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Herding cancer cells to their death



By a News Reporter-Staff News Editor at Cancer Gene Therapy Week -- An advanced tumor is a complex ecosystem. Though derived from a single cell, it evolves as it grows until it contains several subspecies of cells that vary dramatically in their genetic traits and behaviors. This cellular heterogeneity is what makes advanced tumors so difficult to treat. Publishing their findings in today's online issue of Cancer Cell, an international team of scientists led jointly by Professors Colin Goding from the Ludwig Institute for Cancer Research who is based at the University of Oxford and Jose Neptuno Rodriguez-Lopez from the University of Murcia, Spain describe a therapeutic strategy that manipulates a mechanism driving that heterogeneity to treat advanced melanoma. Their preclinical studies show that the strategy, which employs a new drug-like molecule in combination with an existing chemotherapy, is highly specific to melanoma cells and effective against tumors that resist all other therapies (see also Melanomas).


To bypass such resistance, the researchers developed a strategy that essentially pushes subtypes of melanoma cells that are not dividing-and are therefore not susceptible to chemotherapy-to become vulnerable to a shrewdly targeted drug.

To develop their therapy, the scientists first screened a variety of molecules to find one that boosts the expression of MITF, a master gene that, at high levels, pushes melanoma cells to proliferate and to express a protein known as Tyrosinase that fuels pigment production. The scientists found that methotrexate-a drug currently used to treat autoimmune diseases and some other cancers, though not melanoma-had precisely that effect. The Spanish team then synthesized a novel molecule called TMECG that is lethal only when it is chemically modified by Tyrosinase. When activated by Tyrosinase, TMECG disrupts the protein machinery of cell division and so poisons cells that are multiplying rapidly.

"The beauty of the therapy," says Professor Jose Neptuno Rodriguez-Lopez, PhD, leader of the Spanish team at the University of Murcia, is that "TMECG is activated by a process that is specific to pigmented cells but not other cells. So, first the methotrexate sensitizes melanoma cells to the effects of TMECG. Then that molecule gets processed and activated by Tyrosinase to form an active compound that kills rapidly dividing cells. Even better, the methotrexate then delivers a second blow to melanoma cells by prompting them to commit suicide through a very specific mechanism."



"Think about what you ideally want from a cancer therapy," says Professor Colin Goding, PhD, Member of the Ludwig Institute for Cancer Research who is based at the University of Oxford. "You want a therapy that addresses cancer cell heterogeneity, that eradicates the tendency of cancer cells to become invasive, that works on cells that are resistant to other therapies and that targets only the cancer cells and not any others. I think we've ticked all those boxes."



Keywords for this news article include: Drugs, Genetics, Oncology, Melanomas, Treatment, Chemotherapy, Cancer Gene Therapy, Ludwig Institute for Cancer Research.


