A new study from Yale Cancer Center characterizes the functional link between drug resistance and central nervous system (CNS) relapse.
The findings from a study led by Don Nguyen, PhD, associate professor of pathology and of medicine (medical oncology) and assistant Yale Cancer Center director for research development, were recently published in the journal Nature Communications.
The brain has long been considered a sanctuary site based on the limited penetrance of most drugs across the blood-brain barrier. Therefore, historically, patients with brain metastases had few therapeutic options.
“We instinctively associate late stage-metastases with therapeutic failure in the clinic. But from a biological point of view, I found current explanations for this association to be unsatisfying, especially since many presumed that we would solve this problem by developing new drugs that are more CNS penetrant,” Nguyen said.
While outcomes for patients treated with new brain penetrant systemic therapies are indeed improving, the incidence of brain metastasis remains a clinical challenge. This is especially true in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor (EGFR) mutations. These patients are typically non-smokers and are treated with the EGFR-inhibitor drug osimertinib.
“We know from prior collaborations with AstraZeneca that osimertinib can reach into most areas of the brain in mice and primates,” Nguyen said. “But despite initially responding to this drug, most patient will develop drug resistance and up to 40–50% of lung cancer patients eventually metastasize in the CNS." Patients with brain metastases eventually have a worse prognosis than those without.
In their study, Nguyen’s team used mouse models to demonstrate that despite robust penetration of osimertinib and inhibition of its target in the CNS, the brain is particularly hospitable for residual tumor cells.
“The surprise came when we discovered that after the drug gets into the brain and tumors shrink substantially, a small proportion of cancer cells stick around in proximity to blood vessels. It’s almost as if this particular feature of the cancer cell’s environment was a good place for them to hide and eventually proliferate in the brain,” he said.
Nguyen’s team further showed that the extracellular basement membrane protein laminin, which is produced by normal blood vessels in the brain, is in part responsible for this form of drug persistence and resistance.
“Cancer cells utilize Ras homolog family member A (RhoA) signaling and a serum responsive factor (SRF) gene expression program to take advantage of this abundant source of laminin from their microenvironment. This explains how certain pre-existing properties of the cancer cells allow them to adapt over time once they enter the CNS, not only to form brain metastasis, but also to evade treatment.
“Our common goal is to understand how the site of metastases can dictate a patient’s response or resistance to standard of care therapies,” Nguyen added. “This question is at the forefront of cancer biology research and its complexity requires multi-disciplinary approaches. We are now well-positioned to test new biomarkers and drug targets that also take into consideration the role of tumor microenvironment in brain metastasis.”
Funding for this study was provided by AstraZeneca and the Yale SPORE in Lung Cancer. Roy Herbst, MD, PhD, Ensign Professor of Medicine (Medical Oncology), professor of pharmacology, and deputy director of Yale Cancer Center, is principal investigator of the Yale SPORE in Lung Cancer.
Assisting Nguyen in the study were Yale colleagues Veronica Chiang, MD, professor of neurosurgery, and Katerina Politi, PhD, associate professor of pathology.