Story of a CU Anschutz-driven breakthrough

Nichol Miller and family

Under the sunny skies that return to Portland, Ore., every summer, Nichol Miller is enjoying a life of family and purpose. The mother of three soaks in the milestones of graduations, weddings and anniversaries as well as the simple pleasures of seeing her kids head off to school and her husband come home from work.

All this seemed improbable just a few years ago – even impossible. Stricken with an aggressive soft-tissue sarcoma that started in her hip flexor and quickly spread to her lungs, Miller traveled to Denver to participate in a clinical trial of an experimental therapy.

She called it her “hail Mary.”

Breakthrough in the making

At the CU Cancer Center at the CU Anschutz Medical Campus Miller met Robert Doebele, MD, PhD, associate professor of medicine, CU School of Medicine, who had found – thanks to an immortal cell line donated by another cancer patient – the abnormal gene NTRK1 in the cancer of that patient, who also happened to be a mother of three children.

Doebele’s discovery set the stage for a breakthrough therapy.

Nichol Miller and Robert Doebele
Nichol with Dr. Robert Doebele at the CU Cancer Center after undergoing the successful clinical trial drug for her aggressive cancer in 2015.

“The finding of an NTRK1 gene fusion in the lung cancer patient made me want to develop a therapy for patients with this type of genetic mutation as none had existed beforehand,” he said. “This led my lab to perform a number of experiments demonstrating that this gene was cancer-causing and, importantly, that cancer cells with this gene could be inhibited with a selective TRK inhibitor called ARRY-470, now better known as larotrectinib.”

When Miller arrived at the CU Cancer Center, breathing was almost impossible without five litres of oxygen per minute. Put on the targeted-therapy drug in spring 2015, called LOXO-101 at the time and taken orally as a pill, Miller showed immediate improvement.

FDA approves targeted-therapy drug

Miller still takes the drug, now commercially known as Vitrakvi, on cycles that start every 28 days. During the cycles ­– she’s currently on her 56th – Miller takes the pill twice a day, and will continue doing so for the rest of her life.

She and her family celebrated when the Food and Drug Administration (FDA) approved Vitrakvi last November.

Early on in the development of targeted therapies, Doebele said, researchers saw examples of cancers such as EGFR mutation-positive lung cancer in which mutations seemed to occur in only one type of cancer, or that perhaps a therapy would only work on a mutation when it was found in certain types of cancer.

“When we started planning the clinical trial (of LOXO-101) I had the idea, based on data from our laboratory showing that lung, colon and leukemia cells responded to therapy as long as they had the right genetic fusion in an NTRK gene, that we should include any tumor type as long as it had an NTRK gene fusion,” Doebele said.

Drug attacks the genetic markers in cancer

Because Miller’s tumors had this specific gene fusion, the therapy had the desired effect: her lung tumors began to shrink and disappear and tumor markers in her blood showed dramatic declines. The drug works by targeting the proteins that are abnormally turned on by a gene fusion event. It essentially kills the cancer or stops it from growing.

“The term is ‘tumor agnostic,’ and that’s part of what’s unique about this drug,” Miller said. “It’s not linked to a particular cancer, or where a cancer is found in the body, but linked instead to the genetic markers in the cancer.”

Now her life is marked by milestones.

‘Lab saved my life’

This spring, Miller, 46, got to see her oldest son get decked out for prom and then graduate from high school. For her birthday in March, she and her husband enjoyed a week in Florida – the first time in 18 years of marriage they vacationed without their children.

Nichol Miller is now a cancer patient advocate, frequently speaking in her home state of Oregon as well as during a recent trip to Denver. Here, she is pictured with fellow presenters at an Oregon Health & Science University panel. Pictured from left: Lara Davis, MD; Miller; Summer Gibbs, PhD; and Shannon McWeeney, PhD.

“I wouldn’t be talking to you without (the clinical trial at the Cancer Center),” she said. “It was huge. It was my miracle. It gets easier with time, but I still think about how close I came (to dying), and it makes you appreciate everything so much more and gives you a lot more patience.”

Miller likes to say “the lab saved my life” because she gives full credit to the important cancer studies being performed by researchers at the CU Cancer Center as well as, closer to her home, the Oregon Health & Science University. The gene mutation found in her cancer is very rare; only 1 to 3 percent of all solid cancers have the NTRK1 mutation.

“I wouldn’t be here without the all the work of the researchers and the doctors who are trying to solve the cancer puzzle.” – Nichol Miller

“I wouldn’t be here without the all the work of the researchers and the doctors who are trying to solve the cancer puzzle,” she said. “The genetic testing that found my alteration is incredibly important because the chances of finding something are rare, but for that one person it’s life or death. It’s a new way of looking at cancer.”

When physicians do genetic testing on a patient, Doebele said, they look not only for a specific mutation, such as NTRK, but rather a host of other rare genetic events that may already have, or may soon have, effective therapies.

A standout clinical trial

The clinical trial he administered to Miller stood out for a number of reasons. A key part was the 46-year-old mother who had never smoked but, by 2012, had developed metastatic lung cancer. Unfortunately, at the time there were no drugs available that could treat her illness. Before she died, the woman gave Doebele a sample of her tumor to grow an immortal cell line that could be used for further research and to test drugs against this type of cancer.

Nichol and Marc Miller
Nichol and her husband, Marc, take in the sunset at the Snake River gorge in Twin Falls, Idaho, on their return trip home from the clinical trial in Aurora in 2015. “We knew the drug was working,” Nichol says.

Her donation ended up helping another young mother, Miller, and potentially countless patients in the future.

“Her sacrifice and forethought is something I’m so grateful for,” Miller said of the patient who donated her cells. “I know that’s something people are working on at a national level – to make it easier for people to donate genetic material for research. There’s a lot of valuable information that just goes into the incinerator.”

And that’s another part of Miller’s clinical trial that stands out.

It shows how an understanding of cancer biology can reveal genetic markers which are tested in human tumors, thereby accelerating potential therapies to target the cancers, Doebele said. “We identified NTRK1 in lung cancer in 2012, published the initial laboratory findings in 2013 and 2014 and had started the trial by early 2014 with an FDA approval only a few years later in 2018.”

‘There’s always hope’

For Miller, telling her story and furthering the cause of genetic testing is now a big part of her purpose. She recently returned to Denver as a featured speaker at the “Stupid Cancer” conference, and she frequently shares her story at other venues as a patient advocate.

“My story is unique, and it’s a good story for giving people hope,” Miller said. “I read a lot of survivor stories and they’re what kept me going – knowing there’s always hope.”

Mainly, she’s joyful to share in the life of her family, and seeing her teenagers grow into healthy and happy adults.

“Ultimately, I’d like my children to grow up into a world where there is no longer a fear of cancer,” Miller said. “It doesn’t have to be a death sentence.”

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