Colorectal cancer, which causes approximately 10% of cancer deaths in the United States, is the third leading cause of cancer-related mortality;death usually results from uncontrolled metastatic disease. Approximately 25% of patients with colorectal cancer will develop metastatic disease exclusively or largely confined to the liver. Untreated patients with liver metastases share a poor prognosis with an average survival of 12 months. In contrast, patients whose liver metastatic lesions are surgically treated have an average 5-year survival rate of 40%, but only 10-15% of initial colorectal liver metastases are considered resectable. The unresectable cases of liver metastatic disease can be treated with isolated hepatic perfusion (IHP), which involves a method of complete vascular isolation of the liver to allow treatment of liver tumors with toxic systemic doses of chemotherapeutic agents, biologic agents, and mild hyperthermia. We recently completed a phase I trial defining the safe dose of oxaliplatin delivered with IHP. In this grant proposal, we will apply IHP using the chemotherapeutic agent oxaliplatin, the biologic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L), and mild hyperthermia to treat advanced colorectal liver metastases.
The specific aims of this project are to investigate this multimodality approach as to (1) the mechanism of the synergy between the three treatment modalities, and the efficacy of this treatment, (2) preclinical evaluation of multimodality treatment, and (3) clinical trials of multimodality treatment. The proposed studies for the first aim will employ biochemical and molecular techniques to investigate the mechanisms of cell death. For the second aim, we will employ IHP in a syngeneic rat hepatic metastasis model of colorectal carcinoma.
The third aim will evaluate the therapeutic advantage of this treatment on patients. We believe that the successful outcome of this study will support the application of this multimodality approach to colorectal hepatic metastases.

Public Health Relevance

The majority of patients with colorectal liver metastases presents with unresectable disease. The prognosis for these patients is extremely poor. In this study, we will apply isolated hepatic perfusion using the chemotherapeutic agent oxaliplatin, the biologic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L), and mild hyperthermia to treat unresectable liver metastases. We believe that this study will provide crucial information about the development of a novel strategy to treat colorectal hepatic metastases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140554-05
Application #
8653836
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Wong, Rosemary S
Project Start
2010-06-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$342,780
Indirect Cost
$74,042
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Song, Xinxin; Hong, Se-Hoon; Kwon, William T et al. (2016) Secretory TRAIL-Armed Natural Killer Cell-Based Therapy: In Vitro and In Vivo Colorectal Peritoneal Carcinomatosis Xenograft. Mol Cancer Ther 15:1591-601
Lee, Dae-Hee; Sung, Ki Sa; Guo, Zong Sheng et al. (2016) TRAIL-Induced Caspase Activation Is a Prerequisite for Activation of the Endoplasmic Reticulum Stress-Induced Signal Transduction Pathways. J Cell Biochem 117:1078-91
Dilly, Ashok K; Song, Xinxin; Zeh, Herbert J et al. (2015) Mitogen-activated protein kinase inhibition reduces mucin 2 production and mucinous tumor growth. Transl Res 166:344-54
Lee, Dae-Hee; Sung, Ki Sa; Bartlett, David L et al. (2015) HSP90 inhibitor NVP-AUY922 enhances TRAIL-induced apoptosis by suppressing the JAK2-STAT3-Mcl-1 signal transduction pathway in colorectal cancer cells. Cell Signal 27:293-305
Song, Xinxin; Dilly, Ashok-Kumar; Choudry, Haroon Asif et al. (2015) Hypoxia Promotes Synergy between Mitomycin C and Bortezomib through a Coordinated Process of Bcl-xL Phosphorylation and Mitochondrial Translocation of p53. Mol Cancer Res 13:1533-43
Song, X; Kim, S-Y; Zhang, L et al. (2014) Role of AMP-activated protein kinase in cross-talk between apoptosis and autophagy in human colon cancer. Cell Death Dis 5:e1504
Kang, R; Hou, W; Zhang, Q et al. (2014) RAGE is essential for oncogenic KRAS-mediated hypoxic signaling in pancreatic cancer. Cell Death Dis 5:e1480
Lee, Dae-Hee; Kim, Dong-Wook; Jung, Chang-Hwa et al. (2014) Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells. Toxicol Appl Pharmacol 279:253-65
Kim, Seog-Young; Lee, Dae-Hee; Song, Xinxin et al. (2014) Role of Bcl-xL/Beclin-1 in synergistic apoptotic effects of secretory TRAIL-armed adenovirus in combination with mitomycin C and hyperthermia on colon cancer cells. Apoptosis 19:1603-15

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