It is well-known that one molecular change may influence a pathway response to targeted therapies. Capturing this information from many diverse sources presents a challenge, as well as opportunity to leverage these complex molecular profiles in a searchable database that not only represents the underlying biological mechanisms but may predict patient response to a combination of targeted therapies and/or immunotherapies. The Clinical Knowledgebase (CKB), powered by The Jackson Laboratory, is an expertly curated and publically-accessible database that places relational links among gene variant, targeted therapies, efficacy evidence, and oncology clinical trials into the hands of clinicians, researchers, and patients.
Connecting a patient's genetic/genomic variants, which includes multiple mutations, aberrant expression, copy number variations, fusions, tumor mutational burden, and microsatellite instability, to a targeted treatment presents a sizeable challenge to precision medicine. CKB provides evidence-based information and allows visibility into potential opportunities for research that could reveal novel cancer treatments.
CKB relies on connections that link various data elements, such as parent genes connected to variants. Gene variants are built into molecular profiles and are assigned to relevant treatment approaches, supported by available data in the literature. The therapeutic response also takes into account patient indication, which is represented by an integrated disease ontology. Treatment approaches contain drug classes and therapies, as either single or drug combinations, which may be FDA-approved or currently in clinical trials.
Researchers are using CKB to interrogate various types of cancer. For example, prostate cancer is one of the leading cancer diagnosis in men. Those patients diagnosed with localized prostate cancer treated with the intent to cure via prostatectomy often respond to therapy and roughly 30% of patients will endure a relapse within 10 years. Despite advances made in identifying molecular pathway aberrations in these patients, there are noticeable gaps in clinical trials targeting specific inhibitors or signaling pathways, as identified through mining CKB content. Furthermore, from a research perspective, uncovering these gaps quickly and easily becomes a momentous challenge.
In a review by Statz and colleagues, the authors utilized CKB for data acquisition and analysis to identify a class of targeted therapies that are being evaluated for a specific cancer type. Based on their analysis, they revealed a link between a loss of PTEN, a tumor suppressor, and mTOR. Further study using the CKB, identified many trials investigating mTOR inhibition in prostate cancer; however, the use of this therapy has been met with limited efficacy. This lack of clinical efficacy could be predicted by analyzing retrospective preclinical data in CKB. In their analysis, they observed that there is a need for trials targeting both the PI3K and androgen receptor pathways, which may improve clinical outcomes and prolong survival in prostate cancer patients.
CKB, powered by JAX, enables the global medical and scientific communities to rapidly interpret large volumes of data generated by next-generation sequencing technologies. Additionally, the CKB provides critical data, such as informed patient care, developed and disseminated methodologies, and continues to advance precision medicine in the field of oncology.
JAX, the world leader in mammalian genetics and model research, has been enabling the global biomedical community with a comprehensive and innovative range of human disease models and preclinical testing services. As a non-profit research institute, JAX provides access to CKB as part of its mission to discover precise genomic solutions for disease and empowering the research community worldwide in the shared quest to improve human health. The combination of world-renowned principal investigators and its own clinical genomics lab uniquely positions JAX to continue power the depth and quality found in CKB, to have knowledge flow from the latest cancer research to the clinician and the patient.
Visit the JAX CKB page to learn more about this critical resource.
Statz CM., Patterson SE, Mockus SM. (2017) "mTOR Inhibitors in Castration-Resistant Prostate Cancer: A Systematic Review". Targ Oncol. 12: 47-59.