TUBITAK Project, 2013 - 2015
Inhibition of the proteasome (a highly abundant enzymatic complex responsible for intracellular protein turnover) is an effective
anti-cancer therapeutic approach. Among these inhibitors, the first-in-class agent bortezomib has been demonstrated and
actively used in several cancer types in the clinic. On the other hand, alternative inhibitors to bortezomib has been developed
because of its important side effects including neuropathy and the developing resistance against it in some of the cancer types
especially in solid tumors. Carfilzomib, as quite new in the clinic, shows less side effects due to its target-driven effects.
Cancer cells are caused to undergo different types of cell death due to inhibition of different pathways via proteasome inhibition.
Firstly, apoptotic death is aimed but cells may develop resistance because of several degradation mechanisms. Autophagy,
which is higly focused in the literature, is one of these mechanisms. Autophagy has been investigated as macro-, micro- and
chaperone mediated autophagy. There are many studies with autophagy inhibitors showing the decrease in the resistance
development against proteasome inhibition. On the other hand, there are too few work on the role of chaperone mediated
autophagy in this resistance. Therefore this study has been designed to highlight this mechanism and contribute to literature.
Breast cancer is the most frequent reason for the cancer related death in women. Estrogen receptors particularly has important
role in the development and the progression of breast carcinoma. Estrogen receptor is an important prognostic and therapeutic
biomarker in the 75% of breast tumors. Although the tumor growth inducing effects of estrogen has been tried to be blocked by
the therapeutics, 50% of the breast cancer patients do not reply to this treatment after a while and develope de-novo
resistance. There are many studies showing the effect of proteasomal degradation in this developing resistance. Additionally,
ErbB2/HER2 receptor is also a validated target in the clinical therapy of breast cancer and it is known to be degraded by the
proteasome following its ubiquitination.
The aim of this project is to compare the effects of second generation proteasome inhibitor carfilzomib with the clinically used
proteasome inhibitor bortezomib with the combination of chaperone mediated autophagy inhibition. Estrogen receptor
negative/positive and HER2 (human epidermal growth factor) negative/positive cells will be used in the study. There is no
detailed study regarding the use of carfilzomib in breast cancer. On the other hand, the combinational usage of carfilzomib and
bortezomib will be tested to overcome the side effects of bortezomib in the patients. Also usage of carfilzomib instead of
bortezomib and decreased dose of bortezomib in combination with carfilzomib will be evaluated. As another important
approach, proteasome inhibitors and chaperone mediated autophagy inhibition will be tested in combination regarding the cell
death. In this direction, there is no detailed research paper. In this aspect, this study will be extremely unique. On the other
hand, I believe that the results will highlight the future work in my career and will be a source for many new studies.
Keywords: Proteasome, Bortezomib, Carfilzomib, Chaperone Mediated Autophagy, Breast Cancer