In the United States, about 1 in 8 women in the Unites States will develop invasive breast cancer over the course of her lifetime. Triple negative breast cancer (TNBC) accounts for ~15-20% of all breast cancer incidences. They are highly aggressive, malignant, and with the worst prognosis among all types of breast cancers. Despite the fact that targeted therapies have become the first-line treatment for many different types of cancers, no targeted therapy is now available for TNBC. Chemotherapy is the current mainstay of treatment for TNBC. Besides severe side effects associated with chemotherapies, the selection pressure induced by nonspecific chemo drugs and development of drug resistance can promote metastasis. A targeted therapy will revolutionize treatment regimens for TNBC patient by replacing interventions that have life-threatening toxicities. Among all genetic alternations, the tumor suppressor TP53 gene (encoding p53) is inactivated by mutation or deletion in 60-88% of TNBCs. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment. In 67.2% of TNBCs containing partial TP53 deletion, we identified a drug target gene, POLR2A that is co-deleted with TP53. Inhibiting POLR2A with small compound drug ?-Amanitin selectively inhibits proliferation, survival and tumorigenic potential of TNBC cells with partial loss of the TP53 gene. Previous clinical applications of ?-Amanitin have been limited due to its liver toxicity. We found that ?-Amanitin-based antibody drug conjugates (ADCs) are highly effective therapeutic agents with significantly reduced toxicity. In this proposal, we will use Cetuximab, a monoclonal antibody specific for TNBCs, to develop ?-Amanitin-based ADCs. We propose that ?-Amanitin-conjugated Cetuximab is a specific and effective drug for TNBC treatment. Successful development of this project will revolutionize treatment regimens for TNBC patient by replacing interventions that have life-threatening toxicities with novel antibody- drug conjugates that are safe and effective.

Public Health Relevance

Triple negative breast cancer (TNBC) accounts for ~15-20% of all breast cancer incidences. Despite the fact that targeted therapies have become the first-line treatment for many different types of cancers, no targeted therapy is now available for TNBC. In this project, we will revolutionize treatment regimens for TNBC patients by replacing interventions that have life-threatening toxicities with novel antibody-drug conjugates that are safe and effective.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA213535-01A1
Application #
9387634
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Fu, Yali
Project Start
2017-06-13
Project End
2019-05-31
Budget Start
2017-06-13
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$185,933
Indirect Cost
$43,584
Name
Baylor College of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Li, Yujing; Liu, Yunhua; Xu, Hanchen et al. (2018) Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II. Nat Commun 9:4394
Jiang, Xiqian; Wang, Lingfei; Carroll, Shaina L et al. (2018) Challenges and Opportunities for Small-Molecule Fluorescent Probes in Redox Biology Applications. Antioxid Redox Signal 29:518-540
Rothmiller, Simone; Schröder, Sarah; Strobelt, Romano et al. (2018) Sulfur mustard resistant keratinocytes obtained elevated glutathione levels and other changes in the antioxidative defense mechanism. Toxicol Lett 293:51-61
Gates, Leah A; Gu, Guowei; Chen, Yue et al. (2018) Proteomic profiling identifies key coactivators utilized by mutant ER? proteins as potential new therapeutic targets. Oncogene 37:4581-4598
Jiang, Xiqian; Zhang, Chengwei; Chen, Jianwei et al. (2018) Quantitative Real-Time Imaging of Glutathione with Sub-Cellular Resolution. Antioxid Redox Signal :
Chen, Jianwei; Jiang, Xiqian; Zhang, Chengwei et al. (2017) Reversible Reaction-Based Fluorescent Probe for Real-Time Imaging of Glutathione Dynamics in Mitochondria. ACS Sens 2:1257-1261
Jiang, Xiqian; Chen, Jianwei; Baji?, Aleksandar et al. (2017) Quantitative real-time imaging of glutathione. Nat Commun 8:16087