Imagine that your job is to put together an edgeless, 1,000-piece jigsaw puzzle. But you have no corner pieces to guide you, and you have no idea what the final puzzle is supposed to look like. You can only find out if you’re right by running a test on each attempt, which will tell you whether or not you’ve struck the right combination.
Every day, you rearrange the puzzle pieces in different shapes and permutations, guided primarily by what you know doesn’t work from your previous attempts. Now imagine doing that every day for five, ten, fifteen, or twenty or more years. That’s (a super simplified version of) what it’s like to be an oncology researcher at Pfizer.
Cancer, of course, is a far more complex problem than a jigsaw puzzle. Take, for example, ALK-positive non-small cell lung cancer (NSCLC). ALK, short for “anaplastic lymphoma kinase,” is a genetic mutation that codes for an abnormal protein called tyrosine kinase. Tyrosine kinase is an enzyme that drives the growth of cancer cells. ALK-positive lung cancer, then, is a type of lung cancer that tests positive for an ALK mutation — in this case, the EML4-ALK fusion gene. About three to five percent of people with non-small cell lung cancer have this mutation.
Ted W. Johnson, Ph.D., a research fellow at Pfizer, co-designed lorlatinib, an experimental ALK/ROS1 tyrosine kinase inhibitor designed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood-brain barrier. Translation? It controls the “on-off switch” of ALK-positive NSCLC with very few side effects, especially compared to the debilitating side effects of traditional chemotherapy. Lorlatinib received Breakthrough Therapy status from the FDA in 2016 and is currently in phase three clinical trials.
It took Johnson and his team over four years of research and development, including a long, morale-draining phase of virtually no progress for over two and a half years, before discovering lorlatinib’s unique compound structure. That’s over four years of rearranging the puzzle pieces until they found the right fit.
Four years of trial and error might seem like a long time to some, but in the world of cancer research, the team behind lorlatinib was actually extremely lucky. In fact, only ten percent of medicines in phase one research ever make it to market. “You dream of it, but most people go through their careers never achieving this,” Johnson says. “Our foe cancer is unbelievably complicated,” explains Brion W. Murray, Ph.D., another Pfizer research fellow. “You have to deal well with failure. When you’re bamboozled by the disease, get up, dust yourself off, and go back at the problem.” So what keeps researchers like Johnson who are still figuring out their respective jigsaw puzzles motivated?
“Our biggest inspiration in terms of what we do are the patients,” says Jennifer LaFontaine, Ph.D., a senior director leading the Oncology Medicinal Chemistry Synthesis and Analytical Group Chemistry at Pfizer. “It’s really inspiring for us to hear [their] stories,” she says, “because we know that the things that we studied in the lab have translated to the clinic in the way that we had hoped.”
Sometimes, patients can be people that these researchers know well. “My wife is a cancer survivor,” says Murray. “I’ve always been thinking about patients...I know exactly what patients go through.”
About six months ago, Johnson had the opportunity to meet a non-small cell lung cancer patient. “The first thing he said to me when he met me was, ‘Thank you for saving my life,’” Johnson remembers. “There’s nothing more inspiring and motivational than that.”