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Biomarker development in MET-targeted therapy.

Activation of the MET receptor tyrosine kinase by its ligand, hepatocyte growth factor (HGF), has been implicated in a variety of cellular processes, including cell proliferation, survival, migration, motility and invasion, all of which may be enhanced in human cancers. Aberrantly activated MET/HGF signaling correlates with tumorigenesis and metastasis, and is regarded as a robust target for the development of novel anti-cancer treatments. Various clinical trials were conducted to evaluate the safety and efficacy of selective HGF/MET inhibitors in cancer patients. There is currently no optimal or standardized method for accurate and reliable assessment of MET levels, or other biomarkers that are predictive of the patient response to MET-targeted therapeutics. In this review, we discuss the importance of accurate HGF/MET signal detection as a predictive biomarker to guide patient selection for clinical trials of MET-targeted therapies in human cancers.

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Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models.

The identification of optimal target antigens on tumor cells is central to the advancement of new antibody-based cancer therapies. We performed suppression subtraction hybridization and identified nectin-4 (PVRL4), a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules, as a potential target in epithelial cancers. We conducted immunohistochemical analysis of 2394 patient specimens from bladder, breast, lung, pancreatic, ovarian, head/neck, and esophageal tumors and found that 69% of all specimens stained positive for nectin-4. Moderate to strong staining was especially observed in 60% of bladder and 53% of breast tumor specimens, whereas expression of nectin-4 in normal tissue was more limited. We generated a novel antibody drug conjugate (ADC) enfortumab vedotin comprising the human anti-nectin-4 antibody conjugated to the highly potent microtubule disrupting agent MMAE. Hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME) ADC were able to bind to cell surface expressed nectin-4 with high affinity and induced cell death in vitro in a dose-dependent manner. Treatment of mouse xenograft models of human breast, bladder, pancreatic, and lung cancers with enfortumab vedotin significantly inhibited the growth of all four tumor types and resulted in tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors, and support further clinical development, investigation, and application of nectin-4-targeting ADCs.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

Trained immunity in newborn infants of HBV-infected mothers.

The newborn immune system is characterized by an impaired Th1-associated immune response. Hepatitis B virus (HBV) transmitted from infected mothers to newborns is thought to exploit the newborns’ immune system immaturity by inducing a state of immune tolerance that facilitates HBV persistence. Contrary to this hypothesis, we demonstrate here that HBV exposure in utero triggers a state of trained immunity, characterized by innate immune cell maturation and Th1 development, which in turn enhances the ability of cord blood immune cells to respond to bacterial infection in vitro. These training effects are associated with an alteration of the cytokine environment characterized by low IL-10 and, in most cases, high IL-12p40 and IFN-α2. Our data uncover a potentially symbiotic relationship between HBV and its natural host, and highlight the plasticity of the fetal immune system following viral exposure in utero.

Contrasting expression patterns of coding and noncoding parts of the human genome upon oxidative stress.

Oxidative stress (OS) is caused by an imbalance between pro- and anti-oxidant reactions leading to accumulation of reactive oxygen species within cells. We here investigate the effect of OS on the transcriptome of human fibroblasts. OS causes a rapid and transient global induction of transcription characterized by pausing of RNA polymerase II (PolII) in both directions, at specific promoters, within 30 minutes of the OS response. In contrast to protein-coding genes, which are commonly down-regulated, this novel divergent, PolII pausing-phenomenon leads to the generation of thousands of long noncoding RNAs (lncRNAs) with promoter-associated antisense lncRNAs transcripts (si-paancRNAs) representing the major group of stress-induced transcripts. OS causes transient dynamics of si-lncRNAs in nucleus and cytosol, leading to their accumulation at polysomes, in contrast to mRNAs, which get depleted from polysomes. We propose that si-lncRNAs represent a novel component of the transcriptional stress that is known to determine the outcome of immediate-early and later cellular stress responses and we provide insights on the fate of those novel mature lncRNA transcripts by showing that their association with polysomal complexes is significantly increased in OS.

Stanford, SRI to Support Development of Novel Drugs to Treat Triple-Negative Breast Cancer

On March 24, 2016 SRI International announced a new collaborative project between scientists at SRI International and physician-researchers from Stanford Cancer Institute that will support development of novel drugs for treatment of triple-negative breast cancer (Press release, SRI International, MAR 25, 2016, View Source [SID:1234510020]).

Close to 20 percent of breast cancers are triple-negative, a type of tumor that lacks the three most common receptors that fuel most breast cancer growth. These tumors are unresponsive to hormone therapy or drugs targeting these receptors.

The research collaboration will explore the use of a preclinical drug known as sudemycin D6 that targets a "molecular machine" called the spliceosome. The spliceosome is critical to the basic biological transformation of DNA to RNA to proteins.

It "edits" raw RNA transcribed from DNA, cutting and piecing together stretches of code to form the instructions for creating various functional proteins, much as a film editor crafts a finished movie from raw footage. If this biological editor complex is defective, proteins that ultimately result from its actions can be dysfunctional and lead to various forms of cancer, including triple-negative breast cancer.

The research team will be led by Thomas R. Webb, Ph.D., director of Medicinal Chemistry at SRI Biosciences, a division of SRI International, and George Sledge, M.D., professor and chief of the Division of Oncology at Stanford University Medical Center.

"As both a medicinal chemist and cancer survivor, I know that new treatments are desperately needed for cancer," said Webb.

"It is my greatest hope that we can combine the unique strengths of SRI Biosciences and the Stanford Cancer Institute to make long-lasting impact in the treatment of triple-negative breast cancer, where unfortunately there are currently few effective therapeutic options. The strategy may also work for a range of other cancers, including lymphoma, melanoma, and certain brain and colon cancers."

"Stanford and SRI both have unique strengths, and together we can create something wonderful for patients with cancer: new treatments that are more effective and less toxic," said Dr. Sledge.

Webb’s research group designed sudemycin D6 to neutralize the SF3B1 protein of the spliceosome with enhanced activity and duration of action as well as less toxicity than previous spliceosome targeting agents. The team has also developed a marker tumor cell line that fluorescently glows when treated with sudemycin D6. This advance enables real-time monitoring of the drug’s activity, which will support translation to the clinical setting.

The SRI Biosciences and Stanford Cancer Institute collaboration is the first step in determining whether sudemycin D6 may be effective against triple-negative breast cancer. As part of the research, tumor samples from anonymous patients will be analyzed at the molecular level and examined in mouse models.

Nathan Collins Ph.D., vice president of Pharmaceutical and Chemical Technologies in SRI Biosciences and Sanjay Malhotra Ph.D., FRSC, associate professor of radiation oncology at Stanford are co-directors of the SRI Biosciences – Stanford Drug Discovery and Development Program that was announced in January 2016 to combine the translational capabilities of both organizations focused on creating a pipeline of innovative cancer drugs for unmet needs in oncology.

According to Malhotra, "The Webb-Sledge collaboration is an excellent example of how translation of a lab discovery into clinic can be expedited though the Stanford-SRI Drug Discovery and Development program. This is a new program, and we hope our wider research community will benefit from our joint efforts."

"Building on our collaborative program we are delighted to be working with the Stanford Cancer Institute to develop therapies for serious unmet needs in the treatment of cancer," added Collins.