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The future of precision cancer therapy: try everything

Researchers worldwide are blasting patients’ cancer cells with dozens of drugs in the hope of finding the right treatment, with some positive results motivating the scientists to continue in their quest.

In one notable case, Austrian patient Kevin Sander (38) whose blood cancer had returned, was running out of treatment options. A stem-cell transplant was the best chance for long-term survival, but to qualify for the procedure doctors first needed to reduce the extent of his tumour – a seemingly insurmountable goal, because successive treatments had all failed to keep the disease in check.

As a last resort, he joined a landmark clinical trial. Led by haematologist Philipp Staber at the Medical University of Vienna, it is exploring an innovative treatment strategy where drugs are tested on the patient’s own cancer cells, cultured outside the body.

In February 2022, researchers tried 130 compounds on cells grown from Sander’s cancer, essentially trying everything at their disposal to see what might work.

The journal Nature reports that one option looked promising – a type of kinase inhibitor approved to treat thyroid cancer, but seldom, if ever, used for the rare subtype of lymphoma Sander had.

Physicians prescribed him a treatment regimen that included the drug, and it worked. The cancer receded, enabling him to undergo the stem-cell transplant. He has been in remission ever since.

His story is a testament to this kind of intensive, highly personalised drug-screening method, referred to as functional precision medicine. Like all precision medicine, it aims to match treatments to patients, but it differs from the genomics-guided paradigm that has come to dominate the field.

Instead of relying on genetic data and the best available understanding of tumour biology to select a treatment, clinicians throw everything they’ve got at cancer cells in the laboratory and see what sticks.

In pilot studies, Staber and his colleagues found that more than half of the people with blood cancer whose treatment was guided by functional drug testing enjoyed longer periods of remission than with standard treatments.

Large-scale testing of genome-directed approaches suggests the techniques are very effective against some cancers, yet they benefit, at most, only around 10% of patients overall.

Staber and his group’s latest trial is the first to compare functional and genome-guided approaches alongside treatments directed by standard pathology and physician intuition.

“That’ll be a very powerful study, and probably vindicate the utility of these functional assays,” said Anthony Letai, a haematologist at the Dana-Farber Cancer Institute in Boston, Massachusetts, and president of the Society for Functional Precision Medicine.

And, if anecdotal reports are any indication, the try-everything tactic seems to bring about meaningful improvements, even when the genetic sequence of a tumour provides no actionable information, as was the case for Sander.

Companies worldwide are already offering these kinds of personalised drug testing service. But proponents still have much to prove. Although the concept of screening a bunch of drugs seems simple, the methods used to culture cancer cells outside the body can be  demanding, time-consuming and costly.

The challenges are particularly acute for solid tumours, which live in complex environments inside the body; replicating those conditions is not easy.

Researchers are trying wildly differing methods, ranging from growing tumour samples in mice and chicken embryos, to cultivating carefully engineered organoids – and even the delivering infinitesimal amounts of various medicines to a tumour while it’s still in a patient.

Deciding what works and what is practical won’t be easy. But momentum is growing.

Behind the screen

The Vivi-Bank is at the Medical University of Vienna. Short for ‘Viable Biobank’, the room is brimming with liquid-nitrogen dewars, each containing frozen lymphoma samples.

When surgeons extract biopsies from cancerous lymph nodes, they usually immerse the tissue in formaldehyde to prepare for standard pathology analyses. That kills the cells, however, rendering them useless for functional testing. So, to enable drug screens, Staber and haematopathologist Ingrid Simonitsch-Klupp, who jointly oversee the Vivi-Bank, had to convince colleagues to change their ways, keeping the tissue alive and sending it quickly for processing and storage.

Some of that tissue arrives in Staber’s lab, where researchers break up the cells using a knife, forceps and a nylon strainer, creating a slurry to distribute across a 384-well plate. In each well, they test a different drug compound – chemotherapy agents, enzyme-targeted drugs, immune-modulating therapies and more.

After a night of incubation, lab testing reveals which drugs are active against the cancer and which aren’t.

A team of clinicians then uses this information to determine the most appropriate course of treatment for patients.

Several groups have reported success with this general approach. In a University of Helsinki trial, for example, researchers found that individualised drug screening of leukaemia cells provided informative results faster than did genomic profiling, yielding impressive clinical responses as well.

Of 29 people with treatment-resistant acute myeloid leukaemia (AML), 17 responded to drug-screening-informed therapies and entered remission.

Likewise, a study by radiologist Candace Howard, at the University of Mississippi Medical Centre, and colleagues, showed that people with aggressive brain tumours live longer when their chemotherapy regimens are guided by lab testing than when their treatment is directed by a physician’s intuition alone – and costs less.

Functional drug testing was embraced by cancer researchers in the late 20th century, but soon fell out of favour, mainly because of the limitations of assays at the time and a restricted repertoire of anti-cancer drugs.

Technological improvements and an expanded pharmacopoeia have changed things. Yet the equipment can be expensive and requires trained personnel to operate it.

That’s a big limitation, says Joan Montero, a biochemist at the University of Barcelona, because it hinders the broad implementation of functional precision drug testing, especially in low-resource settings. To address these challenges, Montero and his colleagues have been developing inexpensive and portable microfluidic devices for rapid, on-site testing of cancer cells.

Their microfluidic platform remains years away from practical use, however, and might guide treatment only for certain cancers.

That’s because protocols developed for tailoring therapies against blood cancers don’t always work in solid tumours of the breast, lung, liver and other organ systems.

Biopsies from solid tumours often yield lower cell counts, requiring extra steps to culture the cells before drug screening. Moreover, solid tumours have complex interactions with healthy cells in their surroundings, meaning models should be more sophisticated.

Growing pains

The first challenge remains growing enough tumour tissue to test. David Ziegler, a paediatric neuro-oncologist at Sydney Children’s Hospital in Australia, had set out to perform individualised drug screens for around 1 000 children with high-risk cancers as part of the Zero Childhood Cancer Programme.

But he and his team discovered that, after several days under lab conditions, up to one-fifth of the samples either contained no cancer cells at all, or were being outcompeted by normal, healthy cells.

They quickly learnt to check cultures for tumour cells – through imaging, cellular analysis or genetic profiling – before testing them against drugs.

Cell cultures from solid tumours can, in principle, be subjected to the same kind of testing used for blood cancers, but many research teams are crafting elaborate structures, known as organoids, to test. These patient-derived 3D tissue models, made by growing tumour samples in specialised scaffolds over several weeks, replicate the intricate tissue architecture of a tumour, offering a more accurate representation of the cancer physicians are looking to treat.

“We want to put the tumour cells in an environment that’s as close [as possible] to how they were growing in the body,” says Alice Soragni, a cancer biologist at the University of California, Los Angeles.

The process can add weeks to the timeline for obtaining drug sensitivity data, but it’s worth it, says Carla Grandori, co-founder and chief executive of SEngine Precision Medicine in Washington.

In clinical validation studies, Grandori and her SEngine colleagues found that the drug-screening results using organoids aligned with patient outcomes with around 80% accuracy.

Those findings are not yet published, but the company has produced case reports over the past year describing people with difficult-to-treat cancers who, after exhausting their treatment options, found effective remedies through organoid drug testing.

Model of efficiency

In the hope of testing drugs against even more realistic cancer systems, some researchers have studied mice implanted with fresh tumour specimens, a model system known as a patient-derived xenograft.

But it soon became evident that many tumours do not grow in mice, that drug screening in xenografts takes too long to provide timely recommendations and that the cost is more than most patients and healthcare systems can bear.

“It was slow, expensive and not robust enough,” says David Sidransky, an oncologist at Johns Hopkins University School of Medicine, and a co-founder of Champions Oncology, a developer of xenograft models.

Although some companies still use xenografts for research, mostly, researchers have moved away from this, some opting for other living systems.

One such alternative comes from cancer biologist Hon Leong and colleagues at Sunnybrook Hospital in Toronto, who devised a system for screening drugs on tumour biopsy samples cultivated on developing chicken embryos.

The approach is rapid and inexpensive, says Leong, allowing researchers to assess different drug options in weeks rather than the months required for mice.

In ongoing trials focused on advanced breast and kidney cancers that have spread to other parts of the body, Leong and his team have successfully used the chicken-embryo system to identify individuals who would benefit from immune therapies. These are among the most effective cancer treatments today, and a drug class that few other avatar systems can accurately assess, he says.

Another approach comes from Ross Cagan, a developmental biologist at the University of Glasgow, who uses genomic sequencing and genetic engineering to recreate the unique characteristics of a patient’s tumour in a custom-made fruit fly.

This involves introducing mutated forms of cancer-promoting genes or incorporating sequences that restrict cancer-suppressing genes – generally between five and 16 alterations in total.

Feeding the flies with food containing various medications can then reveal therapeutic regimens that suppress cancer growth, either by acting directly on tumour cells or by influencing the animal’s biology in ways that indirectly impede cancer progression.

This is how they identified a new three-drug cocktail – a lymphoma treatment, a blood-pressure medicine and an arthritis therapy – that, when administered to a man with a rare salivary gland tumour, stabilised the cancer for a year.

Any model invariably has biological limitations, however, so some researchers have done away with animal stand-ins or cellular replicas. Instead, they have developed implantable devices allowing clinicians to test drugs directly on patient tumours – while the cancer is still inside the body.

Last year, bio-engineer Oliver Jonas at Brigham and Women’s Hospital in Boston, and his colleagues demonstrated the feasibility of this in people with lung and brain cancers.

In small trials, surgeons inserted tiny drug-releasing devices, loaded with nanodoses of up to 12 drugs, into tumours as people underwent cancer-removal surgery. The drugs flowed into the surrounding tissue from separate reservoirs in a device the size of a grain of rice.

Those tissues, and the device itself, were removed after the procedure, and inspected for molecular indicators of drug action. So far, the data haven’t been used to guide treatments, but retrospective analyses hinted at potential benefits if they had.

Test tissues

Functional testing strategies might even work for conditions outside the cancer arena, the scientists say. In cystic fibrosis, for example, organoid models made from rectal or intestinal tissue are beginning to help clinicians find effective drug regimens for people with rare disease-causing mutations who are not eligible to receive any approved treatments.

Nature article – The future of precision cancer therapy might be to try everything (Open access)


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