The effect of copper depletion therapy on breast cancer patients

The affect on the collagen microenvironment in breast cancer patients

In a recently published study based on a collaboration between Nordic Bioscience, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and Nancy E. and Peter C. Meinig School of Biomedical Engineering, we have examined the effect of copper depletion therapy on the collagen microenvironment in breast cancer patients with a high risk of relapse.

Tetrathiomolybdate (TM) is a novel, copper-depleting compound associated with promising survival in a phase II study of patients with high-risk and triple-negative breast cancer. In the study, levels of all collagen biomarkers were higher in those with the disease, metastatic and adjuvant, as compared with healthy controls. 

Baseline biomarkers of collagen crosslinking (LOXL2), collagen formation (PRO-C3), and collagen degradation (C1M and C6M) in the exploratory cohort

We propose a novel mechanism for preventing metastases through altered collagen processing in the tumor microenvironment. We hypothesize that decreased collagen cross-linking and increased degradation caused by the treatment may alter the immune response in the pre-metastatic sites and thereby decrease the metastatic potential.

The effect of copper depletion therapy on collagen turnover in breast cancer patients

Preclinical studies revealed decreased collagen deposition, lower levels of myeloid-derived suppressor cells, and higher CD4+ T-cell infiltration in TM-treated mice compared with controls.

In conclusion, the study showed novel mechanisms of TM targeting the TME and immune response with potential applications across cancer types.

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    Can we see the future of kidney function with a simple urine test?

    The future of the kidney with a simple urine test

    Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary condition that causes the development of cysts in the kidneys. This condition affects millions of people worldwide and can lead to kidney failure if left untreated. One of the biggest challenges in treating ADPKD is identifying biomarkers that can predict disease progression and response to treatment.

    Our Renal and Cardiovascular Research team showed that biomarkers of collagen remodeling measured in urine and circulation at baseline are associated with the rate of decline in kidney function in patients with ADPKD. In the study (DIPAK-1), we measured the effect of lanreotide on patients with stage 3 chronic kidney disease. The following demographics were involved:

    DIPAK-1 demographics

    To assess the effect of lanreotide, the team selected a number of biomarkers that were best suited to assess the effect of the drug on interstitial matrix turnover and basement membrane turnover. We have selected a number of biomarkers:

    • PRO-C3, measuring collagen type III formation in serum and urine (interstitial matrix turnover)
    • C3M, measuring collagen type III degradation in serum and urine (interstitial matrix turnover)
    • PRO-C6, measuring collagen type VI formation in serum and urine. Also measures the release of the bioactive fragment endotrophin, associated with pro-fibrotic and pro-inflammatory processes (interstitial matrix turnover)
    • LG1M, measuring Laminin gamma 1 degradation in serum and urine (basement membrane turnover)
    Kidney biomarker data compared to baseline values
    Predicting decline in kidney function with prognostic biomarkers

    The data we found implies that fibrogenesis may be an important pathophysiological process driving ADPKD disease progression. In addition, the use and development of drugs that interfere with fibrogenesis may be promising to halt disease progression in ADPKD. However, we still need to validate in an independent cohort, preferably in early-stage disease.

    The findings of the study are significant because they offer new insights into the potential for biomarkers to predict disease progression in ADPKD. This information may help clinicians to identify patients who are at risk of developing kidney failure and to develop more effective treatments to slow or halt disease progression.

    We have shown that biomarkers of collagen remodeling are associated with the rate of decline in kidney function in patients with ADPKD. These findings suggest that fibrogenesis may be an important pathophysiological process driving ADPKD disease progression and that the use of drugs that interfere with fibrogenesis may be promising to halt disease progression. Further research is needed to validate these findings in an independent cohort, but the results of this study offer new hope for patients with ADPKD.

    We believe it is time to put kidney fibrosis more in the center – even in diseases where other aspects (such as kidney volume) are the focus of attention. At Nordic Bioscience, we have the tools to do so. 

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      Load absorption with osteoarthritis

      How much load can the cartilage in the joints absorb?

      Mechanical loading is an essential part of the function and maintenance of the joint. Despite the importance of intermittent mechanical loading, this factor is rarely considered in preclinical models of cartilage, limiting their translatability.

      The cartilage of the joints of patients with osteoarthritis is negatively affected in their capacity to absorb the load. Despite this pivotal role, mechanical load is rarely a component of translational drug screening assays when testing novel OA treatments.

      We showcased our novel translational cartilage loading model in a publication in Applied Sciences.

      Cartilage explant isolation

      In a culture plate format well suited for lead candidate screening we investigated the effect of growth factors on ex-vivo cartilage remodeling and the interaction with dynamic intermittent loading. Cartilage remodeling was investigated in the presence of IGF-1 or TGF-β1, as well as a TGF-β receptor 1 (ALK5) kinase inhibitor and assessed with biomarkers for type II collagen formation and fibronectin degradation (FBN-C).

      Dynamic compression and cartilage remodeling in Bovine Cartilage Explants

      Amongst others, PRO-C2 has shown that not only does mechanical loading preserve cartilage, but it also positively modulates the effect of known growth factors, such as IGF-1.

      Screening potential drug candidates in physiological loading conditions could provide a more accurate translation to push forward the urgent medical need for better treatments of osteoarthritis.

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        MASH – the race to organ death

        Which organ decompensates first?

        The race to organ death is not a show you want to be a part of. The main cause of death in patients with metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) is liver and cardiovascular complications, while disease activity remains a major feature of liver fibrosis progression.

        Metabolic associated steatohepatitis (MASH, formerly NASH) is a consequence of metabolic problems including obesity and is often characterized by multiple organ failure, with hepatic cirrhosis driving organ decompensation. But what is the true event and death rate of MASH patients? What do they suffer from and why do they die? And how do we know which organ decompensates first? 

        The answer is simple.

        It is essential to measure the functions of different organs and their activity/progression rates, including the liverheart, and kidney.

        The organ death race can be traced back to liver diseases, but it’s important not to forget about the big picture.

        Can we thus assume that for MASH patients, the smallest problem is the liver-related event? Yes and no. The liver is important, but we need to consider the patient as a normal human – with not just a liver, but a heart, kidney, and other organs. These patients are also in the highest risk group for osteoarthritis (OA) and inflammatory bowel diseases (IBD), albeit that is not the focus of this blog article.

        We can conclude that it is central to measure several organ functions and their activity/progression rates – which has been the exact focus for Nordic in the recent period. Our technologies, biomarkers, and drug development projects are perfectly aligned for this.

        For example, PRO-C3 (also available on the high-precision Roche Cobas platform), a biomarker of type III collagen formation, is an excellent marker of MASH progression of fibrogenic activity in the liver. PRO-C3 is FDA approved and utilizes Nordic Bioscience’s protein fingerprint technology.

        High levels of PRO-C3 identify responders to the anti-fibrotic activity of farglitazar (Karsdal MA et al. Am J Physiol Gastrointest Liver Physiol, 2016)

        In relation to the organ death race, Nordic Bioscience received a Letter of Support (LoS) from the FDA for the first serological biomarker for enrichment in clinical studies and trials in heart failure (HFpEF).

        Our protein fingerprint biomarkers can be measured in serum and they specifically target the neo-epitopes that are released during protein formation of degradation and signaling the extent of fibrogenesis or fibrolysis.

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          Why measure the right epitope of the right protein

          A targeted approach in contrast to broad total protein arrays

          When we talk about protein quantification, it’s important to talk about the role collagens play in major chronic diseases. As extracellular matrix research is gaining more and more traction, it’s prime time to highlight how they can guide precision medicine development.

          Dr. Morten Karsdal, CEO of Nordic Bioscience, discusses the importance of finding the right epitope of the right protein in clinical trials.

          If you wish to find out more about the extracellular matrix or our technology, visit our YouTube channel!

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            Osteoarthritis Biomarkers – Serum Quantification of Aggrecanase-Generated ARGS Fragments

            Serum Quantification of Aggrecanase-Generated ARGS Fragments

            Osteoarthritis is a serious disease. It affects more than 300 million people across the world. It’s a leading cause of disability among older adults. Therefore, it has a considerable impact on an individual’s quality of life and a huge economic burden on society.

            We redeveloped a highly sensitive and robust sandwich immunoassay, huARGS, for detecting ARGS fragments generated by up-regulated proteases, ADAMTS-4/-5, during osteoarthritis.

            Watch more videos about how our biomarker can increase clinical trial success rates on our YouTube channel!

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              Joint Tissue Remodeling: Joint and Connective Tissue Disorder Profiling

              Joint and Connective Tissue Disorder Profiling

              According to conservative estimates, nearly 26% of all adults in the United States are expected to have at least one form of arthritis by 2040. The tissues of the joints are composed primarily of collagens.

              Collagens are remodeled as part of the normal homeostasis of the joint – that is, collagens are broken down and rebuilt as part of the repair and maintenance mechanisms of the tissue.

              When this balance is disrupted, there is a net breakdown of joint tissue. Learn more how Protein Fingerprint biomarkers can quantify this tissue turnover directly in a serum sample.

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                Biomarkers in Drug Development

                The Protein Fingerprint Technology

                Through our Protein Fingerprint technology, we identify fragments of the Extracellular Matrix (ECM) that are released from affected tissues and develop blood-based biomarker assays to quantify disease activity with the aim of precision medicine.

                By quantifying tissue remodeling, our biomarkers provide true prognostic and predictive value, as we can select the patients who are most likely to respond to a given treatment and thereby function as surrogate biomarkers for clinical trials. Our biomarker assays not only enable faster drug development but also improve disease outcomes for chronically ill patients by predicting treatment response.

                Watch more videos about Nordic Bioscience’s biomarkers and the ECM on our YouTube channel!

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                  Use of Translational Biomarkers in Pulmonary Fibrosis

                  PRO-C6 as a pharmacodynamic biomarker

                  During the development of pulmonary fibrosis, there are changes in the extracellular matrix. We see the destruction of the basement membrane and the formation of various collagens in the interstitial matrix.

                  We can monitor these changes in the ECM in a blood sample using Protein Fingerprint biomarker technology.

                  Watch more videos about the extracellular matrix and the Protein Fingerprint on our YouTube channel!

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                    Endotrophin as a Novel Biomarker in HFpEF – Identification of a High-risk Endotype

                    Identification of a High-risk Endotype

                    Heart failure with preserved ejection fraction (HFpEF) is a highly complex and heterogeneous syndrome that causes substantial morbidity and mortality, positioning this disease as one of the biggest unmet medical needs today.

                    The past years have seen great scientific and clinical efforts on elucidating the driving mechanisms, but much remains unknown and successful therapies at still largely absent.

                    One of the biggest challenges to treating HFpEF is the heterogeneous nature of the syndrome. Risk assessment by conventional biomarkers has not led to any significant therapies, but selection of a more homogenous patient population might be the way forward.

                    Fibrosis is a hallmark feature of HFpEF pathology, acting as a driver of outcome. Understanding the intricate pathways that lead to fibrogenesis, and how they ultimately impact pathogenesis, is important for understanding how to treat HFpEF. We have developed a biomarker of fibroblast activity, PRO-C6, which independently and with high precision can identify a subset of HFpEF patients with a very elevated risk of adverse outcome.

                    Watch more videos about Nordic Bioscience’s biomarkers and technology on our YouTube channel!

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