A recent study led by John Hopkins Medicine has found that combining two ‘old therapies’ can offer a surprising new purpose for fighting pediatric brain tumors.
Medulloblastoma
Medulloblastoma is the most common malignant brain tumor in children. It grows quickly and typically requires surgery, radiation, and chemotherapy.
A potential new therapy combines copper ions with disulfiram (DSF‑Cu++). It may work alone or alongside standard treatments.
“Disulfiram has been used for nearly 70 years to treat chronic alcoholism,” said Betty Tyler of Johns Hopkins. “It shows great promise as an anticancer agent, especially when complexed with metals like copper.”
Finding targets
The team tested DSF‑Cu++ and identified our key findings.
• First: DSF‑Cu++ blocks two pathways medulloblastoma cells use to remove proteins that threaten their survival. When those pathways shut down, the proteins accumulate and kill tumor cells, allowing the immune system to clear them.
• Second: Even brief exposure to DSF‑Cu++ kills medulloblastoma cells and reduces the cancer stem cells that generate them.
• Third: DSF‑Cu++ prevents cancer cells from recovering. It blocks their ability to repair DNA damage, increasing the treatment’s cell‑killing effect.
• Lastly: DSF‑Cu++ significantly increased survival in mice implanted with two medulloblastoma subtypes.
Cancer cells are heterogeneous, different cancer patients with the same origin of cancer had a distinct antigenic phenotype. Observation showed that heterogeneity has also been observed within breast cancers using individual monoclonal reagents. Intense staining of some cells was observed, whereas little, if any, binding could be detected to other cells within the some tumor nodule. On the other hand , cancer cells do not have stable genotype and phenotype. In normal cells, different set of proto-oncogens play important roles to regulate cell survival, development and functioning. The potential of one oncogene in primary tumor provides the aberrant signals to trigger more mutation of genes leading to develop metastatic phenotype. Thus, patients with high levels of growth dominant cancer cells have short survival rates to develop metastasis faster than patients with low levels of growth advantage cancer cells. In primary tumor, cancer cells depend on tumor microenvironment to supply growth factors and support their growth whereas metastatic phenotypes are growth independent, they have ability to release variety of growth factors to support their autocrine growth. In addition, most metastatic cells can easily develop chemo-resistance phenotype after patients undergoing chemotherapy. Evidence proved that, some human cancers can activate immune cells to release immunosuppressive factors and inhibit proliferation of lymphoid cells, this is an example of how cancers might escape or disarm the immune system.
Clinical investigation showed that Madullablastoma can be effectively blocked their survival pathways, suppressed cancer stem cells and inhibited them from repairing DNA damage by DSF-Cu2+ to prolong survival rates of cancer patients. However, cancer cells are heterogeneous, they do not have stable genotype and phenotype. Although majority of cancer cells can be effectively respond to DSF-Cu2+, a minor population of cancer cells can escape and mutate into resistance phenotypes. This resistance phenotypes which has growth advantage ability can become more aggressive leading to high risk of incidents in cancer relapse or recurrence of cancer patients. Sadly, humans immune system do not provide additional protection to the brain due to inability of immune system cannot respond in usual way to infection, injury or tumor in the brain and spinal cord. The blood brain barrier prevent immune cells from entering and leaving the brain.