A new method that scans huge libraries of single-stranded oligodeoxynucleotides (ssODNs) for complex molecular signatures may be used to develop assays that distinguish between populations, according to proof-of-concept studies published in Scientific Reports and Nature Communications.1,2 The method may help to diagnose cancer or to determine the likelihood of a patient responding to a specific treatment, for example.
“As we look at the complexity of biology, especially with respect to predicting therapeutic response for cancer patients, we are keenly aware that modulations within the inherent molecular network are very difficult to understand with single biomarkers. We are seeing this more and more play out,” David Spetzler, PhD, MBA, president and chief scientific officer of Caris Life Sciences, told Cancer Therapy Advisor.
This technology is being developed by Caris Life Sciences to help improve the understanding of these aberrant modulations that drive cancer. Dr Spetzler said that “as we embarked upon that journey, it became clear that we needed to take a different approach to truly measure perturbations than was currently available with existing technologies.”
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The ADAPT Platform
According to Dr Spetzler, this methodology “gives you the ability to measure millions of things simultaneously. […] It gave us a way to begin to understand what is driving clinical phenotypes.”
This novel approach is called the adaptive dynamic artificial poly-ligand targeting (ADAPT) system, in which multiple rounds of ssODN, or aptamer, library enrichment occur against biological samples. In one of the studies, the sample consisted of exomes harvested from patient plasma, whereas the second study used tumor tissue samples. The enrichment separates and enhances the levels of molecules characteristic of that biological sample, which may differ between 2 sets of samples, such as those of healthy participants vs those of patients with cancer.
Predicting Response to Trastuzumab
The study published in Nature Communications demonstrated the proof-of-concept that the ADAPT system could be used to develop a sensitive assay to help predict therapeutic response.2 “HER2 and trastuzumab is a nice example because it’s well-understood and has been studied for so long,” Dr Spetzler said.
Though trastuzumab and other HER2-targeted agents are the standard of care for patients with HER2-positive breast cancer, about 38% to 50% of patients with HER2-positive disease do not respond to trastuzumab. According to Dr Spetzler, “that is because downstream of that receptor there is attenuation of the signal, which means that HER2 is not really the driver. If you can identify that the downstream signaling is not amplified, then you would know which HER2-positive patient is not going have clinical benefit.”
