown to reduce the growth of tumors in in vivo models of cancer. While the first TTK inhibitors have entered phase 1 dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy was still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, NTRC scientists profiled a set of pre-clinical and clinical TTK inhibitors from different chemical series on the Oncolines™ cancer cell line panel. Oncolines™ are proliferation assays on a large panel of genetically characterized cell lines derived from different tumors. As shown in the article in Molecular Cancer Therapeutics, cell lines harboring activating mutations in the CTNNB1 gene were on average up to five times more sensitive to TTK inhibitors than cell lines wild-type for CTNNB1. The mutations are located in a so-called ‘cancer hot spot’, a region frequently mutated in human tumours. The mutations cause β-catenin to become an oncogene. In the article, it is outlined how these mutations make cancer cell lines more dependent on TTK.

The association of CTNNB1 mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed by gene expression analysis using GeneNominator™. NTRC scientists translated these findings to an in vivo cancer model: Treatment of a xenograft model of a CTNNB1 mutant cell line with the TTK inhibitor NTRC 0066-0 resulted in complete inhibition of tumor growth.

The discovery that mutant CTNNB1 is a prognostic drug response biomarker for TTK inhibitors will enable the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-principle clinical trials. Mutations in the CTNNB1 gene occur at high frequency in endometrial cancer (30%) and hepatocellular carcinoma (27%), which is known to express high levels of TTK. Interestingly, β-catenin signaling has also been implicated in intrinsic resistance against immunotherapy in melanoma by regulation of T cell infiltration. Thus, new areas of potential clinical application of TTK inhibitor drugs have been uncovered by Oncolines™ profiling.

Oncolines™ and GeneNominator™ are offered as commercial services to customers worldwide by NTRC.

To access the article, follow: http://mct.aacrjournals.org/content/early/2017/07/27/1535-7163.MCT-17-0342

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, GeneNominator™, SynergyFinder™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. For more information please visit www.ntrc.nl or contact info@ntrc.nl

NTRC expands Oncolines™ cell line panel to 102 cell lines

Oss, June 22nd 2017 – Today NTRC has launched an expansion of its Oncolines™ cancer cell line panel, from 66 to 102 cell lines. Oncolines™ are proliferation assays on a panel of genetically well-characterized cancer cell lines from diverse tumor tissue origin. NTRC has a commercial license from the American Type Culture Collection (ATCC). Oncolines™ profiling includes genomic biomarker analysis and comparative profiling against a library of more than 150 pre-profiled anti-cancer agents. In recent publications in Molecular Cancer Therapeutics [1] and Nature Communications [2] the reproducibility of Oncolines™ cell panel profiling and its application in mechanism-of-action studies has been demonstrated. The Oncolines™ biomarker analysis can be extended with gene expression analysis through GeneNominator™.

Characteristics Oncolines™:
– Readout ATPlite™
– Low passage number and ATCC recommended culturing conditions
– No IC50 extrapolation
– 384-well, automated liquid handling
– Manual inspection of curves

Recent publications with Oncolines™ and OncolinesProfiler™ results:
[1] Uitdehaag et al. (2016) Cell panel profiling reveals conserved therapeutic clusters and differentiates the mechanism of action of different PI3K/mTOR, Aurora kinase and EZH2 inhibitors. Molecular Cancer Therapeutics 15, 3097-3109
[2] Bohnacker et al. (2017) Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention. Nature Communication 8:14683

For more information or quotations, please sent e-mail to services@ntrc.nl

About NTRC
NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, and SynergyFinder™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. For more information please visit www.ntrc.nl or contact info@ntrc.nl

NTRC publishes target residence time-guided optimization of TTK inhibitors

Oss, May 22nd 2017 – This week, NTRC published results from its TTK (Mps1) drug discovery programme in the Journal of Molecular Biology. TTK is a promising new drug target for the treatment of aggressive cancers such as triple-negative breast cancer. NTRC combined the ResidenceTimer™ platform for determination of binding kinetics with protein crystallography to develop inhibitors with a unique mechanism of action. Compared to reference inhibitors, NTRC’s TTK inhibitors bind in a unique ‘lysine trap’ binding mode that shifts the so-called glycine rich loop in TTK and locks the catalytic lysine in a dysfunctional state. As a result of these stabilizing rearrangements, the inhibitors have long target residence times which translate into very potent antiproliferative activities that rival those of classic cytotoxic therapy. This was measured in NTRC’s Oncolines™ cancer cell line panel. The unique properties and potent activity open up new and specific applications for TTK inhibitors in cancer treatment. To access the article follow: http://dx.doi.org/10.1016/j.jmb.2017.05.014

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, GeneNominator™ and SynergyFinder™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. For more information please visit www.ntrc.nl or contact info@ntrc.nl

NTRC launches GeneNominator™ tool for drug sensitivity and gene expression analysis

Oss, March 30th, 2017 – NTRC announces its GeneNominator™ bioinformatics package to study the biology of inhibitor response at the mRNA expression level. With NTRC’s Oncolines™ panel, the IC50 values of inhibitors can be determined in a rapid and reproducible fashion. With the new GeneNominator™ tool, these IC50 values can be connected to the expression levels of more than 18,000 individual genes in each of the cell lines. This enables identification of pathways that confer sensitivity or resistance to customer inhibitors. False positive scoring genes are filtered out by comparing responses with a proprietary database of response profiles of 150 different drugs and drug candidates. Interesting genes are highlighted through the use of relevant subsets. GeneNominator™ makes use of state-of-the-art analyses such as protein-protein-interaction predictions and Gene Set Analysis to give meaning to gene lists and identify the important pathways in responsive and resistant cell populations. This includes the prediction of responder populations at the clinical level.
GeneNominator™ will be presented at the NTRC booth (#3050) at the American Association of Cancer Research 2017 Annual meeting in Washington D.C. For more information: info@ntrc.nl.

GeneNominator_PR.png
MDM2 gene expression in cell lines, which inhibits TP53 activity, strongly correlates with sensitivity for the MDM2 inhibitor nutlin-3a (left). This is complementary to the Oncolines™ genomic biomarker association which shows that TP53 wild type cell lines are sensitive for nutlin-3a (right).

About NTRC
NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, and SynergyFinder™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. For more information please visit www.ntrc.nl or contact info@ntrc.nl