Trastuzumab has proven to be a very effective therapy for HER2-positive breast cancer, but de novo or acquired resistance limits its long-term value. New observations from our laboratory suggest several hypotheses on the mechanisms of resistance to trastuzumab and other therapies targeting the HER network. First, our results suggest that this resistance might stem from incomplete blockade of the signals generated from the various HER-family dimer pairs in the network input layer. Using a limited number of HER2- overexpressing xenograft models we have found that combined drug therapies designed to more completely block these heterodimers can overcome resistance to single agents and are even capable of eradicating many of these tumors in mice. Our preclinical models and preliminary patient data also suggest alternative mechanisms for resistance to HER-directed therapy that involve the estrogen receptor in some tumors and the MUC4 mucins in others. Here we propose a series of preclinical studies and an early phase clinical trial to begin to test these hypotheses. Specifically we will: 1) Confirm our preliminary data that resistance to single-agent HER targeted therapy can be overcome by various combinations of trastuzumab, lapatinib, and pertuzumab, designed to more completely block signaling from the HER network input layer, in a large panel of HER2-amplified breast cancer cell lines, and to identify and establish models resistant to these single and combined antiHER2 drugs for later studies;2) Determine using these various preclinical HER2-positive models whether upregulation of ER or ER signaling to an alternative survival pathway can be induced by HER blockade as a resistance mechanism, and whether simultaneous targeting of ER and HER2 is then necessary for optimal treatment;3) Investigate whether upregulation of MUC4 causes resistance to HER targeted therapy in our preclinical in vivo model system, thereby providing a new potential diagnostic and treatment target to investigate in human samples;4) Lead a multi-institutional phase 2 neoadjuvant clinical trial of lapatinib combined with trastuzumab, with serial tissue sampling to assess molecular mechanisms of action and resistance, in order to begin to translate our exciting preclinical findings to patients. This work will facilitate new strategies to circumvent resistance to HER-targeted therapy for improved patient survival.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA058183-18
Application #
8374575
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
2013-05-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
18
Fiscal Year
2012
Total Cost
$226,364
Indirect Cost
$72,398
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Yu, L; Liang, Y; Cao, X et al. (2017) Identification of MYST3 as a novel epigenetic activator of ER? frequently amplified in breast cancer. Oncogene 36:2910-2918
Holloway, Kimberly R; Sinha, Vidya C; Bu, Wen et al. (2016) Targeting Oncogenes into a Defined Subset of Mammary Cells Demonstrates That the Initiating Oncogenic Mutation Defines the Resulting Tumor Phenotype. Int J Biol Sci 12:381-8
Malorni, Luca; Giuliano, Mario; Migliaccio, Ilenia et al. (2016) Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance. Mol Cancer Res 14:470-81
Fu, Xiaoyong; Jeselsohn, Rinath; Pereira, Resel et al. (2016) FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer. Proc Natl Acad Sci U S A 113:E6600-E6609
Erdem, Cemal; Nagle, Alison M; Casa, Angelo J et al. (2016) Proteomic Screening and Lasso Regression Reveal Differential Signaling in Insulin and Insulin-like Growth Factor I (IGF1) Pathways. Mol Cell Proteomics 15:3045-57
Chaluvally-Raghavan, Pradeep; Jeong, Kang Jin; Pradeep, Sunila et al. (2016) Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer. Cell Rep 15:1493-1504
Dobrolecki, Lacey E; Airhart, Susie D; Alferez, Denis G et al. (2016) Patient-derived xenograft (PDX) models in basic and translational breast cancer research. Cancer Metastasis Rev 35:547-573
Shi, Aiping; Dong, Jie; Hilsenbeck, Susan et al. (2015) The Status of STAT3 and STAT5 in Human Breast Atypical Ductal Hyperplasia. PLoS One 10:e0132214
Canfield, Kaleigh; Li, Jiaqi; Wilkins, Owen M et al. (2015) Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells. Cell Cycle 14:648-55
Sine, Jessica; Urban, Cordula; Thayer, Derek et al. (2015) Photo activation of HPPH encapsulated in ""Pocket"" liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts. Int J Nanomedicine 10:125-45

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