Download pdf - New Insights into Cancer Cachexia

Denis Guttridge, PhD

Ohio State University

10th Cachexia Conference

Rome, Italy

December 8-10, 2017

New Insights into Cancer Cachexia

Patients with pancreatic cancer have a high incidence of weight loss

Baracos et al., 2017, Nature Primer, In Press

Patients with

Pancreatic

Cancer

Cachectic

Pancreatic Cancer

Patients

Median % Weight Loss of

Cachectic Patients

(Range)

Females 45 66% 10.5% (5-30%)

Males 46 65% 9% (5-31%)

Patients with confirmed pancreatic adenocarcinoma (PDAC)

that are candidates for surgical resection (stage I and II)

Analyzing Serum Markers

SDF IL-15 TRAIL

TNF IL-17 TGFa

INFg LIF CD-40L

IL-1b MCP-1 FGF2

IL-4 G-CSF PDGFBB

IL-6 GM-CSF VEGF-A

IL-8 HGF MMP13

IL-10 RANKL Leptin

M-CSF

Non-cachectic (0% WL) (n=28)

Cachectic (>5% WL) (n=50)

P = 0.13

Chemotherapy Naïve Neoadjuvant Chemotherapy

P = 0.008

Talbert et al., 2017, JCSM, In Press

P = 0.03 P = 0.17

Increases in MCP-1 associates with weight loss but not BMI


P=0.002P=0.19

P=0.18


NF-kB

NF-kB

The role of NF-kB in pancreatic cancer-induced cachexia

GDF-15 is Elevated in Pancreatic Cancer

Wang et al., 2014, BMC Cancer

Elevated GDF-15 Associates with Poor Survival in Pancreatic Cancer

Ratnam et al., 2017, JCI

GDF-15 is a driver of cancer cachexia

Lerner et al., 2016, JCSM

RNA Seq Screen Between p65+/+ and p65-/- MEFs


GDF-15 Gene NF-kB binding site


NF-kB is a direct regulator of GDF-15 in pancreatic cancer


GDF-15 is required for the development of pancreatic cancer

KPC Control

KPC shGDF-15


NF-kBNF-kB

NF-kB Regulates GDF-15 to promote pancreatic cancer

GDF-15

Erin Talbert, PhD

Mary Dillhoff, MD Carl Schmidt, MD Phil Hart, MDAngela Sarna

Priyani Rajasekera Nivi Ratnam

Mitchell Ramsey, MD

September 14-16, 2018 – Philadelphia, USA

4th Cancer Cachexia Conference:Insights into New Discoveries and Translational Therapies