Disulfiram/Copper Combination In The Treatment of Newly Diagnosed Glioblastoma Multiform
Status:
Unknown status
Trial end date:
2020-01-01
Target enrollment:
Participant gender:
Summary
Glioblastoma multiform (GBM) is the most common malignant primary brain tumor in adults.
Despite maximal treatment tumor relapse occurs regularly accompanied by unfavourable
prognosis. Among other reasons, it is believed that this could be in part due to the
existence of the so-called tumor stem cells (TSCs), a cellular subfraction within GBM which
escape therapy by being highly resistant to irradiation and chemotherapy and thus
constituting the source of tumor recurrence.
GBM, like many other cancers, show a sub-population of aldehyde dehydrogenase (ALDH)
overexpressing TSCs. More specifically, ALDH1A1, a cytoplasmatic isoform of ALDH, proved to
be a novel stem cell marker in human GBM. In addition, ALDH1A1 has been shown to be a
mediator for resistance of GBM to temozolomide (TMZ) and a reliable predictor of clinical
outcome; prognosis of patients with a high level of ALDH1A1 expression was poor compared with
that of patients with low levels. Consequently, ALDH1A1 may serve as a potential target to
improve treatment of human GBM through inhibition of the enzyme.
Disulfiram (DSF) has been used for more than sixty years in the treatment of chronic
alcoholism because of the unpleasant symptoms it provokes after ethanol intake. The
underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to
inhibition of the liver ALDHs. Actually, DSF is a strong inhibitor of ALDH1A1 and relatively
non-toxic at therapeutic (for chronic alcoholism) doses that can penetrate the blood-brain
barrier. In addition, DSF has been shown to be cytotoxic on GBM stem-like cells, inhibiting
the growth of TMZ resistant GBM cells and blocking self-renewal by ~100% , while it has been
identified as an inhibitor of human GBM stem cells in high-throughput chemical screens.
Interestingly, a number of these actions were copper-dependent.
In the current Phase II clinical trial, DSF/copper combination will be tested as an
adjunctive and concurrent chemotherapy in the treatment of newly diagnosed GBM. According to
our hypothesis, initiation of DSF chemotherapy after the resection of the tumor and before
the introduction of the standard radio-chemotherapy will inhibit ALDH1A1 of GBM TSCs making
them more susceptible to radio-chemotherapy and possibly reducing the recurrence rate of GBM.
On the other hand, the addition of copper will probably enhance the cytotoxic effects of DSF
possibly through augmentation of its pro-apoptotic and proteasomal inhibitory actions.
Phase:
Phase 2
Details
Lead Sponsor:
Olympion Medical Center
Collaborators:
University of Eastern Finland University of Ioannina University of Ulm