Colorectal cancer is the third most common cause of cancer death. Surgery, in conjunction with adjuvant chemotherapy and radiation therapy, is the most common and effective treatment for colorectal cancer. However, even in patients with presumed resectable cancer, the threat of unrecognized occult disease remains a major challenge for the surgeon. Therefore, 40% of the patients ultimately develop recurrent or metastatic disease. In patients with distant metastases, long-term survival rates fall to below 10%.To date, no reliable systems have been developed to provide the surgeon with real-time intraoperative information to accurately predict the adequacy of resection (both surgical margins and occult disease). More than half of the colorectal cancer patients with recurrent disease, however, cannot undergo surgical procedure due to the tumor's critical location. For these patients with recurrent colorectal cancer, the standard chemotherapy yields a 15% to 50% response rate, so new therapeutic regimens need to be explored. Considering that most cancers generally have multiple genetic abnormalities, a single drug targeting a particular oncogene is unlikely to be completely effective. In this regard, geldanamycin (GA) and its analogs provide a hope for treating the advanced colorectal cancer by inhibiting the molecular chaperone Hsp90 to simultaneously down-regulate many oncogenes. Their severe toxicity, though, has limited their clinical evaluation, and new modifications or drug delivery methods are required for future clinical application. Therefore, we intend to develop a system for intraoperative real-time detection of occult tumors and abnormal lymph nodes, as well as to provide a therapeutic regimen for unresectable and advanced chemo- resistant colorectal cancer. The long term goal is to integrate intraoperative tumor detection for surgery and targeted drug therapy into one system with the same tumor targeting antibody. We hypothesize that the anti-TAG-72 antibody (HuCC49ACH2)-glycosidase conjugate will target gross tumors, occult tumors, and lymph nodes involved in the disease process, and will be used in radioimmunoguided surgery (RIGS) to accurately assess the resection margin and ultimately improve patient survival. In cases where surgery is impossible, we will take advantage of the tumor-localized antibody-enzyme conjugate for site-specific activation of the geldanamycin prodrug in the tumor. We hypothesize that the site-specific activation of GA prodrug will increase the local active drug concentration in the tumor improving its anticancer efficacy, while the prodrug will remain inactive in normal tissue (due to the lack of antibody- enzyme conjugate) and thereby reducing its side effects.
Three specific aims are proposed in the project:
Specific aim I : To deliver the anti-TAG-72 antibody-galactosidase conjugate (AbE) to colorectal cancer for tumor detection in surgery and for future prodrug activation.
Specific aim II : To synthesize geldanamycin-galactose prodrugs (GA-prodrug) with enzyme specific activation properties in tumors.
Specific aim III : To site-specifically activate the geldanamycin prodrug (GA prodrug) by the tumor-localized antibody-enzyme (AbE) in order to increase their efficacy and decrease their side effects. In summary, this integrated system offers a strong clinical application to revolutionize the surgical procedure and provides a new targeted drug therapy for advanced chemo-resistant colorectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120023-05
Application #
7802086
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2007-07-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$278,809
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Sun, Lichao; Burnett, Joseph; Gasparyan, Mari et al. (2016) Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer. Oncotarget 7:51408-51422
Burnett, Joseph P; Korkaya, Hasan; Ouzounova, Maria D et al. (2015) Trastuzumab resistance induces EMT to transform HER2(+) PTEN(-) to a triple negative breast cancer that requires unique treatment options. Sci Rep 5:15821
Zou, Peng; Stern, Stephan T; Sun, Duxin (2014) PLGA/liposome hybrid nanoparticles for short-chain ceramide delivery. Pharm Res 31:684-93
Connarn, Jamie N; Assimon, Victoria A; Reed, Rebecca A et al. (2014) The molecular chaperone Hsp70 activates protein phosphatase 5 (PP5) by binding the tetratricopeptide repeat (TPR) domain. J Biol Chem 289:2908-17
Gu, Mancang; Yu, Yanke; Gunaherath, G M Kamal B et al. (2014) Structure-activity relationship (SAR) of withanolides to inhibit Hsp90 for its activity in pancreatic cancer cells. Invest New Drugs 32:68-74
Chen, Hongwei; Zou, Hao; Paholak, Hayley J et al. (2014) Thiol-reactive amphiphilic block copolymer for coating gold nanoparticles with neutral and functionable surfaces. Polym Chem 5:2768-2773
Li, Yanyan; Zhang, Tao; Li, Xiaoqin et al. (2013) Kinetics of sulforaphane in mice after consumption of sulforaphane-enriched broccoli sprout preparation. Mol Nutr Food Res 57:2128-36
Zou, Peng; Chen, Hongwei; Paholak, Hayley J et al. (2013) Noninvasive fluorescence resonance energy transfer imaging of in vivo premature drug release from polymeric nanoparticles. Mol Pharm 10:4185-94
Chen, Hongwei; Paholak, Hayley; Ito, Masayuki et al. (2013) 'Living' PEGylation on gold nanoparticles to optimize cancer cell uptake by controlling targeting ligand and charge densities. Nanotechnology 24:355101
Zou, Peng; Yu, Yanke; Zheng, Nan et al. (2012) Applications of human pharmacokinetic prediction in first-in-human dose estimation. AAPS J 14:262-81

Showing the most recent 10 out of 31 publications