Project-1 will further develop and help evaluate clinically new immunoliposomal agents that target HER2-positive breast tumor cells in order to improve the survival of women with advanced breast cancer. The growth factor receptor tyrosine kinase encoded by the protooncogene HER2 (c-erbB-2/neu) represents an attractive target for therapy because its amplification and overexpression occur early in the development of breast cancer, resulting in aggressive disease resistant to systemic therapy. Several anti-HER2 antibodies, including a humanized monoclonal (rhuMAbHER2; Genentech, Inc.) showing clinical promise in patients with metastatic and chemotherapy-resistant HER2-positive breast cancer, are known to produce in vivo tumoristatic effects that become tumoricidal when administered in synergistic combination with either doxorubicin, cisplatin, or taxol. This project will proceed with the development of a first-generation tumoricidal immunoliposomal agent (l-L-dox) composed of humanized anti- HER2 monoclonal fragments, rhuMAbHER-Fab', expressed on the surface of liposomes (conventional or sterically stabilized) encapsulated with doxorubicin. Progress to date indicates that some but not all I-L-dox formulations exhibit in vitro membrane binding, intracellular uptake, and toxicity that is specific to HER2-positive breast cancer cells. Furthermore, preliminary in vivo studies suggest that when these I-L-dox formulations are administered i.v. or i.p. into SCID mice bearing HER2- positive BT-474 breast tumor xenografts, the immunoliposomes and their contents accumulate within the tumors and produce enhanced antitumor effects relative to treatment with free doxorubicin. Over the next project interval, emphasis will be given to the completion of in vivo preclinical studies and the initiation of a Phase-I clinical trial (conducted by the SPORE's Clinical Core) using the most effective preclinical formulation of I-L-dox. Collaborations have been established to facilitate the translational development toward ND approval of I-L-dox and to complete the pharmacokinetic, toxicologic, and efficacy testing necessary to demonstrate that tumor-targeting by anti-HER2 immunoliposomes enhances the therapeutic index of an established breast cancer agent like doxorubicin. With confirmatory in vivo evidence for the targeting advantages of I-L- dox, increased attention will be given to the encapsulation of a Pt(II) or taxane derivative to initiate preclinical development of an additional tumoricidal anti-HER2 immunoliposomal agent. Furthermore, feasibility testing will begin on a second-generation of targeted therapeutics designed to exploit the novel property that anti-HER2 immunoliposomes (unlike untargeted conventional or sterically stabilized Iiposomes) deliver their contents beyond the coated pit-lysosome pathway and into the cytoplasm of HER2-positive breast cancer cells. This unique intracellular delivery potential of anti-HER2 immunoliposomes makes possible future development of alternative (non-chemotherapy-based) treatment approaches such as HER2-targeted breast cancer gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
3P50CA058207-08S5
Application #
6664485
Study Section
Project Start
2002-08-01
Project End
2002-11-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
8
Fiscal Year
2002
Total Cost
$206,819
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Rice, Megan S; Tamimi, Rulla M; Bertrand, Kimberly A et al. (2018) Does mammographic density mediate risk factor associations with breast cancer? An analysis by tumor characteristics. Breast Cancer Res Treat 170:129-141
Zhou, Yu; Zou, Hao; Yau, Christina et al. (2018) Discovery of internalizing antibodies to basal breast cancer cells. Protein Eng Des Sel 31:17-28
Campbell, Jeffrey I; Yau, Christina; Krass, Polina et al. (2017) Comparison of residual cancer burden, American Joint Committee on Cancer staging and pathologic complete response in breast cancer after neoadjuvant chemotherapy: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res Treat 165:181-191
Campbell, Michael J; Baehner, Frederick; O'Meara, Tess et al. (2017) Characterizing the immune microenvironment in high-risk ductal carcinoma in situ of the breast. Breast Cancer Res Treat 161:17-28
Bolan, Patrick J; Kim, Eunhee; Herman, Benjamin A et al. (2017) MR spectroscopy of breast cancer for assessing early treatment response: Results from the ACRIN 6657 MRS trial. J Magn Reson Imaging 46:290-302
Olow, Aleksandra; Chen, Zhongzhong; Niedner, R Hannes et al. (2016) An Atlas of the Human Kinome Reveals the Mutational Landscape Underlying Dysregulated Phosphorylation Cascades in Cancer. Cancer Res 76:1733-45
Takai, Ken; Le, Annie; Weaver, Valerie M et al. (2016) Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget 7:82889-82901
Hu, Zhi; Mao, Jian-Hua; Curtis, Christina et al. (2016) Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer. Breast Cancer Res 18:70
Malkov, Serghei; Shepherd, John A; Scott, Christopher G et al. (2016) Mammographic texture and risk of breast cancer by tumor type and estrogen receptor status. Breast Cancer Res 18:122
Gu, Shenda; Hu, Zhi; Ngamcherdtrakul, Worapol et al. (2016) Therapeutic siRNA for drug-resistant HER2-positive breast cancer. Oncotarget 7:14727-41

Showing the most recent 10 out of 339 publications