Cachexia, recognized by progressive loss of skeletal muscle and adipose tissue, contributes directly to morbidity and mortality in diseases as diverse as organ failure, AIDS, burn, trauma and cancer. Indeed, cachexia itself and not other effects of the tumor is thought to be the cause of up to 1/3 of all cancer deaths. Relatively little is understood regarding the molecular and cellular pathways leading to weight loss and dysmetabolism in cachexia and currently there are no approved, effective therapies.
My group, working with a large and diverse group of collaborators, seeks to fill that knowledge gap by using novel animal models and correlative phenotypic and molecular data from patients to identify molecular, cellular and organ system mechanisms leading to cachexia. In this fashion we have:
1. Identified a key role for IL-6/IL6R/GP130/STAT3 in organ crosstalk among wound/tumor, muscle and fat wasting in cancer and burn cacheixa.
2. Identified a causal role for Activins in burn-induced muscle wasting and shown efficacy in targeting Activin, myostatin and GDF11 in cachexia.
3. Identified key roles of sonic hedgehog/GLI proteins and Smoothened in muscle wasting of cancer cachexia.
4. Developed or characterized new models of pancreatic cancer cachexia, including congenic orthotopic, patient-derived xenografts ("cachexia avatars"), and genetically engineered mouse models (GEMMs).
5. Collected thousands of biological specimens from 160 patients under study for pancreatic cancer cachexia to enable serum proteomics and adipose and muscle transcritomics.
6. Discovered novel targetable molecular pathways and organ cross-talk contributing to cachexia in cancer and burns.
Our current work focuses upon studying these novel molecular and organ cross-talk pathways in cell cultures and animal models. At the same time we are undertaking clinical studies in cancer cachexia. At this time we are searching for funding for a proposed clinical trial to treat cachexia in patients with pancreatic cancer as well as to examine the systemic response and rates of muscle and fat wasting in an open trial in pancreatic cancer.
I am the founding director of the IU Simon Cancer Center Cachexia Working Group and the former IUPUI Center for Cachexia Research Innovation and Therapy. I am co-founder and President of the Cancer Cachexia Society. Through multi-disciplinary collaboration, these groups seek to improve diagnosis, treatment and educational outreach for patients with cachexia.
PRIOR WORK ON LETHAL INJECTION FOR EXECUTION
American support for the death penalty rests upon the perception that lethal injection provides a humane, painless death. Using execution records and autopsy data, my colleage Leonidas Koniaris and I worked with a team of attorneys, anesthesiologists and pharmacologists and showed that evidence of blood thiopental levels, heart rate, respiratory rate and time to death did not support the presumed sequence of events leading to death—a surgical plane of anesthesia rendered by thiopental, followed by paralysis with pancuronium bromide and cardiac arrest by potassium chloride. Rather, we showed the evidence was more consistent with conscious asphyxiation. Our work was cited in Baez v. Rees by Supreme Court Justice Stephen Breyer and has since been cited around substantial changes in execution practice, although whether for better or worse is unclear.
Rupert JE, Narasimhan A, Jengelley DHA, Jiang Y, Liu J, Au E, Silverman LM, Sandusky G, Bonetto A, Cao S, Lu X, O'Connell TM, Liu Y, Koniaris LG, Zimmers TA. Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia. J Exp Med. 2021 Jun 7;218(6):e20190450. doi: 10.1084/jem.20190450. PMID: 33851955; PMCID: PMC8185651.
Narasimhan A, Shahda S, Kays JK, Perkins SM, Cheng L, Schloss KNH, Schloss DEI, Koniaris LG, Zimmers TA. Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform. Cancers (Basel). 2020 Dec 15;12(12):3787. doi: 10.3390/cancers12123787. PMID: 33334063; PMCID: PMC7765482.
Zhong X, Pons M, Poirier C, Jiang Y, Liu J, Sandusky GE, Shahda S, Nakeeb A, Schmidt CM, House MG, Ceppa EP, Zyromski NJ, Liu Y, Jiang G, Couch ME, Koniaris LG, Zimmers TA. The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy. J Cachexia Sarcopenia Muscle. 2019 Oct;10(5):1083-1101. doi: 10.1002/jcsm.12461. Epub 2019 Jul 8. PMID: 31286691; PMCID: PMC6818463.
Rupert JE, Jengelley DHA, Zimmers TA. In Vitro, In Vivo, and In Silico Methods for Assessment of Muscle Size and Muscle Growth Regulation. Shock. 2020 May;53(5):605-615. doi: 10.1097/SHK.0000000000001498. PMID: 31939770; PMCID: PMC7161725.
Titles & Appointments
- Adjunct Professor of Surgery