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ROS1 Cancer Model Project Demonstrates Power of Patient Advocacy

NEW YORK – Every once in a while, medical oncologist Robert Doebele's lung cancer lab at the University of Colorado receives packages containing very small samples that he and others hope will have a big impact for a subset of patients with lung and other cancers.

The lab, which specializes in lung cancers driven by changes in oncogenes such as ALK, ROS1, or RET, has been establishing cell lines and other cancer models for a long time.

Recently, though, the samples used to start these lines — tumor tissue or pleural effusion fluid from cancer patients with rare rearrangements involving the receptor tyrosine kinase-coding gene ROS1 — have come from far-off cities and states.

One of those patients is Tori Tomalia, a Michigan woman in her early 40s with stage IV, ROS1-positive lung cancer — a disease she was first diagnosed with around six years ago. There are a growing number of targeted treatment options for patients who harbor rearrangements in ROS1, which show up in around 1 percent to 2 percent of non-small cell lung cancers. However, as with all molecularly targeted treatments, recurrence and therapy resistance remains a looming reality for patients.

After a recent computerized tomography scan revealed a pleural effusion, or fluid buildup around her lung, that needed draining, Tomalia and her healthcare providers arranged to have some of the drained fluid sent to Colorado, where investigators will now start developing a cell line that matches the biological features of her tumor.

"It's never good to have a progression," Tomalia said, "but if you're going to have it, at least you know it's going toward something that can hopefully do some good."

If anyone knows the value of the sample and its potential, it is Tomalia, a cofounder of the ROS1 patient advocacy group the ROS1ders. From the group's early days in 2015, Tomalia and other ROS1ders such as Janet Freeman-Daley and Lisa Goldman set out to improve research and treatment options for other patients with their rare tumor subtype.

In their early conversations with doctors and scientists, the ROS1ders had one key question, Tomalia recalled recently: "How do we move this forward to increase our chances at survival?"

The answers they received: Research. In this case, that meant cell lines.

"We've been doing this for a long time, and one of the things we know is that one model is basically equal to one patient," Doebele explained. "We know that patients are different. Even when patients have some similar characteristics like a ROS1 gene fusion, there can be inter-patient differences in how they respond to therapy."

"A handful of us said, 'Well, then that's what we're going to work on,'" Tomalia recalled. At the time, just a handful of ROS1-rearranged cell lines existed anywhere, making it difficult to draw broad conclusions about ROS1-positive disease and treatment strategies for it.

Through the ROS1 Cancer Model Program stemming from those early conversations, ROS1-positive cancer patients in the US can now donate samples from biopsies or pleural effusions by contacting the study nurse beforehand to coordinate consent, sample collection kit delivery, shipping, and so on.

Samples are sent to either Doebele's lab, where investigators attempt to establish patient-derived cell lines, or to Champions Oncology for mouse xenograft model work. The program officially launched late last year, though Doebele's team began generating ROS1-rearranged cell lines from patient samples even earlier.

With funding from GO2 Foundation for Lung Cancer (previously known as the Bonnie J. Addario Lung Cancer Foundation), the investigators plan to continue growing and characterizing the collection of ROS1-positive cell lines with exome sequencing and RNA sequencing, as well as functional experiments and drug sensitivity screens.

It can be tricky to establish stable cell lines from patient samples, even with practice, Doebele said, and the process inevitably takes time. In the meantime, he expects at least some patients will get information on actionable mutations in their tumors through clinical sequencing offered by their providers, which may unearth treatment options for those with drug resistance or disease progression.

Even so, Doebele emphasized the complementary information that can be gleaned through functional profiling on cell lines or PDx mouse models, particularly in patients for whom current clinical sequencing does not unearth realistic treatment strategies. In cell line experiments, investigators sometimes see functional changes and resistance pathways "that we would not be able to detect with any existing clinical assay."

There have been rare instances when functional experiments have yielded treatment information that his team returned to oncologists for patients running out of treatment options, but Doebele cautioned that the ROS1 Cancer Model Project is not designed to find information to guide treatment. The aim of the project is to learn more about ROS1-positive disease, and it will take time to translate that knowledge into personalized drugs and tests.

"We try to be careful about jumping the gun on research results that might not be directly translatable into a therapy for a patient," he said.

Indeed, turning functional clues into one or more clinical tests "is going to be a real challenge," Doebele said, since insights may come from gene knockdown experiments in one case and a proteomic assay in another.

"There might not be an immediate impact on that patient," Tomalia said, "but for the greater good it's definitely a step in the right direction."

The Colorado team is aiming to establish at least eight new cell lines, ideally from samples collected across disease stages to get a look at ROS1-positive tumor changes from diagnosis to treatment and progression.

So far, the lab has mostly been working with drug-resistant samples and has generated half a dozen new ROS1 lines over the lab's history, including around four lines developed from remote samples for the project.

"Once we have the cells stably characterized, we plan to publish our findings, including the genetic alterations associated with the samples, and then start sharing them with groups worldwide for their research purposes," Doebele explained. "We'll make these all freely available in, hopefully, a short amount of time."

The cancer model program at the University of Colorado falls within a global ROS1 initiative that brings together researchers, patients, caregivers, and physicians from around the world, explained Merel Hennink, a ROS1der from the Netherlands, who outlined the ROS1 Cancer Model Project for European and other oncologists at the European Society for Medical Oncology Congress in Barcelona last month.

She praised the effort, but noted that that project in the US currently remains out of reach for ROS1-positive patients in Europe, since samples need to stay alive during shipping to yield cell lines or PDx models, meaning 24-hour turnaround from collection to the lab is essential.

"We've gotten a few questions on whether we could accept samples from Canada or Europe," Doebele said, noting that customs-related delays are the primary hurdle. "We're working on whether we can do Canada as a test case first."

As with lung cancer, ROS1-rearrangements also show up at a similar 1 to 2 percent rate in other major cancer types, including breast, colon, ovarian, and pancreatic cancers, glioblastoma, and melanoma.

"Most healthcare professionals have never met a ROS1 patient," Hennink noted during her ESMO presentation. "That means they have no experience with our disease, [and] they have no current knowledge about diagnostics or treatment options."

But because lung cancer itself is so common, these cases start to add up when considered globally, explained Hennink, who also belongs to a ROS1/ALK patient group in the Netherlands. 

With the advent of an approved tyrosine kinase inhibitor treatment (TKI) for the disease, the importance of ROS1 tumor testing has been increasingly recognized for patients with NSCLC in the US and beyond.

"When I was diagnosed in 2013, there wasn't anything FDA-approved for ROS1," noted Tomalia, who is currently on her fourth treatment. Now, she said, "there are several that people can try, and we're hoping that more and more will keep coming." 

In mid-August, the FDA approved entrectinib (Genentech's Rozlytrek ) as a second targeted therapy for adults with ROS1-mutated, metastatic NSCLC, Hennink noted. And still other approved or experimental treatments are sometimes used off label for ROS1-mutated cancers, though availability varies by country.

Even so, she explained, lung cancer patients in healthcare systems in other parts of the world are still having trouble getting treated with crizotinib (Pfizer's Xalkori) — the first FDA-approved targeted treatment for ROS1-positive, metastatic cases.

And despite the growing arsenal of drugs targeting ROS1-positive cancers — and testing guidance from organizations such as the International Association for the Study of Lung Cancer (IASLC), the College of American Pathologists (CAP), the Association for Molecular Pathology (AMP) — an international survey presented at an IASLC-hosted meeting last month suggested testing gaps remain for lung cancer patients who might benefit from treatments targeting ROS1, ALK, or other driver oncogenes.

As advocates like Tomalia and Hennink use their voice to spread the word about ROS1 testing and treatment access at medical conferences and in discussions with oncologists, the ROS1ders have grown to nearly 500 people with related patient advocacy and research efforts cropping up in the Netherlands, Belgium, other parts of Europe, and Australia.

Through her own speaking engagements, Hennink has urged other centers closer to home to continue developing related strategies, arguing that they can "copy and paste" from the US-based project to grow collaborations and resources in Europe.

She acknowledges that unique challenges do exist in Europe — from country-specific health systems within the European Union to cultural norms that may make patients more reticent to question their oncologist's treatment recommendations.

"We are taken care of by our healthcare system," Hennink said. "That's a good thing, but it also becomes difficult when you have a rare disease."

Still, progress has been made toward new ROS1-rearranged cell lines, with the first patient sample submitted for cell line production in the Netherlands earlier this month, Hennink explained, after two years of preparation.

"It makes me proud," she said, that "we, a small country like the Netherlands, can do something like that. Now, we want to explore all the research for ROS1."

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