PARIS – The National Cancer Institute is conducting several projects aimed at improving the tools and pre-clinical models that researchers can use to investigate precision oncology treatment approaches.
At an annual symposium hosted by the WIN (Worldwide Innovative Networking) Consortium this week, James Doroshow, deputy director for clinical and translational research at the NCI, discussed a number of these efforts, including a soon-to-launch lab network that will provide centralized assays to researchers conducting genomic and pharmcodynamic analysis to understand the molecular mechanism of cancer drugs. He also highlighted a project through which the US cancer agency is giving researchers access to patient-derived xenograft models that are annotated with clinical and DNA and RNA sequencing data.
Among the difficulties in precision oncology are the lack of precise tools for measuring whether the treatment is active against its intended molecular target. “Developing analytical tools to really understand proof of mechanism is not only difficult, but very expensive, and often outside the realm of possibility for a single investigator, even often for a single institution,” Doroshow said. “So, we’ve tried to think how we could develop a clinical trials network that can take advantage of proof-of-mechanism studies and develop those assays themselves.”
In an effort to mitigate this challenge, the NCI is slated to launch a lab network next month that will provide researchers in its early-phase clinical trial network with centralized assays for conducting genomic and pharmacodynamic analysis for molecularly targeted drugs.
For the past year, the NCI has been working on making its early-phase clinical trials network more efficient. This new lab network is part of these efforts, along with plans for providing Phase I study sites centralized clinical trial support and a cloud-based shared data environment.
At the WIN Symposium, Doroshow noted that the lab network will provide exome sequencing, RNASeq, whole-genome sequencing, panel tests, and a circulating tumor DNA panel that can be used in early studies for molecular characterization of cancers and therapeutic monitoring. The network will also include multiplex immunofluorescence assays to enable exploration of pharmacodynamic biomarkers.
As an example of the kinds of evaluations that will be enabled by the network, Doroshow described a multiplexed analysis from a needle biopsy that demonstrated four different mechanisms of DNA damage following treatment with a DNA damaging agent. Researchers used this information to develop baseline parameters for determining in tissue whether or not drugs were effective against various aspects of DNA damage and repair.
"These [parameters] are now being applied to a series of different assays and drug studies as the whole area of DNA damage modulation becomes a critically important part of our clinical trials network," Doroshow said.
Another challenge in precision oncology, particularly as the next generation of trials turn to combination therapies, is the inadequacy of current preclinical models, according to Doroshow. A few years ago, the NCI met with researchers in academia and at pharmaceutical companies to discuss gaps in preclinical cancer research and learned they had significant need for models that mimicked human tumors more closely than traditional cancer cell lines.
Subsequently, the NCI decided to advance the Patient-Derived Models Repository for housing patient-derived xenografts (PDX), 2D tissue culture models, and 3D organoids. To develop these models, NCI has collected 3,000 primary and metastatic tumor tissue samples from NCI-supported clinical trials and NCI-designated cancer centers.
The hope, Doroshow said, "is to be able to provide these tissues to investigators around the country and the world, [and] improve our ability to predict what treatments are useful." Each PDX model contains information, such as patients’ medical information, exome and RNASeq data from four to six representative PDXs, and genetic ancestry assessments.
Currently, researchers can request access to some 150 patient-derived xenograft models available at the NCI’s public website for this effort. The institute is planning to release more than 300 models in the next six to nine months, many of which are modeled from tissues in rare cancer types.
The agency also plans to distribute 700 cell lines from cancer-associated fibroblast, aimed at providing a more realistic snapshot of the tumor microenvironment, along with 2D and 3D models.
In a related effort, the NCI last fall launched the PDx Development and Trial Centers Research Network, or PDxNet, a consortium of institutions with large-scale facilities in PDX modeling, to advance translational research. These institutions will conduct preclinical trials of single and combination investigational new drugs that will inform the work of researchers in NCI’s Experimental Therapeutics Clinical Trials Network.
"We’re currently in the process of developing a pipeline [of PDX models] so that every new drug and new combination we hope to test will go through a screening platform, [and] that will assist us in our choice of clinical trials that we move forward," Doroshow said.