Cachexia: Understand and reverse cachexia and declining performance status in cancer patients.
Professor Eileen White Team Lead
Deputy Director, Chief Scientific Officer, and Associate Director of Basic Research
Dr Marcus DaSilva Goncalves, Co-Team Lead
Assistant Professor of Medicine
Dr Tobias Janowitz, Co-Team Lead
Cancer Research UK, National Cancer Institute
oncology, metabolism, neuroendocrinology, immunology, preclinical modeling, clinical research, advocacy and more
The Cancer Cachexia Action Network
Guided by the hypothesis that cachexia is a tumour-driven metabolic imbalance, the CANCAN team is exploring different pillars of basic research to understand the interconnected components of cachexia biology. These pillars are underpinned by a large clinical study to define clinical subtypes, towards the aim of developing individualised therapies.
Many patients with advanced cancer experience cachexia, a debilitating wasting syndrome characterised by extensive weight loss from both skeletal muscle and fatty tissue, which can’t be reversed with nutritional therapy. Cachexia is often accompanied by fatigue, broad organ and tissue dysfunction, and a greatly diminished quality of life. In addition, cachexia limits patients’ ability to receive systemic cancer therapies and imparts a poor prognosis.
Despite these major clinical implications, relatively little is known about cachexia, and effective therapies are lacking. Although cachexia’s major manifestation is muscular atrophy, the condition is now being understood to be a systemic phenomenon arising from a complex set of interactions between tumours and patients, through metabolism and the immune, endocrine and central nervous systems.
A deep understanding of the mechanisms causing this syndrome would enable the development of novel interventions that could improve treatment response, quality of life and ultimately survival. The CANCAN team aims to expand the mechanistic understanding of cachexia and build a platform to develop therapeutic approaches that could reverse this debilitating condition.
Tackling the Cachexia Challenge
Cancer imposes a metabolic stress, diverting nutrients from patients to meet its high energy needs. The team believes that this metabolic imbalance causes cancer cachexia, and that the key to finding the first successful therapy to alleviate cachexia will be targeting the metabolic imbalance itself or its upstream mediators.
The team is pursuing three pillars of basic research, underpinned by a large clinical study to define clinical subtypes.
- Explore cancer cachexia as a systemic metabolic imbalance
Cachexia is an amalgam of metabolic conditions that affect carbohydrate, fat, protein and energy metabolism. The team hypothesises that this metabolic imbalance is orchestrated by the tumour to favour its own metabolic demands at the expense of the patient.
Using preclinical models, the team will map how metabolism and nutrient distribution and utilisation change with cachexia progression. Additionally, they aim to identify the genes driving these changes, and explore dietary or pharmacologic strategies to rescue distinct metabolic imbalances.
- Identify tumour-secreted factors that drive cancer cachexia
Tumour-secreted factors appear to strongly influence cancer cachexia development, although interactions between the tumour and its environment remain to be explored in cachexia. Central to this pillar is a comprehensive pipeline of target-discovery and validation models, from Drosophila and mouse models to the analysis of patient samples.
Data and biospecimens from TRACERx, a major Cancer Research UK-funded programme profiling patients’ progression from lung cancer diagnosis to cure or relapse, will enable the team to study cachexia development in people with early-stage cancer who have not yet received treatment through to people with later disease stages.
- Understand the how neuroendocrine dysregulation drives cancer cachexia by altering food intake and nutrient processing
Systemic metabolism and food-intake behaviour are tightly regulated by the neuroendocrine system, in which the brain receives, integrates and orchestrates myriad signals to maintain energy homeostasis. Although cachexia cannot be reversed with nutritional therapy, patients experience major changes in energy balance, metabolism, hormone levels and sickness, including loss of appetite – this paradox in the context of weight loss is highly damaging yet poorly understood.
Here, the team will develop a neuroendocrine atlas of cancer cachexia, to expand mechanistic knowledge of how hormones and cytokines drive metabolism and food-intake behaviour, and identify hormones that could be targeted as a novel treatment option.
- Integrating the pillars: identify distinct clinical subtypes of cancer cachexia
The CANCAN team believes that cancer cachexia is not a single disease but rather has several diverse subtypes with differing biomedical and physiological characteristics – currently, all people with cancer cachexia are considered a homogeneous group.
The team will perform the largest multi-centre, longitudinal cohort study of its kind among patients at high risk for cachexia, collaborating with two of the largest healthcare networks in the US: Kaiser Permanente Northern California and the National Cancer Institute Community Oncology Research Program (NCORP) Research Base, an expansive community-based clinical-trial network. Through this cohort, the team hopes to identify and validate distinct cachexia subtypes and ultimately develop tailored therapeutic strategies for each disease subtype.
Professor Eileen White Team Lead
Deputy Director, Chief Scientific Officer, and Associate Director of Basic Research
We’ve assembled a team with diverse and complementary expertise, which we believe can advance the field of cachexia from this nascent, descriptive stage and find novel ways to remedy the condition.
Professor Eileen White is a cancer biologist known for her work establishing that a DNA tumor virus oncogene functions by inhibiting programmed cell death by apoptosis and is a homologue of the human BCL-2 oncogene. She is also known for establishing that tumor cells induce intracellular nutrient scavenging by autophagy, which promotes their metabolism, growth, survival, and malignancy. These findings informed the means to target the apoptosis and autophagy pathways for cancer therapy.
Eileen’s has held leadership roles at the Rutgers Cancer Institute since its inception and the Ludwig Princeton Branch of the Ludwig Institute for Cancer Research. Amongst Eileen’s honors are membership in the US of the National Academy of Sciences, and she is an elected fellow of the American Association for the Advancement of Science, the American Academy of Microbiology, and the American Association for Cancer Research Academy.
Rutgers Cancer Institute of New Jersey
Marcus Goncalves is a physician-scientist at Weill Cornell Medicine in New York. As a practicing endocrinologist, he has developed therapeutic and dietary strategies to modulate systemic glucose and insulin levels in patients with cancer, and he is currently involved in several clinical studies to assess dietary interventions in this population. His research group is focused on Metabolic Oncology, where systemic hormones, dietary nutrients, and tumor nutrient sensing pathways are manipulated to enhance anti-cancer therapy or protect the host against cancer-induced complications like cachexia.
Dr. Goncalves is the inaugural Ralph L. Nachman, M.D. Research Scholar at Weill Cornell and has received grants from the National Cancer Institute, the AACR-The Mark Foundation for Cancer Research, and The Lung Cancer Research Foundation. He regularly cares for patients with cancer experiencing endocrine complications such as cachexia and other metabolic disease in his clinical practice.
Weill Cornell Medicine
Tobias Janowitz is a biochemist and medical oncologist, leading a laboratory and clinical research program focused on the connections between metabolism, endocrinology, and immunology to discover how the body’s response to a tumor can be used to improve treatment for patients with cancer.
Cold Spring Harbor Laboratory
Dr. Bette Caan is a senior research scientist and a nutritional epidemiologist at the Kaiser Permanente Northern California Division of Research. She has been at the Division of Research since 1983. Dr. Caan holds a master's degree in nutrition from Columbia University, a master's degree in epidemiology from the University of California, Berkeley, and a doctorate in public health nutrition from the University of California, Berkeley.
Dr. Caan directs a research program in the examination of modifiable lifestyle risk factors for the prevention and progression of cancer, with a focus on body composition and energy balance risk factors. Dr. Caan has expertise in the assessment of diet and body composition and the conduct of dietary intervention trials. She has authored or co-authored over 450 publications while a researcher at DOR. Her research publications cover a wide range of topics, primarily in nutrition and body size, cancer epidemiology, and women's health.
Dr. Caan is currently the Principal Investigator of several federally funded research projects including two large observational studies examining effects of body composition on breast and colorectal cancer outcomes; an intervention trial studying if strength training can reduce side effects of chemotherapy; and the LILAC Women's Health Initiative (WHI) Cancer Survivor Cohort, a cohort of 20,000 older women diagnosed with cancer during the WHI follow-up period currently being followed for recurrence and survival and survivorship outcomes. Dr. Caan has recently published several papers on the obesity paradox in cancer, advocating that body mass index (BMI) misclassifies patients with regard to adiposity; she is also in part responsible for identifying the obesity paradox. However, equally important in explaining the obesity paradox is that low muscle or sarcopenia is an important, underappreciated risk factor for poor survival, and that it is highly prevalent in normal-weight cancer patients.
Kaiser Permanente Medical Program of Northern California
David Lewis is a Group Leader at the CRUK Beatson Institute in Glasgow, where he leads a multi-disciplinary team of chemists, physicists, biologists and mathematicians developing better ways to image cancer. David’s research focusses on metabolic imaging of nutrient use in cancer, he is passionate about combining imaging and spatial biology technologies to provide new insights into cancer and cachexia development. In the Cancer Cachexia Cancer Grand Challenge, David will be using state-of the-art imaging technologies such as Total-Body PET to visualise metabolic rewiring during cachexia development. These imaging methods offer new insights into the causes of cachexia and provide ways to identify and characterise cachexia early offering the best chance of cure.
Cancer Research UK Beatson Institute
Janelle Ayres is a molecular and systems physiologist who studies evolutionary theory and microbes to understand how all of our physiological systems and our brain interact with each other to promote optimal health. Ayres’ research into how our physiologies are regulated by microbes and the mechanisms by which microbes affect us is paving the way to an entirely new understanding of normal and dysfunctional biological processes.
How a host responds to a pathogen determines outcome of infection, and the long-standing belief was that a host needed to kill an invading pathogen in order to survive. Ayres’ discovery of the host “co-operative defense” system has challenged this notion. As part of her paradigm-shifting work, Ayres showed that a host can employ disease tolerance defenses executed by the co-operative defense system during infection that limits pathology and promotes host survival while having no effect on the pathogen. Ayres made a number of other breakthroughs in this area, revealing not only more about fundamental, dynamic biological processes but also charting discoveries that have potential translational applications for treating a wide array of diseases as well as ways to promote healthy aging.
The Salk Institute for Biological Studies
Dr. Mustian is a Dean’s Professor in the Department of Surgery. She is Co-Leader of the Cancer Prevention and Control Research Program at the Wilmot Cancer Institute, MPI and Co-Director of the NCI-funded University of Rochester Cancer Center NCI Community Oncology Research Program Research Base, Director of the PEAK Human Performance Clinical Research Laboratory and a member of the NCI Board of Scientific Advisors. Her pioneering discoveries of Tai Chi Chuan, Yoga and exercise as effective treatments for cancer- and cancer-treatment-related toxicities have revolutionized our ability to treat some of the most noxious toxicities cancer patients experience such as fatigue, insomnia, functional loss, and more. Her transformative clinical and translational research is honored with more than 40 awards across the globe. Dr. Mustian is a Fellow in the Society of Behavioral Medicine.
University of Rochester
Professor Norbert Perrimon is best known for his studies on signal transduction in Drosophila as well as the development of many methods in functional genomics. He has been elected to the American Academy of Arts and Sciences, EMBO, and National Academy of Sciences.
Harvard Medical School
Sheng (Tony) Hui is an Assistant Professor in the Department of Molecular Metabolism at Harvard T.H. Chan School of Public Health. He integrates in vivo isotope tracing and mass spectrometry to study energy metabolism. Among his discoveries is that circulating lactate is a major fuel for tissues and tumors. He aims to apply the in vivo flux quantification approach to understand cancer cachexia.
Tony earned his PhD in Biophysics from University of California, San Diego in 2014 and completed his postdoctoral training in mammalian metabolism at Princeton University in 2019.
Harvard T.H. Chan School of Public Health
Steven B. Heymsfield, M.D. is Professor and Director of the Body Composition-Metabolism Laboratory at the Pennington Biomedical Research Center of the Louisiana State University System in Baton Rouge. Dr. Heymsfield has published more than 700 peer-reviewed papers covering topics such as obesity, malnutrition, cancer, cachexia, body composition, and caloric expenditure. His contributions to the study of human nutrition led to the TOPS Award from The Obesity Society (TOS), the Rhoads Award from the American Society of Parenteral and Enteral Nutrition (ASPEN), the Robert H. Herman Memorial Award, American Society of Nutrition (ASN), and the George Bray Founders Award from TOS. Dr. Heymsfield is past president of ASPEN, ASN and TOS. He was recently appointed as an Amazon Scholar and Dr. Heymsfield works closely with computer scientists in the company’s emerging digital health care division.
Louisiana State University
After her PhD at the University of Cambridge, CRUK Cambridge Institute, Dr Giulia Biffi trained at Cold Spring Harbor Laboratory as an EMBO and HFSP Post-doctoral Fellow. Since 2020, she has worked as a Junior Group Leader at the CRUK Cambridge Institute. She is also a UKRI Future Leaders Fellow and co-director of the Pancreatic Cancer Programme at the CRUK Cambridge Centre. Giulia's laboratory focuses on understanding the tumour-promoting cross-talks between cancer cells and non-cancerous cells in pancreatic cancer to develop new treatments and diagnostics.
University of Cambridge and CRUK Cambridge Institute
Dr Mariam Jamal-Hanjani is a lung medical oncologist and cancer researcher at the University College London Cancer Institute. Her early research in chromosomal instability and intratumour heterogeneity demonstrated the prognostic relevance of genomic instability in lung cancer. In 2012 she was awarded a CRUK Clinical Research Fellowship to complete her PhD studies for which she was awarded the McElwain and the Sylvia Lawler Scientific Prizes. In 2016 she was awarded an NIHR Clinical Lectureship to continue to her work in the field of cancer evolution in the UK-wide TRACERx and PEACE studies. In 2021 she was awarded a CRUK Career Establishment Award to study the biological processes driving metastatic disease and death in lung cancer, including tumour- and host-initiated mediators of cachexia, and failure of the adaptive immune system leading to tumour immune escape.
University College London
University of Glasgow
Dr Tony Coll is an Honorary Consultant Physician (Addenbrooke’s Hospital, CUHFT) and a University Associate Professor (University of Cambridge) Clinical Biochemistry). He works in the Wellcome Trust-MRC Institute of Metabolic Science where he co-leads (with O’Rahilly and Yeo) a research programme that aims to understand biological processes controlling eating behaviour and how we store and use energy. He also has an active clinical practice based within the Wolfson Diabetes and Endocrine Clinic.
University of Cambridge
Dr. Amy Moore is a virologist and cancer researcher with over a decade of experience in the nonprofit sector working on unique initiatives to build research capacity and improve cancer outcomes.
Before joining LUNGevity, Amy served at the Go2 Foundation as the Director of Science and Research, where she oversaw the foundation’s portfolio of scientific programs. During her tenure, Amy facilitated new research initiatives and collaborations and also vetted new technologies and partnerships for Go2 Foundation’s sister organization, the Addario Lung Cancer Medical Institute. She also served as primary liaison with oncogene-driven lung cancer patient groups.
With extensive experience in academia, Amy has published seven peer-reviewed papers, covering topics such as biomarker testing for non–small cell lung cancer and T-cell factors. She received her bachelor's degree in biology from Furman University in Greenville, SC, where she graduated summa cum laude. She obtained her Ph.D. in microbiology and immunology from Wake Forest University School of Medicine in Winston-Salem, NC.
Dave Chuter is an oesophageal cancer survivor, his lifesaving oesophagectomy in 2006 was the moment that started his journey into patient support and cancer research. When he received his diagnosis, there was no patient-to-patient support locally, so, with the help of his local hospital medical team, he started up a support group in December 2006 that is still running. During the support group meetings, as newly diagnosed patients started asking questions about the clinical trials they were invited to join, Dave realised there was a gap in knowledge. To fill that gap, he decided to get involved in cancer research to help new patients make informed decisions before joining a research trial.
His aims as a patient advocate are to help ensure that:
- The lived experience and knowledge gained by patients of the patients’ journey becomes part of medical and clinical research to ensure Quality of Life
- Patient wellbeing and the best outcomes are the objectives of research and researchers
- The patients’ and carers’ voices are heard, and are recognised as an equal voice and partner in research
Dave serves as the DiCE (Digestive Cancers Europe) Vice-Chair of the Board, Chair of the DiCE Patient Advisory Committee, and is a Public Governor for the Royal Surrey NHS Foundation Trust. He also serves as a PPI member for multiple National (UK) committees and advisory groups (use MY data, European Organisation for Research and Treatment of Cancer, NIHR Academy, to name a few) as well as chairing the UK Oesophageal Patients Association (OPA) from 2017-2020.
Stephen O’Rahilly’s research has been concerned with the elucidation of the fundamental mechanisms underlying obesity, insulin resistance and Type 2 diabetes and the translation of those discoveries into improvements in patient care. His work has uncovered several previously unrecognised genetic causes of these diseases including some that are amenable to specific treatments. He graduated in Medicine from University College Dublin in 1981.
From 1982 to 1991 he undertook postgraduate clinical and research training in general medicine, diabetes and endocrinology in London, Oxford and Harvard. In 1991 he obtained a Wellcome Trust Senior Clinical Fellowship and established his laboratory at the University of Cambridge where he now holds Chair of Clinical Biochemistry and Medicine, Co-Director of the Wellcome-MRC Institute of Metabolic Science (IMS) (the establishment of which he led) and Director of the MRC Metabolic Diseases Unit. He is also Scientific Director, NIHR Cambridge Biomedical Research Centre and Honorary Consultant Physician at Addenbrooke’s Hospital.
He has won many awards including the Heinrich Wieland Prize, the Inbev Baillet Latour Prize, the Zülch Prize, the European Hormone Medal, the first EASD/Novo Nordisk Foundation Diabetes Prize for Excellence, the Banting Medal for Scientific Achievement, the Manpei Suzuki Prize and the Royal Society Croonian Medal. He was appointed Knight Bachelor in 2013.
University of Cambridge and Wellcome-MRC Institute of Metabolic Science