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        Hunt for the Cure

        The Biotech Startup Taking on Pancreatic Cancer by Throwing Out the Rules

        CANCER-FIGHTING SIDEKICK

        Harvard researchers discovered a pathway that might offer a new way to fight cancer drug resistance.

        Nathaniel Brooks Horwitz

        Updated Feb. 26, 2018 10:41AM ET / Published Feb. 21, 2018 5:18AM ET 

        Photo Illustration by The Daily Beast

        Despite better diagnostics and new drugs, cancer continues to kill 8 million people every year. While certain cancers are caught early and treated effectively, many others go undetected and—once discovered—resist every available treatment.

        The ability of these cancers to resist our current arsenal of drugs is, in many ways, the final frontier of the war on cancer. In December, I left my senior year at Harvard to launch Nivien Therapeutics, a biotechnology startup that is taking a novel approach to fighting these cancers based on exciting new research from Harvard Medical School.

        The discoveries at Harvard focused on pancreatic cancer, one of the worst treatment-resistant cancers: By the time you show symptoms (jaundice, nausea, abdominal pain), it’s almost always too late. Pancreatic cancer will kill a projected 44,000 people in the U.S. during 2018. Only one in 20 patients are alive five years after diagnosis because the standard chemotherapy adds just five weeks to average post-diagnosis survival, which is about 6 months.

        While no one with inoperable pancreatic cancer survives, a rare subset of patients live years longer than the 6-month average. Last May, scientists at Harvard Medical School published groundbreaking research that explains this phenomenon and enables a new strategy to defeat treatment-resistant cancer.

        The team at Harvard, led by cell biologist Marc Kirschner, discovered that a biochemical system called Hippo plays a previously-unknown-but-crucial role in how well cancer patients respond to treatment. In normal cells, Hippo is a biological switch that regulates organ growth during early development. In cancerous cells, Hippo acts like a molecular traffic cop, controlling a suite of proteins such as CDA and ABCG2 that cancer uses to metabolize and remove chemo from inside the cell, rendering it ineffective and poisoning healthy surrounding tissue.

        When Hippo is active, amounts of these proteins are elevated as much as 10-fold their normal levels and chemo doesn’t work. When Hippo is inactive, levels of these proteins are low and chemo kills tumors more effectively. The patients surviving three or even four times longer than average, it turns out, had a rare, naturally-occurring mutation that inactivated Hippo.

        I learned about Kirschner’s research before publication while working on my undergraduate thesis in molecular biology with another lab at Harvard Medical School.

        Alongside a fellow student-scientist, Nikita Shah, we took Kirschner’s work a step further. If chemo killed cancer more effectively when Hippo was inactive, we asked, what if we created the first drugs that disrupted Hippo? Instead of targeting cancer directly, these drugs would be a sidekick, enabling chemo to work in cancers like pancreatic cancer that currently resist all available treatments.

        After we began working on drugs to block Hippo activity, another academic group showed that blocking Hippo also completely prevents tumor growth in mice by reversing cancer’s ability to suppress a signal required for the immune system to target and destroy malignant cells. While prior scientists and companies have developed add-on therapies for other diseases, Hippo is the first target in cancer shown to play an important role in resistance to both chemo and the immune system. By disrupting Hippo, our drugs could be the first to simultaneously enhance chemo effectiveness and activate the body’s natural immune defense against cancer.

        With this data, Nikita and I raised venture capital, filed patents, recruited Kirschner to lead Nivien’s scientific advisory board and launched preclinical trials in pancreatic cancer. There’s a lot of challenging work ahead, but we aim to reach the clinic in three years. It’s starting to get competitive: two other companies have now begun developing their own drugs to target Hippo.

        Even in the best case scenario, Nivien's drugs will not directly cure cancer. What they could do is enable other therapies that work well in some cancers to become cures in cancers where we still have no good options. By combining our drugs with existing treatments, we hope to help win the war on cancer.

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