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Closing In on the Elusive
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CLOSING IN ON THE ELUSIVEINSIDE THE RACE AGAINST CANCER

Dr. Gregory Friberg is a former clinician who went into oncology when cancer was considered, he says, “a death sentence.” Today, as vice president for global development at Amgen, Friberg is part of a team closing in on once unthinkable gains against cancer, halting tumors long seen as perfectly weaponized against the human body.

“I pinch myself almost every day,” says P.K. Morrow, vice president of Global Development at Amgen, “because I can’t believe we are sitting where we are, truly on the cusp of a potential cure for certain cancers.”

The subject of almost four decades of research, the RAS gene family are the most frequently mutated oncogenes in human cancers.1, 2 Within this family, KRAS is the most prevalent variant and is particularly common in solid tumors.2 A specific mutation known as KRAS G12C is found in approximately 13% of non-small cell lung cancers, three to five percent of colorectal cancers and one to two percent of numerous other solid tumors.3  Although scientists have understood for decades how KRAS causes cancer, they’ve been unable to do anything about it. Morrow recalls attending a conference only two years ago at which a colleague put up a slide showing all available targeted treatments.

“It was blank,” she says.

The cancers caused by mutations in KRAS are difficult to treat because the KRAS molecule is smooth and spherical, almost like a billiard ball, preventing other molecules from latching on4 – including those of cancer drugs. Among scientists and doctors, KRAS was considered an elusive target.

“Oncology has to be built upon the basis of hope,” Morrow says. Yet when it came to KRAS, pessimism ran unusually deep. Some scientists thought “we might never really get to” an answer, according to Friberg.

Despite the seeming intractability of cancers caused by KRAS, the company had focused resources on precisely those tumors, in part because of a conviction, according to Morrow, that “we didn’t really understand the protein well enough.” In other words, while the intransigence of KRAS seemed fundamental to its very nature, Amgen pursued a strategy predicated on rethinking assumptions not just about KRAS but about the immune system itself.

“One thing that we really emphasize at Amgen is collaboration with academics who can help us accelerate scientific discovery, as well as potentially further treatments,” says Morrow. “How can we fundamentally change the treatment of cancer?”

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Starting in 2013, scientists began reporting progress – that the molecule indeed had surface features that could be latched onto, but only during brief moments when it shifted from active to inactive.2

Friberg calls this part of an intentional company strategy. “We want to focus as much of our attention on this finding as possible,” he says. “Speaking as a former clinician, cancer patients are waiting.”

Traditionally, the only ways to treat cancer have been surgery, radiation, and chemotherapy. Such treatments attempt to kill cancer cells faster than healthy ones, and unfortunately can have side effects of their own.

A key goal of cancer treatment has evolved to focus on fighting tumors while minimizing the harm to the patient. Two innovative approaches include precision medicine and next generation immunotherapy. According to Morrow, Amgen’s BiTE® (bispecific T cell engager) platform is designed to reprogram the patient’s immune system to hone in on cancer cells, instead of “just killing every cell that proliferates quickly.”

“There are opportunities right now for us to harness the immune system and precisely target genetic drivers of cancer, essentially fighting cancer cells where it hurts the most,” says Morrow. “We’re at the dawn of a very new age.”

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1Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov. 2014;13(11):828–851.

2Fernández-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer. 2011;2(3):344–358.

3Lipford JR. Pre-clinical Development of AMG 510: The First Inhibitor of KRASG12C in Clinical Testing. Presented at: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA.

4Lanman BA. Chen JJ, Liu L, et al. Discovery of AMG 510, a first-in-human covalent inhibitor of KRASG12C for the treatment of solid tumors. Cancer Res. 2019;79(Suppl 13). Abstract 4455.