The goal of UCSF Breast Cancer SPORE Project #4 is to develop and assess the translational potential ofagents we have developed that force telomerase interference in breast cancer. This Project focuses onexploitation for clinical use of a new strategy: to turn the action of active telomerase against the breastcancer cells. In this current funding cycle, we have successfully demonstrated that a low threshold ofexpression of mutant-template telomerase RNA (MT-hTer) genes in human breast cancer cells is sufficientfor a potent killing and growth inhibitory effect on these cells. The telomeres that result from MT-hTer actionare 'toxic' to cells, inducing a robust apoptotic response. Additionally, during the previous SPORE fundingperiod, new science arising from the Blackburn laboratory's research on telomerase also led to two]unanticipated discoveries: first, that simply decreasing the endogenous telomerase level by ribozyme or RNAtargeting methods rapidly decreased cancer potential. Specifically, we found that lowering overall telomerasediminishes the metastatic potential of cancer cells in vivo, and rapidly inhibited the growth of breast and othercancer cells in vitro. Second, cell death induced by MT-hTer expression is dominant and does not require thep53 or pRb checkpoint pathways. Based on these findings, we then showed that combining the expressionof MT-hTer with small interfering RNA directed against the endogenous WT-hTER of cancer cellssynergistically increases the potency of the MT-hTer effects in killing cancer cells. The following SpecificAims, which have the goal of bringing this work to the clinic, are to: #1 Further test and characterize thepreviously developed immunoliposome ('ILS') constituted with Her2-targeting antibody developed inSPORE Project 3 containing the MT-hTer/anti-hTER siRNA construct ('MT-Rx' agent). In order to monitorMT-Rx efficacy we will use relevant biomarkers of response to the agent, suitable for early stage clinicatrials. #2 Identify telomere/telomerase-based biomarker patterns predictive of apoptotic response tanticancer treatments and to specific MT-Rx therapy. We will identify the subset(s) of breast cancers that wilbe most responsive to existing therapies and to 'MT-Rx' using (i) a panel of 60 breast cancer cell linegrouped by genomic and expression profiling, telomere maintenance status and other clinically relevancharacteristics and (ii) patient-derived primary breast cancer cells, including stem/progenitor cell lines; thatargets the most sensitive patient subpopulation, as identified. #3. Validate and optimize the assays fobiomarkers of telomerase and telomere status on tumor and biopsy specimens, with the goal of validating]these assays per CLIA regulations in a CLIA certified laboratory such that the results can be used clinically.)Toward translation of MT-Rx, we will finalize the product configuration, perform initial manufacturing sealup, and evaluate initial toxicology targeted systemic delivery of MT-Rx agent in rodent models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA058207-14
Application #
7384761
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (O1))
Project Start
2007-12-01
Project End
2012-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
14
Fiscal Year
2008
Total Cost
$143,984
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
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

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