A different kind of TROLL

MANCHESTER, UK—Cancer biomarkers have proved to be a strong ally in the fight against cancer, helping clinicians to better predict which patients might respond best to certain treatments or even if their cancer is likely to metastasize. 

And in some of the latest work on this front, APIS Assay Technologies Ltd. has begun a research and development agreement with the laboratory of Drs. Elsa Flores and Marco Napoli at Moffitt Cancer Center centered on two biomarkers: TROLL-2 and TROLL-3. The partners will evaluate the potential of these long non-coding RNAs (lncRNAs) as predictive biomarkers of cancer progression to gauge patient response to chemotherapy.

While cancer mutations vary between tumor types, some of the most commonly seen alterations are mutations in the tumor suppressor TP53 and the activation of the PI3K/AKT pathway. In 2020, Flores' laboratory published a paper in Nature Communications detailing how TROLL-2 and TROLL-3 mediate crosstalk between p53 mutations and the AKT pathway.

“So far, cancer progression [with TROLL-2 and TROLL-3] has been shown in at least six different tumor types. At APIS, we have built and continue to build a portfolio of biomarkers related to the TP53 family, which is all about regulation of apoptosis,” Dr. Joachim Schorr, CEO of APIS Assay, tells DDN. “We see this also with another marker which we have in development, ASPP2-kappa, that it seems the long non-coding RNA prove what I think some years ago had been published in Cell—that cancer is not a disease of an organ, it's a disease of the pathway. That's why you see cross activity in various cancers.

“So currently under this agreement, we're looking at breast cancer, non-small cell lung cancer, and melanoma; those are the first three we are looking at in parallel, in order to see if we can have a prognosis of treatment outcome and also the prediction of efficacy of treatment. That's really the goal for this broad agreement.”

Schorr says that the seeds of this agreement were planted roughly a year ago when he heard Dr. Flores presenting on TROLL-2 and TROLL-3. Flores is chair and senior member of the Department of Molecular Oncology and leads the Cancer Biology and Evolution Program at Moffitt. Her expertise includes more than 20 years of experience in cancer biology, the p53 pathway, RNA biology, and mouse models of human cancer. 

“To make a long story short, we had a meeting during the conference, and that's when we felt we both could really work well together,” he comments. “So we signed a license agreement and then also said we want to have a longer-term research agreement in order to explore all the different possibilities of these very interesting biomarkers.”

Within the subset of breast cancer, this collaboration will focus specifically on triple-negative breast cancers, which regularly present with hyperactivation of the PI3K/AKT pathway and the gain-of-function mutation of TP53. Additionally, triple-negative breast cancers typically have higher levels of both TROLL-2 and TROLL-3 than non-triple-negative breast cancers. A pan-cancer analysis of TCGA datasets and human cancer tissue microarrays highlighted TROLL-2 and TROLL-3 as prognostic in breast cancer. 

APIS Assay, together with Moffitt researchers, will evaluate whether the two lncRNAs can be used to predict the efficacy of treatment pathways and treatment outcome in chemoresistant triple-negative breast cancers, in addition to determining whether the TROLL biomarkers could be diagnostic in non-small cell lung cancer and melanoma as well.

According to Schorr, when it comes to APIS Assay's approach, “We're aiming to first reach clinical validation; this is what our principle has been and is, to find early biomarkers out of research and development and then develop it and really use the very strong, stringent IVD regulations in order to set up the assays, and then have statistically significant patient populations and data in order to show this.”

He reports that the research agreement is slated to run over the next three-plus years, adding that “They have a great group [at the Moffitt Cancer Center], technology, and knowledge, while we of course bring 150-plus years of IVD experience, having developed hundreds of in-vitro diagnostic products.”

“The R&D collaboration with APIS will provide a clear and realistic path to provide new diagnostic applications to the patients,” Flores remarked.