Disulfiram/Copper Combination In The Treatment of Newly Diagnosed Glioblastoma Multiform

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.

Conditions

• Glioblastoma Multiforme

Interventions

DRUG

Temozolomide

already included

DRUG

Disulfiram

already included

DRUG

Copper

already included

Sponsors & Collaborators

• University of Ioannina

  collaborator OTHER

• University of Eastern Finland

  collaborator OTHER

• University of Ulm

  collaborator OTHER

• Olympion Medical Center

  lead OTHER

Principal Investigators

• Petros N Karamanakos, MD, PhD · Department of Neurosurgery, Olympion Medical Center, 26443, Patras, GREECE

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2027-01-31

Primary Completion

2029-01-31

Completion

2030-01-31

Countries

• Greece

Study Locations