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Ras Matazz

The saying “fool me once, shame on you; fool me twice, shame on me!” could be proposed as applying to drug discovery targeting the oncogene Ras to treat cancer, but it would be more like “fool me all 100 times and all in a row, shame on everybody.” Ever since the Ras gene was discovered as a necessary and sufficient transferable gene in oncogenic viruses that turned human epithelial cells cancerous and grew tumors in mice, cancer scientists have been gaga over Ras. Their enthusiasm only rose when it was discovered that the human version of the viral oncogene was mutated and overactive or overexpressed in over 90% of incurable metastatic cancers such as pancreatic cancer and others. Overall, Ras is probably the most mutated oncogene in some of the most prevalent and incurable cancers, which are those that arise from epithelial or body surface tissues such as breast, colon/gut, pancreas, lung and skin (carcinomas). You can see why it is maybe the most prominent drug target in molecular cancer research history.

But a little problem occurred on the way to the clinic. No one could ever prove that Ras was causing the target carcinomas, despite its strong statistical association. And, lo and behold, every drug discovery and development effort targeting Ras has failed expensively and miserably. As usual for the dogmatists the lay public has mistaken for scientists, the excuses came fast and thick: ‘There are different isoforms!”, “The affinity of Ras for its natural substrate is too high for competitive inhibition!”, “We can target it with THIS creative reach-around!” Fail. Fail. Fail. But not a whisper about giving up on Ras as a drug target in cancer.

This isn’t the only elephant in the room in biomedical science today. You need only look at medical problems that have remained unsolved for 20+ years despite tons of funding and then look at the leading theories to find them: HIV vaccine and cure (broadly neutralizing antibodies), Cancer (Ras), Alzheimers (plaques and fibrils), Opioid abuse (opioid receptor blockers), gene therapy (everything) . . . You name it, there’s a waste of money and energy going on and the correct path to the answer being ignored or obfuscated. Maybe the better quote is “they have eyes, but they do not see.” Well, they won’t “see” until companies and scientists stop making/winning tons of money for incremental advances.

Or maybe there is redemption in the form of new or maturing technologies! Certainly, the travesty that was gene therapy for the last 30 years finally got their weak belated “I told you so. Well, maybe its finally Ras' time. This week marks the one year anniversary of Amgen starting clinical trials with their covalent inhibitor targeting the Ras Glycine12-to-Cysteine (G12C) mutation. Promising Phase I results were already reported. The new technology in this case is covalent inhibition, which seeks to have the drug make an actual physical bond with the target, thereby irreversibly inhibiting it. There are several benefits to this approach, not the least of which is that Ras’ incredibly high affinity for its substrate nevertheless cannot compete with an irreversible covalent bond. This technology has a promising track record, although there are significant concerns about specificity, which is of particular interest to GeneCentrix R&D. Still, the developers recognized that the mutation to a cysteine was an opportunity, as cysteine is the most common target of covalent drug technology. And, lo and behold, the drug is performing well so far and may be a flower growing in the historic wasteland of Ras-targeted drug discovery and development.

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