" New Paradigms for Radiotracer Development in Oncology"
Date
Michael J. Evans, PhD
Postdoctoral research with Professor Charles L. Sawyers
Human Oncology and Pathogenesis Program
Memorial Sloan-Kettering Cancer Center
New York, NY
Abstract: As parallel advances in cancer biology and drug development continue to elevate the role of targeted therapies in oncology, the need for imaging biomarkers that systematically measure patho-biology impacted by effective therapeutic intervention has become more urgent. Although the molecular imaging community has a commitment to develop technologies to this end, few investigational radiotracers have been deliberately engineered to measure the activity of common oncogenic signaling pathways often addressed by targeted therapies. For prostate cancer, we have begun to address this challenge by developing a panel of radiotracers for positron emission tomography (PET) to measure the output of several important transcription factors, including the androgen receptor, MYC, and HIF1a. The common design strategy among these radiotracer development programs is to exploit expression changes among imageable target genes to non-invasively measure the pathological activation (and pharmacological inhibition) of the respective transcription factor. Our work in preclinical models has effectively established proof-of-concept, in many cases providing clearer evidence of oncogene status than several common radiotracers that measure a symptom of tumor burden. Another provocative finding from these studies was that the epidemiological history of a serum isoform for a respective imageable tumor antigen can provide a framework to instruct radiotracer development. We conceived of this notion while studying a radiotracer targeting prostate specific antigen (PSA), wherein it became reasonable to propose that an imaging tool could rescue the documented shortcomings associated with interpreting serum PSA levels in castration resistant prostate cancer. We have since found that many other well studied serum biomarkers have limitations that could be overcome with an appropriately designed cognate imaging tool (e.g. CA19.9, CA125), and have begun preclinical validation studies. In summary, these findings can be condensed into two themes that I wish to represent to the community: (1) imaging events more closely related to the biology of important drug targets may increase the information content of PET scans, and (2) deliberately targeting an imageable form of a serum biomarker could more clearly define a clinical utility for investigational radiotracers. Importantly, these concepts can be readily applied to other malignancies known to be enriched in a handful of recurrent oncogenic lesions to streamline radiotracer development.
Please note that Dr. Michael J. Evans is an applicant for the Biomarker Imaging faculty position.
Type
Time Duration
Michael J. Evans, PhD
Postdoctoral research with Professor Charles L. Sawyers
Human Oncology and Pathogenesis Program
Memorial Sloan-Kettering Cancer Center
New York, NY
Abstract: As parallel advances in cancer biology and drug development continue to elevate the role of targeted therapies in oncology, the need for imaging biomarkers that systematically measure patho-biology impacted by effective therapeutic intervention has become more urgent. Although the molecular imaging community has a commitment to develop technologies to this end, few investigational radiotracers have been deliberately engineered to measure the activity of common oncogenic signaling pathways often addressed by targeted therapies. For prostate cancer, we have begun to address this challenge by developing a panel of radiotracers for positron emission tomography (PET) to measure the output of several important transcription factors, including the androgen receptor, MYC, and HIF1a. The common design strategy among these radiotracer development programs is to exploit expression changes among imageable target genes to non-invasively measure the pathological activation (and pharmacological inhibition) of the respective transcription factor. Our work in preclinical models has effectively established proof-of-concept, in many cases providing clearer evidence of oncogene status than several common radiotracers that measure a symptom of tumor burden. Another provocative finding from these studies was that the epidemiological history of a serum isoform for a respective imageable tumor antigen can provide a framework to instruct radiotracer development. We conceived of this notion while studying a radiotracer targeting prostate specific antigen (PSA), wherein it became reasonable to propose that an imaging tool could rescue the documented shortcomings associated with interpreting serum PSA levels in castration resistant prostate cancer. We have since found that many other well studied serum biomarkers have limitations that could be overcome with an appropriately designed cognate imaging tool (e.g. CA19.9, CA125), and have begun preclinical validation studies. In summary, these findings can be condensed into two themes that I wish to represent to the community: (1) imaging events more closely related to the biology of important drug targets may increase the information content of PET scans, and (2) deliberately targeting an imageable form of a serum biomarker could more clearly define a clinical utility for investigational radiotracers. Importantly, these concepts can be readily applied to other malignancies known to be enriched in a handful of recurrent oncogenic lesions to streamline radiotracer development.
Please note that Dr. Michael J. Evans is an applicant for the Biomarker Imaging faculty position.