Fibrosis as a Driver of Cancer, Liver, and Heart-related Outcomes

Join us for an insightful webinar, where experts will shed light on the multifaceted role of fibrosis in various health conditions.

This webinar offers a unique opportunity to gain comprehensive insights into the role of fibrosis in driving outcomes across various health conditions with a common component, providing valuable knowledge for researchers, clinicians, and healthcare professionals alike.

Agenda

  • Fibroblast Activity Kills: The Basics of Extracellular Matrix in Health and Disease in Predicting Outcomes – Dr. Morten A. Karsdal
  • The Extracellular Matrix of Cancers and The Modulation of the ECM – Dr. Raghu Kalluri
  • Collagen biomarkers of Liver, Heart, and HCC Outcome – Dr. Diana Julie Leeming
  • Q&A Break
  • Liver Fibrosis and HCC –  Cause or Consequence?  – Dr. Scott Friedman
  • Questions from the chat​​​​​​​

Overview and speakers

Our presentations will cover a wide array of topics, starting with an exploration of the fundamentals of the extracellular matrix in health and disease, emphasizing the impact of fibroblast activity on outcomes. The complex relationship between liver fibrosis and hepatocellular carcinoma (HCC) will be explored, examining whether fibrosis is a cause or consequence of this condition.

Further discussions will delve into the extracellular matrix of cancers and the modulation of the ECM, providing insights into the interplay between fibrosis and cancer outcomes. Lastly, we’ll explore collagen biomarkers and their role in predicting outcomes related to liver, heart, and HCC.

Dr. Scott L. Friedman

  • Dr. Scott L. Friedman is the Dean for Therapeutic Discovery and Chief of the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai. He is renowned for his pioneering research into the underlying causes of scarring, or fibrosis, associated with chronic liver disease, which affects millions worldwide.
  • Dr. Friedman was among the first to isolate and characterize the hepatic stellate cell, the key cell type responsible for scar production in the liver, leading to significant advancements in the field.
  • His groundbreaking work has led to the development of new anti-fibrotic therapies for liver disease that are currently reaching clinical trials, contributing to the translation of basic science into clinically meaningful advances. Dr. Friedman’s research has been continuously funded by the NIH since 1985, and he received his first faculty NIH grant (RO1) in 1986 at the age of 31.
  • He has authored over 300 peer-reviewed publications and has been recognized with numerous awards, including the International Hans Popper Award in 2003 for his outstanding contributions to the understanding and treatment of liver disease.
  • Dr. Friedman’s leadership as Chief of the Division of Liver Diseases at Mount Sinai has led to significant expansion, including increasing the faculty from 5 to 25 individuals and overseeing the creation of the largest liver fellowship in the United States.
  • He is a fellow of multiple prestigious medical societies, including the American Gastroenterological Association, the American College of Physicians, and the American Association for the Study of Liver Diseases, among others.

Dr. Raghu Kalluri

  • Dr. Kalluri is a medical researcher focused on the cellular microenvironment and exosomes in health and disease.
    He has mentored over 200 research trainees and led numerous education and training initiatives at Harvard and MD Anderson Cancer Center.
  • He is co-Director of the MSTP, Assistant Dean of the graduate school, and Director of the Office of Mentoring and Training of Scientists at MD Anderson Cancer Center. His research has focused on extracellular matrix (ECM) biology, specifically basement membrane biology, and the discovery of several new ECM-derived endogenous angiogenesis inhibitors.
  • He has contributed to our understanding of the role of TGF-β and BMP-induced epithelial to mesenchymal transition and mesenchymal to epithelial transition in organ fibrosis and cancer progression. His research has led to the identification of new therapeutic targets to combat organ fibrosis and the subsequent expansion of research on the cellular microenvironment to solid tumors, specifically pancreatic cancer.
  • His research group has published over 350 papers in peer-reviewed journals, and his work has been translated into three successful Phase I clinical trials for cancer and the launch of five biotechnology companies.

Dr. Morten A. Karsdal

  • Dr. Karsdal chairs the Extracellular Matrix Pharmacology Congress, an influential forum dedicated to advancing drug development by identifying changes in the ECM as common denominators in chronic diseases.
  • Dr. Morten Karsdal joined Nordic Bioscience in 2001 and has been serving as CEO since June 2010.
  • He is a prolific author, with more than 650 peer-reviewed articles to his name, accumulating over 34,000 citations and an h-index of 95.
  • He is renowned for his expertise and commitment to biomarker development, extracellular matrix biology, and disease research, particularly in fibrosis, rheumatology, and diabetes. He possesses extensive experience in clinical trial design and the clinical application of biochemical markers, consulting for major pharmaceutical companies.
  • As an honorary professor of inflammation research at the University of Southern Denmark, Dr. Karsdal supervises PhD students and contributes to advancing scientific knowledge in the field.
  • In 2016, he authored the first edition of “Biochemistry of Collagens, Laminins and Elastin,” published by Elsevier Science, which is now in its 3rd edition, providing a comprehensive overview of structural proteins and their relevance in chronic diseases.
  • Dr. Karsdal’s leadership and contributions to the Nordic Life Science community were recognized with the Arthur D. Little Nordic Life Science Award in 2023, highlighting his outstanding management and leadership achievements.

Dr. Diana Julie Leeming

  • Dr. Diana Julie Leeming is the Senior Director of Fibrosis, Hepatic, and Pulmonary Research at Nordic Bioscience.
    She joined Nordic Bioscience in 2004 and assumed the role of Director of Fibrosis in 2010, later being promoted to Senior Director in 2024.
  • Diana leads a team of 20 scientists and technicians dedicated to the development and clinical application of extracellular matrix (ECM) biomarkers in hepatic and pulmonary diseases with a fibrotic component. Her role involves overseeing the development of novel ECM biomarkers and implementing them in preclinical drug testing and clinical trials.
  • Dr. Leeming focuses on developing serologically assessed markers to evaluate extracellular matrix remodeling in patients with pulmonary or hepatic fibrosis, aiding in diagnosis and pharmacodynamic evaluation.
  • She is a principal inventor of the PRO-C3 assay, a fibrogenesis marker utilized in multiple clinical trial studies.
  • Dr. Leeming has authored over 180 peer-reviewed publications, demonstrating her extensive contributions to the field. Her H-index is 61, her I10-index is 174, and her research has garnered over 11,825 citations as of March 2024.

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    Single Joint Tissue Destruction Biomarkers

    Single joint tissue destruction biomarkers: association between type III collagen degradation and local tissue damage of a single joint

    Introduction

    The landscape of osteoarthritis (OA) research and therapeutic development has undergone significant transformation, shifting from a primarily structural focus to an emphasis on patient-reported outcomes (PROs). Pain, which primarily originates from the soft tissue of the joint, is intricately linked with the structural integrity of joint tissues. Serological biomarkers are considered potential surrogate endpoints, but their contribution from single joints to systemic levels in OA patients is unclear.

    This study explored systemic biomarker levels’ response to tissue damage and healing in patients undergoing knee or hip joint replacement revision for aseptic failure, compared to patients with chronic pain from a joint replacement, but not receiving surgery.

    Poster

    Conclusion

    C3M degradation was found to increase in response to tissue insult to the joint from revision surgery, while no change was observed in a non-surgical group with chronic pain of the joint over 6 months. The increase and gradual decrease throughout the study period indicate a relationship between systemic levels of type III collagen degradation fragments and soft-tissue destruction and inflammation of the joint.

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      Weight Loss Lead to Significant Effects on OA Pain and Function: Do the Benefits Outweigh the Risks?

      Introduction

      Drug development in the osteoarthritis (OA) field has proven extremely difficult, with a discordance between joint structure and pain. Weight loss has been associated with an effect on pain and function. Several molecular endotypes have been suggested for OA, which could be treatable, such as bone, inflammation, and lately, an overweight endotype.

      The aim was to investigate the relationship between obesity, weight loss and patient-reported outcomes (PROs) in patients with persistent pain, and the effect on joint and bone tissue related soluble biomarkers.

      Poster

      Conclusion

      Changes in PROs were significantly associated with obesity. Weight loss was associated with an increase in bone and cartilage degradation, as well as lowering in the interstitial matrix degradation. These data indicate that weight loss comes with a risk of increased joint tissue loss, but improvement in tissue inflammation.

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        Stakeholder Alignment Under the Clinical Trial Symposium (CTS) & OARSI Umbrella

        Regulatory enablement of molecular endotypes for drug development. Definition of the context of use (COU) and molecular endotype which most urgently will assist in drug development: Stakeholder alignment under the Clinical Trial Symposium (CTS) & OARSI umbrella

        Introduction

        For a biomarker to be considered in therapeutic development, it must navigate various approval pathways. In the US, acceptance for single therapeutic trials is via IND, NDA, and BLA submissions, while for multiple drug development programs, it’s through the Biomarker Qualification Program. This program specifically evaluates the biomarker itself, not the measurement method.

        Alternatively, in the US, a biomarker test can be approved by CDRH, leading to a legally marketable In-Vitro Diagnostic (IVD). The De Novo classification offers a pathway for novel medical devices, based on risk classification. Additionally, the 510(k) submission demonstrates equivalence to predicate devices, while PMA evaluates Class III device safety and efficacy. In the EU, approval is through CE marking, aligning with US FDA pathways.

        A biomarker for general drug development can be qualified by CDER through the Biomarker Qualification Program, resulting in a tool usable under specific COUs. This process involves collaborative efforts with regulatory agencies and stakeholders, often in consortia, to streamline qualification. Monitoring biomarkers play a pivotal role in medical product development, furnishing tangible evidence of treatment impact, while predictive biomarkers serve to mitigate trial risks and minimize failures by pinpointing responsive patient subgroups.

        Poster

        Conclusion

        Defining the Context of Use (COU) within real-world or clinical study populations is essential for biomarker development. Following CLSI guidelines ensures technical robustness, while careful risk-benefit evaluation supports clinical relevance. The regulatory enablement of molecular endotypes is essential for drug development.

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          Evaluation of Biomarkers in PJI After Hip and Knee Arthroplasty

          Evaluation of biomarkers in patients with potential periprosthetic joint infections after hip and knee arthroplasty

          Introduction

          The number of total joint replacements performed each year to treat pain related to end stage knee osteoarthritis (OA) has steadily increased in the last decade. Despite overall efficacy in the majority of patients, a subset of about 20% experience prosthetic complications in the short or in the long run, most often due to aseptic failure or prosthetic joint infection. Accurate diagnosis is therefore crucial. Biomarkers of tissue remodeling are promising diagnostic tools to characterize joint pathological mechanisms, provide a better understanding of how prosthetic complications affect the tissue remodeling to improve diagnosis and intervention

          Poster

          Conclusion

          This study aimed to investigate the relationship between joint tissue remodeling and inflammation biomarkers with diagnosis in patients with hip or knee prosthetic joint complications, as well as to assess the effect of joint corrective surgery on acute and long-term biomarker levels.

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            COMP-M: A Potential Serological Biomarker of Osteoarthritis

            Introduction

            Cartilage oligomeric matrix protein (COMP) is an extracellular matrix (ECM) glycoprotein, consisting of five identical chains. It plays a crucial role in maintaining ECM integrity, facilitating collagen fibrils formation, and regulating cell phenotypes and functions. It is primarily found in human skeleton system, also present in adipose tissue, heart etc. Osteoarthritis (OA) involves increased activity of matrix-degrading enzymes, leading to the fragmentation of ECM.

            In this study, we developed a high-sensitive chemiluminescence immunoassay for quantifying a neoepitope of COMP (DACGMQQS77↓) and explored its application as a biomarker of OA.

            Poster

            Conclusion

            The data generated interest in the use of COMP-M as a tissue degradation biomarker of osteoarthritis.

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              BigH3 Is a Promising Biomarker in NSLC Patients

              Proteolytic degradation of BigH3 can be quantified non-invasively in serum with biomarker potential for patients with non-small cell lung cancer

              Introduction

              Transforming growth factor beta induced protein ig-h3 (BigH3/TGFBI) is widely expressed and is participating in various biological processes including adhesion, migration, and angiogenesis. BigH3 is known to bind multiple collagens and are often embedded in the matrix where it seems
              to function as a linker between ECM and cell surfaces. In non-small cell lung cancer (NSCLC), the increased proteolytic activity found may degrade BigH3, disrupting its ECM interactions and generating peptide fragments that could potentially serve as novel non-invasive biomarkers if released into circulation.

              Our aim is to develop a tool to quantify degraded BigH3 non-invasively and explore its potential as a biomarker in NSCLC.

              Poster

              Conclusion

              Degradation of BIGH3 can be reflected by non-invasive quantification of the cleaved fragment of BigH3,
              BigH3M-N, in serum. This suggests BigH3M-N as a promising biomarker in NSCLC with potential for discriminating between subtypes. However, as BigH3M-N is connected to fibroblast matrix biology, the optimal use for this biomarker might be in combination with other ECM biomarkers.

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                Tissue-Derived Peripheral Biomarkers (C4G, VICM, Cpa9-HNE) in Patients with Solid Tumors

                Tissue-derived peripheral biomarkers that reflect activity of T-cells, macrophages, and neutrophils in patients with solid tumors

                Introduction

                By identifying and quantifying specific extracellular protein fragments with neo-epitopes that are generated by proteolytic cleavage and post-translational modifications specific for T-cells, neutrophils and macrophages, respectively, it is possible to develop peripheral biomarkers that reflect the activity of these immune cells.

                Poster

                Conclusion

                Tissue-derived peripheral biomarkers that reflect the activity of T-cells (C4G), macrophages (VICM) and neutrophils (nordicCPa9-HNE™) has biomarker potential in solid tumors and may serve as prognostic, predictive and pharmacodynamic biomarkers in clinical trials investigating cancer immunotherapy.

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                  myCAF Activity Can Be Assessed by Specific Collagen Pro-Peptide Biomarkers

                  Serological assessment of cancer associated myo-fibroblast (myCAF) activity by collagen pro-peptide biomarkers provides high prognostic power

                  Introduction

                  Myofibroblast Cancer Associated Fibroblasts (myCAFs) are the main tumor fibrosis drivers and hence different from inflammatory CAFs (iCAFs). CAFs produce type III, V, VI and XI collagen that are the essential components of tumor fibrosis. Pro-peptides of these collagens can be quantified both in serum with the nordicPRO-C3™, PRO-C5, nordicPRO-C6™ and PRO-C11 biomarkers where they are prognostic for poor overall survival in patients with various solid tumor types and may be applied in vitro.

                  In this study we investigated the association and difference between myCAFs and iCAFs and their collagen expression profile and related that to data available data on serological assessments of nordicPRO-C3™, PRO-C5, nordicPRO-C6™ and PRO-C11, and cultured CAFs.

                  Poster

                  Conclusion

                  Profiling collagen expression in fibroblast from PDAC and NSCLC reveals that type V collagen and type XI collagen are found in myCAF. Biomarkers of these collagens can be measured in serum from cancer patients and are prognostic for poor overall survival. Thus, these data suggest that cancer associated myo-fibroblast (myCAF) activity can be assessed non-invasively by specific collagen pro-peptide biomarkers.

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                    IL1RAP Blockade Mediates Anti-Fibrotic Effects in Pancreatic Cancer-Associated Fibroblasts

                    Introduction

                    Pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis partly due to excessive activity of cancer-associated fibroblasts (CAFs). CAFs drive the fibrosis that causes excessive type III collagen and extracellular matrix deposition that in turn reduces drug response resulting in poor survival. High levels of the type III collagen serum biomarker nordicPRO-C3™ correlates with poor survival in PDAC. While TGF-β is thought to be one of the main drivers of nordicPRO-C3™ and tumor fibrosis, cytokines such as Interleukin 1 (IL-1) play a key role in the pancreatic tumor microenvironment and may play a significant role in also tumor fibrosis.
                    In this study, we first investigated the potential of IL-1 in activating fibroblasts to drive fibrosis and produce nordicPRO-C3™. Subsequently, we established a co-culture of pancreatic cancer cells and pancreatic CAFs to investigate the anti-fibrotic properties of nadunolimab, a fully humanized ADCC-enhanced monoclonal IgG1 antibody that targets IL1RAP and disrupts both IL-1α and IL-1β signaling.

                    Poster

                    Conclusion

                    Co-cultures of pancreatic tumor cells and CAFs induced formation, including collagen type III formation, and nadunolimab inhibited the collagen type III formation, suggesting anti-fibrotic properties. Activated fibroblasts had induced type III collagen formation (nordicPRO-C3™) suggesting that IL-1 is a driver of tumor fibrosis in PDAC. Nadunolimab, which is currently in clinical development for treatment of pancreatic cancer, has the potential to counteract the detrimental, fibrotic progression in tumors by targeting IL1RAP and blocking both IL-1α and IL-1β signaling. These findings suggest that nordicPRO-C3™ could potentially be used for prognostic/predictive enrichment and as a pharmacodynamic marker in future studies evaluating anti-IL-1 modalities in PDAC.

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