#TRAILR2

[pharmaphorumuk]

Boehringer and MD Anderson extend KRAS cancer collaboration

Boehringer Ingelheim and The University of Texas MD Anderson Cancer Center have extended and expanded a collaboration exploring medicines targeting lung cancer with KRAS mutations. 

The collaboration was launched in 2019 and in its next phase will explore new molecules from Boehringer’s KRAS (Kirsten rat sarcoma) and TRAILR2 (TNF-related apoptosis-inducing ligand receptor 2) portfolios, with a particular focus on non-small cell lung cancer.

Under the new agreement, joint research will continue for five additional years.

The two organisations began their collaboration shortly after Amgen created a stir at the American Society of Clinical Oncology (ASCO) conference with the first clinical evidence of an effect on solid tumours from a KRAS-targeting drug.

Amgen has now filed sotorasib with the FDA, based on data from a phase 2 trial in patients with advanced or metastatic KRAS G12C mutated non-small cell lung cancer.

Mirati, a biotech from California, specialises in drugs targeting the mutation and is a step behind Amgen with its rival adagrasib.

Novartis signed a deal to evaluate Mirati’s drug soon after ASCO 2019.

Boehringer and MD Anderson said the new agreement allows them to research a first in first-in-class SOS1 pan-KRAS inhibitor known as BI 1701963.

They will also work on an inhibitor of KRAS G12C that could compete with sotorasib (BI 1823911) and an MEK inhibitor (BI 3011441), as well as a novel undisclosed bi-specific TRAILR2 agonist.

Boehringer Ingelheim expects several drugs to be entered into a “Virtual Research and Development Center” with MD Anderson.

KRAS is the most frequently mutated gene that causes cancer and is expressed in one in seven of all human metastatic cancers.

Mutation rates are more than 30% in lung adenocarcinomas, more than 40% in colorectal cancers and more than 90% in pancreatic cancers.

Tumour cell-selective activation of TRAILR2 can trigger cancer cell death in indications of high medical need, including lung and gastrointestinal malignancies.

Scientists from MD Anderson earlier this week published evidence from mouse models showing that blocking a protein called CREB1 could block mutant KRAS, plus another cancer gene called g53, potentially slowing or halting the spread of pancreatic cancer.

The post Boehringer and MD Anderson extend KRAS cancer collaboration appeared first on .

from https://pharmaphorum.com/news/boehringer-and-md-anderson-extend-kras-cancer-collaboration/

[healthtimetaylor]

Thymoquinone upregulates TRAIL/TRAILR2 expression and attenuates hepatocellular carcinoma in vivo model.

PMID:  Life Sci. 2019 Jul 20:116673. Epub 2019 Jul 20. PMID: 31336121 Abstract Title:  Thymoquinone upregulates TRAIL/TRAILR2 expression and attenuates hepatocellular carcinoma in vivo model. Abstract:  AIMS: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Indeed, chemotherapeutic drugs-induced systemic toxicity results in suboptimal cancer treatment. Consequently, there is a need for exploring of a safe and effective therapy for cancer patients. This study aimed to evaluate the hepatoprotective effect of thymoquinone (TQ) against thioacetamide (TAA)-induced HCC. Also, we investigated TQ's ability to sensitize cancer cells toward TRAIL/TRAILR2 apoptotic pathway.MAIN METHODS: Forty male Sprague Dawley rats were divided into 4 groups (n = 10) as follows: control group, CMC group, HCC group and HCC + TQ group. Serum levels of liver function biomarkers and Alpha-Fetoprotein (AFP), as well as hepatic levels of glutathione (GSH) and Alpha-Fetoprotein (MDA) were measured. Transforming growth factor-beta 1 (TGF-β1), TRAILR2, TRAIL, caspase-3, caspase-9, caspase-8 and B cell lymphoma-2 (Bcl-2) mRNA levels were assessed by Quantitative, Real-Time PCR. Fibrosis percentage and necroinflammation were quantified by histopathological examination.KEY FINDINGS: Our results indicated improvement in liver functions, decrease in AFP level and attenuation of HCC progression in TQ treated rats. TQ upregulated TRAIL/TRAILR2 and subsequently enhanced apoptosis as hinted by caspase-3 upregulation and Bcl-2 downregulation. Also, TQ decreased TGF-β1 gene expression level. Moreover, HCC + TQ group showed significant increase in hepatic GSH level and marked decrease in hepatic MDA level.SIGNIFICANCE: This study proved that TQ is able to suppress HCC development via decreasing oxidative stress, suppression of TGF-β1 and induction of TRAIL-mediated apoptosis.

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[cancersfakianakis1]

Optoacoustic detection of early therapy-induced tumor cell death using a targeted imaging agent

Purpose: The development of new treatments and their deployment in the clinic may be assisted by imaging methods that allow an early assessment of treatment response in individual patients. The C2A domain of Synaptotagmin-I (C2Am), which binds to the phosphatidylserine (PS) exposed by apoptotic and necrotic cells, has been developed as an imaging probe for detecting cell death. Multispectral optoacoustic tomography (MSOT) is a real-time and clinically applicable imaging modality that was used here with a near infrared (NIR) fluorophore-labeled C2Am to image tumor cell death in mice treated with a TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) agonist and with 5-fluorouracil (5-FU).<br /><br />Experimental Design: C2Am was labeled with a near infrared (NIR) fluorophore and injected intravenously into mice bearing human colorectal TRAIL-sensitive Colo205 and TRAIL-resistant HT-29 xenografts that had been treated with a potent agonist of TRAILR2 and in Colo205 tumors treated with 5-FU.<br /><br />Results: Three dimensional MSOT images of probe distribution showed development of tumor contrast within 3 h of probe administration and a signal-to-background ratio in regions containing dead cells of >10 after 24 h. A site-directed mutant of C2Am that is inactive in PS binding showed negligible binding. Tumor retention of the active probe was strongly correlated (R2=0.97, P value<0.01) with a marker of apoptotic cell death measured in histological sections obtained post mortem.<br /><br />Conclusions: The rapid development of relatively high levels of contrast suggests that NIR fluorophore-labeled C2Am could be a useful optoacoustic imaging probe for detecting early therapy-induced tumor cell death in the clinic.

http://ift.tt/2vM1c17

#Oncology-Sfakianakis

[pharmaphorumuk]

Boehringer jumps on KRAS cancer drug bandwagon with MD Anderson

Boehringer Ingelheim has become the latest pharma company to investigate KRAS as a potential target for cancer drugs, striking a multi-year oncology research deal with the University of Texas MD Anderson Center.

Amgen created a stir at this year’s American Society of Clinical Oncology (ASCO) conference by announcing data suggesting its KRAS targeting drug AMG 510 may work against solid tumours.

The phase 1 data was the closest anyone has got to making a drug that works against KRAS, a gene which when mutated is associated with several different kinds of cancer.

Pharma has been trying for years to develop inhibitors for KRAS, but Amgen has taken the lead in research by targeting a single mutation called G12C that allows binding of AMG 510 and irreversibly forces the gene into an inactive state.

Novartis is also looking at this mechanism with San Diego-based Mirati in a tie-up announced last month and other companies are likely to follow after the results announced at ASCO pushed up Amgen’s shares by as much as 5%.

A new Virtual Research and Development Center created by the agreement between Boehringer and MD Andersen will focus on KRAS inhibition concepts, in certain types of lung and gastrointestinal cancers.

The research will also focus on a TRAILR2 agonistic antibody that could selectively induce cancer cell death.

The partnership is built on a flexible framework, allowing for projects to enter at different stages – research, development and/or clinical stage – over several years.

It will combine MD Anderson’s patient-driven Therapeutics Discovery division with novel drugs from Boehringer’s pipeline.

Research will involve MD Anderson’s Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION)  platform, which conducts translational research to better understand how new drugs and work and which patients will benefit.

Dr Victoria Zazulina, corporate vice president and global head of oncology medicine at Boehringer Ingelheim, said: “We could not have chosen a better partner with all its research, translational and clinical expertise in lung and gastrointestinal cancers. Together, we hope to transform the treatment landscape for these diseases by tackling their root causes and drivers, that have so far remained elusive, exploring new and smart ways of killing cancer cells.”

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