Targeted use of camptothecin as a specific pharmacological agent for the treatment of triple negative breast cancer

• Main Author: Shah, Ankur K.
• Language: en_US
• Published: Boston University 2015
• Online Access: https://hdl.handle.net/2144/12846

Thesis (Ph.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at [e-mail]. Thank you. === Triple negative breast cancer (TNBC) accounts for 15 to 20% of all new breast cancers diagnosed in the United States. This figure increases to greater than 30% in minority populations. Currently, targeted therapeutic options are not available for TNBC, thus resulting in the use of general chemotherapeutics and lower survival rates for those afflicted with the disease. Camptothecin and its structural analogues (CPTs) are specific, reversible inhibitors of topoisomerase I (topoi), and have recently shown promise in the treatment ofTNBC, with a response rate of nearly 40%. CPTs are targeted drugs, but only effective within a subset of cancer patient populations. In order to understand the regulation of topoi upon CPT administration and elucidate the resistance mechanism, we isolated a topoi interacting protein complex. We further investigated the role of proteins associated with topoi, and have determined that: (I) following CPT administration, topoi is phosphorylated at serine 10 (S10) by the DNA-PK/Ku-70/Ku-80 complex, (II) S10 phosphorylation ensures the ubiquitination oftopoi by the BRCA1/BARD1 heterodimer, (Ill) topoi is subsequently degraded by the ubiquitin-proteasomal pathway (UPP), and (IV) the rate oftopoi degradation determines the cellular response to CPT. In summary, BRCA1/BARD1 E3 ligase activity leads to the ubiquitination and rapid degradation of to poi, conferring cellular resistance to CPT. Phosphorylation levels of S10 on topol correlates to the rate of topol degradation, thus can be used as a predictive biomarker for CPT response. Taken together, CPT can be an effective treatment for a subset of the TNBC patient population.