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Confronting Cachexia - A Disease within a Disease

WEBINAR

Only

Confronting Cachexia - A Disease within a Disease

Friday, April 16, 2021, 10:00 AM - 5:00 PM EDT

Webinar

Presented By

The Biochemical Pharmacology Discussion Group

The New York Academy of Sciences

 

Cachexia is a multifactorial and multi-organ syndrome that is one of the main causes of morbidity and mortality in late stages of chronic conditions such as cancer, acquired immune deficiency syndrome (AIDS), chronic obstructive pulmonary disease (COPD), heart failure, and chronic kidney disease (CKD). As such, cachexia is often referred to as “a disease within a disease”.

Cachexia is a wasting syndrome characterized by signs and symptoms that may include weight loss, anorexia, decreased muscle strength, increased fatigue, abnormal biochemistry and increase of inflammatory markers. These changes have been associated with increased morbidity and mortality as well as reduced quality of life.

This virtual symposium will bring together researchers from academia and industry to discuss the latest advancements in studying cachexia as a distinct disorder uncovering how inflammation and metabolic imbalances drive its pathology.

Registration

Member
$30
Nonmember Academia, Faculty, etc.
$65
Nonmember Corporate, Other
$85
Nonmember Not for Profit
$65
Nonmember Student, Undergrad, Grad, Fellow
$45
Member Student, Post-Doc, Fellow
$15
Deadline:
0
days
left

Scientific Organizing Committee

Antonio Filareto, PhD
Antonio Filareto, PhD

Boehringer Ingelheim Pharmaceuticals Inc

Marcus Goncalves
Marcus Goncalves, MD, PhD

Weill Cornell Medicine

Christine Grimaldi
Christine Grimaldi, PhD

Boehringer Ingelheim Pharmaceuticals Inc

John Hambor, PhD
John Hambor, PhD

Boehringer Ingelheim Pharmaceuticals Inc

Claire Steppan, PhD
Claire Steppan, PhD

Pfizer Inc

Bei B. Zhang
Bei B. Zhang, PhD

Pfizer Inc

Sonya Dougal, PhD
Sonya Dougal, PhD

The New York Academy of Sciences

Barbara Knappmeyer
Barbara Knappmeyer

The New York Academy of Sciences

Keynote Speaker

Daniel L. Marks, MD, PhD
Daniel L. Marks, MD, PhD

Oregon Health & Science University

Speakers

Vickie Baracos, PhD
Vickie Baracos, PhD

University of Alberta

Laure Bindels, PhD
Laure Bindels, PhD

Louvain Drug Research Institute

Morris Birnbaum
Morris Birnbaum, MD, PhD

Pfizer

Jeffrey Crawford
Jeffrey Crawford, MD

Duke University School of Medicine

Marcus Goncalves
Marcus Goncalves, MD, PhD

Weill Cornell Medicine

Denis Guttridge
Denis Guttridge, PhD

Medical University of South Carolina

Carla Prado
Carla Prado, PHD

University of Alberta

Maria Rohm
Maria Rohm, MD

Helmholtz Center, Munich

Teresa A. Zimmers
Teresa A. Zimmers, PhD

Indiana University

Event Support

Friday

April 16, 2021

10:00 AM

Welcome Remarks

Speaker

Barbara Knappmeyer, PhD
The New York Academy of Sciences
10:05 AM

Keynote Address: Hypothalamic Mechanisms in Cachexia

Speaker

Daniel L. Marks, MD, PhD
Oregon Health & Science University

Cachexia is characterized by weight loss, muscle and adipose tissue wasting, anorexia, and fatigue. Cachexia is common in cancer patients and has a devastating impact upon physical function, quality of life, and survival. We, along with others, demonstrated that signaling between tumor and the central nervous system (CNS) is critical for the metabolic, behavioral, and neuroendocrine dysfunction observed during tumor growth. We determined that the mediobasal hypothalamus (MBH) is uniquely equipped as both a sensor and amplifier of peripheral inflammatory signaling. This region has an attenuated, dynamic blood brain barrier and contains specialized cells that regulate appetite, endocrine function, and the autonomic nervous system. In this talk, the role of MBH inflammation in driving the behavioral and metabolic features of cachexia will be discussed, with emphasis on mechanisms of anorexia, fatigue, and neuroendocrine dysfunction. Potential opportunities for therapeutic intervention based on this research will also be highlighted.

Session 1: New Frontiers in Disease Understanding

Session Chairperson
Bei B. Zhang, PhD, Pfizer
10:50 AM

Radiological Criteria to Quantify Catabolic Losses in Patients with Cancer

Speaker

Vickie Baracos, PhD
Univ. Alberta, Canada
11:20 AM

A Clinical Algorithm to Manage Patients with Cachexia

Speaker

Marcus Goncalves, MD, PhD
Weill Cornell Medicine

Cancer-associated cachexia is a syndrome that is clinically defined by weight loss. The current definition is useful in that it predicts chemotherapy toxicity, complications from cancer surgery, and mortality across many tumor types. However, it lacks the appropriate specificity required for routine clinical care and clinical trial enrollment. Many physiologic processes can lead to weight loss and it is unlikely that one therapy will benefit all conditions. Data from our and other cancer cachexia clinics suggest that there are subtypes of cachexia that uniquely benefit from existing interventions. In the first half of this talk, I will review our algorithm for clinical cachexia management. In the second half, I will discuss pre-clinical data that support the need for a multi-modal approach to treating cachexia.

11:50 AM

Poster Session 1 / Lunch Break

Session 2: Delineating Underlying Biological Pathways

Session Chairperson
Christine Grimaldi, PhD, Boehringer Ingelheim & Barbara Knappmeyer, PhD, The New York Academy of Sciences
12:20 PM

Tissue Crosstalk in Cancer Metabolism

Speaker

Maria Rohm, PhD
Helmholtz Institute Munich

Cancer cachexia is a multifactorial energy‐wasting syndrome reducing the efficiency of anti‐cancer therapies, quality of life, and survival of cancer patients. It is becoming increasingly evident that both tumor- and host-derived signalling molecules mediate tissue wasting. Tissue crosstalk therefore is an important aspect of cachexia development and progression.

Using secretome analyses, we have identified novel tumor-secreted proteins driving organ dysfunction and catabolism. These may serve as biomarkers for the early disease detection, and represent potential new mechanisms for intervention. In addition, we are addressing the knowledge gap regarding bioactive lipids in cachexia, which exists despite ample evidence of altered lipid metabolism in metabolic organs such as adipose tissue. Circulating bioactive lipids are important endocrine mediators regulating inflammation, metabolism, and energy expenditure, playing central roles in metabolic disease.

We have measured the lipid profile in plasma of multiple different mouse models of cachexia and weight-losing cancer patients. We identified 8 lipid species consistently and significantly altered in all mice and patients with cachexia, and correlating with weight loss. Altered lipid metabolism in the liver was key to altered lipid levels. With the identification of specific signalling lipids and underlying mechanisms, we have come closer to understanding the complexity of multi-organ dysfunction in metabolic wasting.

12:50 PM

Gut Microbiota and Cachexia

Speaker

Laure Bindels, PhD
Louvain Drug Research Institute, Belgium

Cancer cachexia is a complex multi-organ syndrome characterized by weight loss, muscle atrophy, fat mass loss, anorexia and inflammation. With a prevalence of 1 million people in Europe and only limited therapeutic options, there is a high medical need for new approaches to treat cachexia. In this context, we started a few years ago studying the therapeutic interest of modulating the gut microbiota in the context of cancer cachexia.

We discovered not only that the gut microbiota composition and function were deeply altered in cancer cachexia but also that the gut function itself was altered at several levels (gut immunity, gut barrier, epithelium renewal, intestinal morphology), independently of any chemotherapeutic intervention. Furthermore, our experimental results establish that nutritional modulation of the gut microbiota could constitute an interesting adjuvant therapeutic tool for cancer and associated cachexia. Among the mechanisms involved in these beneficial effects, we can pinpoint some nutritionally derived microbial metabolites being able to influence cancer progression outside the gastrointestinal tract. In addition, our recent findings support a therapeutic interest for modulating the gut microbiota to target the gut dysfunction as well as a role for microbial metabolites in the regulation of the hepatic inflammation associated with cancer development.

1:20 PM

Break

1:30 PM

NF-kB Signaling and Skeletal Muscle Wasting in Cancer Cachexia

Speaker

Denis Guttridge, PhD
Medical University of South Carolina

Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle mass. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic cancer, 85% of patients lose on average 14% of their pre-illness weight, and cachexia dramatically limits their ability to tolerate surgery, chemo- or radiotherapy. New therapies will likely evolve from an enhanced understanding of the mechanisms leading to muscle wasting and tumor development. Our laboratory has been examining the role of the NF-kB signaling pathway in tumorigenesis for several decades and that interest led us to discover the connection between NF-kB and muscle wasting in cancer cachexia. We view the pathway as playing an important function in cancer-induced cachexia. We have found that during cancer progression, skeletal muscle undergoes a type of injury response leading to the activation of resident stem cells to engage in a regeneration program. NF-kB is activated in these stem cells and functions to inhibit regeneration, which contributes to the overall wasting process in cachexia. New data reveal that NF-kB activity in progenitor cells also regulates a local muscle inflammatory environment that might also contribute to skeletal muscle catabolism. The mechanism of this regulation will be discussed in more details and is consistent with the notion that NF-kB functions in cancer cachexia by acting in muscle stem cells to block muscle repair.

2:00 PM

The Role of Signaling by the Activin and IL-6 Family in Cachexia

Speaker

Teresa Zimmers, PhD
Indiana University
2:30 PM

Mitochondria-Targeted Strategies Ameliorate Chemotherapy-Induced Cachexia

Speaker

Andrea Bonetto, PhD
Indiana University

We have shown that muscle depletion and weakness occur as a direct consequence of anticancer treatments (i.e., chemotherapy), mainly by affecting mitochondrial homeostasis and energy metabolism. We sought to investigate whether preservation of muscle mitochondria may prevent muscle loss and neurodegeneration following chemotherapy. Here, we showed that chemotherapy drives loss of muscle mass and strength, accompanied by neurodegeneration and changes in electrophysiological parameters (e.g., MUNE, SMUP). C2C12 cultures overexpressing OPA1, a regulator of mitochondrial fusion, maintained their myotube size when exposed to chemotherapy, whereas administration of the mitochondria-targeted antioxidant MitoQ to C2C12 cultures in combination with Folfiri was able to preserve myotube size, also consistent with improved OPA1 expression. Similarly, cisplatin-treated mice infected with AAV-OPA1 showed preserved plantar flexion force and innervation. Interestingly, 18- month-old transgenic mice overexpressing the regulator of mitochondrial biogenesis PGC1alpha in their skeletal muscle were protected from cisplatin-induced loss of muscle mass and weakness and presented preservation of MUNE and SMUP, unlike young animals. Our results suggest that preserving mitochondria may be a novel therapeutic strategy to counteract chemotherapy-induced muscle toxicities. Hence, prospective multi-modal therapies including mitochondria-targeted agents in combination with chemotherapy are warranted.

2:45 PM

Downregulation of PGC1-α in the Skeletal Muscle Endothelium Mediates Cancer Cachexia by Compromising Vascular Barrier

Speaker

Young-Mee Kim, PhD
University of Illinois at Chicago

Cancer patients experience cachexia which is characterized by extensive skeletal muscle wasting that worsens the quality of life and increases mortality. Currently, there are no approved treatments that can effectively counteract cancer cachexia. Vascular endothelial cells (ECs) are essential for maintaining tissue perfusion, nutrient supply and preventing inappropriate transmigration of immune cells into the tissue. However, little is known about the role of the muscle vasculature in cancer cachexia. We hypothesized that endothelial dysfunction in the skeletal muscle mediates cancer cachexia. Using genetically modified KPCpancreatic ductal adenocarcinoma (PDAC) mice and a tissue clearing and high-resolution 3Dtissue imaging approach, we found that the loss of skeletal muscle vascular density precedes the loss of muscle mass. Circulating Activin-A released by the tumor suppresses expression of the transcriptional co-activator PGC1α in the muscle endothelium of cachexic mice, thus disrupting junctional integrity in the vasculature and increasing vascular leak. Furthermore, an EC-specific inducible PGC1α deletion (ECΔPGC1α) mouse phenocopied the decreased vascular density and muscle loss observed in tumor-bearing mice. Our study suggests that EC-PGC1α is essential for maintaining the integrity of the skeletal muscle vascular barrier and that restoring muscle endothelial dysfunction could be a novel therapeutic approach to prevent or reverse cancer cachexia.

3:00 PM

Poster Session 2 / Networking Break

Session 3: Approaches Targeting Therapeutic Intervention

Session Chairperson
Marcus Goncalves, MD, PhD, Weill Cornell Medicine
3:30 PM

Cachexia as a Metabolic Disease – Novel Transformative Therapies

Speaker

Morris Birnbaum, MD, PhD
Pfizer
4:00 PM

Clinical trials in cancer cachexia: challenges and opportunities

Speaker

Jeffrey Crawford, MD
Duke University School of Medicine

Cancer cachexia is a complex condition from both a biological and clinical perspective resulting in a major area of unmet medical need.  The current lack of effective interventions have limited guideline recommendations and resulted in lack of recognition of the disorder and under-management.  Clinical trials have provided important insights into patient outcomes, both in the control and treatment groups.  However, a limited number of agents under study, combined with lack of agreement on major endpoints and limited regulatory guidance have all been barriers to the success of clinical trials.  Fortunately, with the scientific advances in the preclinical study of cancer cachexia, many pathways and potential targets have emerged with several new promising agents in development.  The recent approval of anamorelin for the treatment of cachexia in cancer patients in Japan is an exciting step forward that will hopefully help provide guidance for regulatory authorities, as well as clinical investigators involved with clinical trial design, leading to an expansion of clinical research in this field in the years ahead.

4:30 PM

Targeted Nutrition Interventions for the Prevention and Treatment of Cachexia

Speaker

Carla Prado, PhD
University of Alberta

Cachexia is a disease associated with malnutrition, with severe loss of skeletal muscle mass. Optimizing nutritional status is one of the unmet needs in optimal disease care. For example, in the cancer context, International oncology societies now recognize that nutrition is part of the comprehensive management of cancer care, which should be initiated early in the disease trajectory.

Patients with cachexia have anabolic potential. Importantly, the quality and quantity of nutrients is essential to prevent and reverse muscle loss. Although targeted nutrition care goals and expected outcomes are different among precachexia, cachexia and refractory cachexia, they provide a framework for the role of nutrition support in the context of multimodal interventions. The latter is considered the way of the future to optimize outcomes in cachexia.

5:00 PM

Adjourn

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