Researchers at the National Cancer Research Centre (CNIO) in Spain have designed a screening platform, called METPlatform, which allows researchers to use patients’ own tumor tissue for testing whether drugs might be used to treat brain metastases. Through an initial screen using a collection of FDA-approved and clinical trials-stage drugs, the researchers identified HSP90 inhibitors as potential drug candidates for brain metastases. Subsequent studies confirmed the validity of HSP90 as a potential therapeutic target in brain metastases, and identified biomarkers of poor prognosis.

Research lead Manuel Valiente, PhD, head of the Brain Metastasis Group, said, “Cancer is not just a tumor, but the tumor and its context, and this system allows us to conduct investigations with patient samples in a real context in which metastatic cells grow in the microenvironment around the tumor, in this case, the brain.” The tool, which offers an alternative to animal testing is, the team claimed, simple, fast, cheap, and “infinitely superior” to other screening methods.

Valiente and colleagues reported on the development and evaluation of the METPlatform technology in EMBO Molecular Medicine, in a paper titled, “A clinically-compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis.”

It is estimated that about a quarter of cancer patients are at risk of brain metastases, and the rate is increasing, especially among individuals who relapse following cancer therapies. “The incidence of brain metastasis continues to increase and yet, current therapies available for patients with disseminated cancer cells in their central nervous system (CNS) have a limited efficacy and fail to improve survival,” the authors wrote.

One of the major limitations in the treatment of brain metastasis is that these patients have traditionally been excluded from clinical trials, and so there are no specific curative treatments for brain metastasis. “As a result, information regarding CNS clinical efficacy of most anticancer agents that are FDA-approved or in clinical trials is limited,” the team continued. “Thus, exploring therapeutic vulnerabilities and corresponding pharmacological agents with high CNS activity in preclinical models is crucial to promote urgently needed prospective clinical trials that include patients with brain metastases.” However, current in vivo drug-screening approaches using mouse models are unaffordable by most academic research institutions, the authors pointed out. Conversely, cell-based assays lack the contribution of the tumor-associated microenvironment (TME).

The new ex vivo organotypic culture-based drug-screening METPlatform has been designed to overcome limitations of both in vivo and in vitro approaches, by enabling drug screens using the patients’ own samples. The strategy is based on the use of organotypic cultures, which have already been used in cancer research because they can mimic the progression of metastatic disease, but which have not, as far as Valiente and team say they are aware, been used for drug screening.

For the new METPlatform technology, samples of fresh metastatic brain tissue received from hospitals are processed using a simple methodology that allows them to be cultured in the laboratory over a few days. Screening can then simultaneously analyze the behavior of hundreds of compounds.

The team claims the process is “infinitely superior to others in use,” because it is very simple and easy to deploy in the laboratory, does not require sophisticated technology, is much cheaper, and is very fast, so results can be obtained in seven days, compared with the months of time before results would be seen in mice.

Image of metastasis in a mouse brain. In green, tumor cells that remain “hidden” after surgery and act as potential seeds for recurrence of metastasis. [CNIO]
For their reported study, in which the researchers used the METPlatform to identify drugs, including those that are already approved or in clinical trials, which might be used to treat brain metastasis, they carried out an initial screen with a library of 114 compounds, from the CNIO Experimental Therapeutics Programme. Of the drugs identified, inhibitors of the molecular chaperone HSP90 were highlighted. “In addition to other hits, METPlatform identified inhibitors of heat shock protein 90 (HSP90) as a potential target to increase the vulnerability of brain metastasis,” they wrote. HSP90 inhibitors have already been tested against different types of tumors, although never against brain metastasis.

The researchers also confirmed that the target, HSP90, was increased in brain metastases. “… our results demonstrate that high levels of HSP90 in cancer cells are a frequent finding among human brain metastasis independently of the primary tumor,” they wrote. “Indeed, a clear tendency to maintain or further increase the levels of this protein is evident when compared to matched primary tumors … To validate the vulnerabilities identified by METPlatform we proved the dependency of brain metastasis on HSP90 signaling in vivo.” The investigators further commented that their results support the potential functional implications of HSP90 in human brain metastasis.

Subsequent experiments in animal models, and in organotypic cultures of brain metastases obtained from 19 patients with different types of cancer, showed that an HSP90 inhibitor, DEBIO-0932, demonstrated strong antitumor activity. “DEBIO-0932 is a second-generation inhibitor of HSP90, which is currently under evaluation in a Phase I/II study for patients with advanced NSCLC,” the team explained.

The researchers claim that their results validate METPlatform as an effective ex vivo drug-screening strategy for identifying brain metastasis vulnerabilities, such as HSP90, which could be translated to in vivo metastasis assays. “Our findings suggest that inhibition of HSP90 could be a novel strategy to prevent brain metastasis, including a clinically relevant situation of local relapse after neurosurgery … our work provides the rationale and proof-of-principle to include patients with CNS disease in current clinical trials with BBB-permeable HSP90 inhibitors and/or to design a specific one for this patient population in the adjuvant setting after neurosurgery.” Valiente does acknowledge caution, as such molecules have shown side effects and toxicities in clinical trials with cancer patients, and he noted that a safe therapeutic window must be sought or their use in combination with other drugs explored.

The researchers were also able to identify a molecular signature of four HSP90-related genes, that indicated poor prognosis. “… in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance,” they wrote. “We speculate that this poor prognosis signature could identify patients with greater sensitivity to the HSP90 inhibitor,” said Valiente. If validated, these results may aid decision making for better clinical management of brain metastases.

Valiente hopes that the METPlatform could be developed as a patient “avatar.” “Looking to the future, our goal is to incorporate this platform into clinical trials, so that we can test the drug we intend to administer to the patient using the patient’s own biopsies, so we know as soon as possible if it will work, and better prepare ourselves for possible therapeutic resistance with a battery of drugs that we would test in parallel on these same biopsies.”

As a first proof of concept, the team showed the predictive value of METPlatform, by reproducing in organotypic cultures the responses of 14 glioblastoma patients treated with standard therapy. “ … we show the potential of METPlatform to outperform established clinical biomarkers to predict therapeutic response in a clinically-compatible time frame when applied to a difficult-to-treat cancer (i.e., glioblastoma),” they wrote. In the next phase of research, Valiente’s team, together with the CNIO Biobank and hospitals associated with the RENACER hospital network, will study whether this possibility can be validated on a large scale.

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