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A recent study led by John Hopkins Medicine has found that combining two ‘old therapies’ can offer a surprising new purpose – fighting Medulloblastoma, the most common malignant brain tumor in children. The fast-growing cancerous tumor originates in the brain or spinal cord and has traditionally been treated with surgery to remove the tumor followed by radiation and chemotherapy.
The prospective therapy which comprises of copper ions and Disulfiram (DSF-Cu++), paves the way toward a successful treatment that can be used alone or in conjunction with traditional therapy. “Disulfiram, [is] a medication that’s been used for nearly 70 years to treat chronic alcoholism,” explains Betty Tyler, the study’s senior author and associate professor of neurosurgery at Johns Hopkins. “It has great promise being ‘repurposed’ as an anticancer agent, especially when it is complexed with metal ions such as copper.”
The researchers tested the anticancer activity of DSF-Cu++ and, in their attempts to define what it targeted at the molecular level to achieve these effects, were able to highlight four key findings.
First, the team of researchers found that DSF-Cu++ blocks two biological pathways in medulloblastomas that the cancer cells need in order to remove proteins threatening their survival. With these pathways blocked, these proteins accumulate in the tumor and cause the malignant cells to die, leaving them to eventually be removed by the body’s own immune system.
Second, the researchers discovered that just a few hours of exposure to DSF-Cu++ not only kills medulloblastoma cells but can also effectively reduce the cancer stem cells responsible for their creation.
The third finding in the study revealed that DSF-CU++ keeps cancer cells from recovering. By impairing the ability of medulloblastoma cells to repair the damage done to their DNA, DSF-CU++ enhances the cell killing power of the treatment.
Lastly, the promising combo of DSF-CU++ demonstrated significant increases in prolonging survival days of mice whose brains were implanted with two subtypes of medulloblastoma.
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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.