This R01 application from Memorial Sloan-Kettering Cancer Center is founded on recent work spearheaded by the MPIs Professor Jason Lewis and Dr. Michael Evans in close collaboration with basic science and clinical investigators. Based on the evocative preliminary data, the central hypothesis is that the novel radiotracer 89Zr- labeled transferrin (89Zr-Tf) will be a non-invasive tool for the staging and management of prostate cancer. What distinguishes this radiotracer from its contemporaries (18F-FDG, 18F-FACBC, ProstascintTM) is that it systematically targets a tumor associated protein (the transferrin receptor [TFRC]) whose expression and bioactivity is directly linked to the pathological activation of MYC or PI3K-two oncogenes deeply relevant to the pathogenesis of prostate cancer. To address our hypothesis three Specific Aims have been proposed;
Specific Aim 1 (SA1) intends to establish that 89Zr-Tf can measure the changes in MYC signaling required to confer a tumor response to JQ1, an inhibitor of the epigenetic protein BRD4 (and MYC);
Specific Aim 2 (SA2) intends to show that 89Zr-Tf can measure aberrant PI3K signaling in prostate cancer and monitor tumor response to targeted therapies;and, Specific Aim 3 (SA3) proposes to conduct first-in-human studies (Phase 0) of 89Zr-Tf in newly diagnosed prostate cancer to initiate a larger clinical program to evaluate the many potential applications for 89Zr-T in man. The innovation of this proposal derives from the original design of 89Zr-Tf. By invoking a clear biological mandate for its development (i.e. the straightforward functional relationship between TFRC and MYC or PI3K), the application of 89Zr-Tf extends beyond the detection of a gross tumor property to measuring the degree of signaling through two important oncogenic pathways. Moreover, the exceptional pharmacokinetics of 89Zr-Tf clearly distinguishes it from other clinically validated technologies targeting the transferrin receptor (67Ga-citrate). These considerations directly influence the impact of the proposal, as we respectfully submit that we may answer at least three questions related to fundamentally important themes in cancer diagnostics: (1) does the basal uptake of 89Zr-Tf quantitatively distinguish tumors bearing pathological activation of MYC and/or PI3K signaling (prognostic biomarker development), (2) do post-therapy changes in 89Zr-Tf uptake measure target inhibition (drug pharmaco- dynamics and clinical trial endpoints), and (3) can 89Zr-Tf more clearly distinguish tumor topography and dissemination in newly diagnosed prostate cancer (accurate staging and treatment planning). If successful this PET agent could cause a significant paradigm shift in radiotracer development strategies and the diagnosis and management of prostate cancer in man.
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 the biology associated with therapeutic intervention has become more urgent. Indeed, that variable treatment responses or emergent resistance phenotypes are often documented in man argues strongly for diagnostic technologies that can be realistically applied post therapy to capture dynamic patterns of disease response. Although the molecular imaging community has a commitment to develop technologies to this end, relatively few investigational radiotracers relate to common oncogenic signaling pathways via obviously interpretable biology. This R01 proposal directly addresses this unmet clinical need by capitalizing on evidence showing that expression of the transferrin receptor (TFRC)-a cell surface protein that can be targeted in vivo for imaging with the PET radiotracer 89Zr-labeled transferrin (89Zr-Tf)-is regulated by aberrant MYC and PI3K pathway signaling. Activation of these pathways is centrally relevant to the pathogenesis of many cancers (including prostate cancer), and several drug development programs have been initiated in animal and man to target these events. Consequently, we propose to expand upon our recently published proof-of-concept work to evaluate the use of 89Zr-Tf PET as a pharmacodynamic biomarker or an early response indicator to therapies targeting the pathological activation of MYC and PI3K pathway signaling in models of prostate cancer, a pathology known to be enriched in both oncogenic lesions. Moreover, we will conduct phase 0 and first-in-man studies in the context of newly diagnosed prostate cancer to begin the clinical assessment of 89Zr-Tf PET.
|Flavell, Robert R; Truillet, Charles; Regan, Melanie K et al. (2016) Caged [(18)F]FDG Glycosylamines for Imaging Acidic Tumor Microenvironments Using Positron Emission Tomography. Bioconjug Chem 27:170-8|
|Carroll, V N; Truillet, C; Shen, B et al. (2016) [(11)C]Ascorbic and [(11)C]dehydroascorbic acid, an endogenous redox pair for sensing reactive oxygen species using positron emission tomography. Chem Commun (Camb) 52:4888-90|
|Truillet, Charles; Cunningham, John T; Parker, Matthew F L et al. (2016) Non-invasive measurement of mTORC1 signaling with 89Zr-transferrin. Clin Cancer Res :|
|Sharma, Sai Kiran; Nemieboka, Brandon; Sala, Evis et al. (2016) Molecular Imaging of Ovarian Cancer. J Nucl Med 57:827-33|
|Zeglis, Brian M; Houghton, Jacob L; Evans, Michael J et al. (2014) Underscoring the influence of inorganic chemistry on nuclear imaging with radiometals. Inorg Chem 53:1880-99|
|Doran, Michael G; Watson, Philip A; Cheal, Sarah M et al. (2014) Annotating STEAP1 regulation in prostate cancer with 89Zr immuno-PET. J Nucl Med 55:2045-9|
|Huang, Chun-Hao; Lujambio, Amaia; Zuber, Johannes et al. (2014) CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev 28:1800-14|
|Thorek, Daniel L J; Evans, Michael J; Carlsson, Sigrid V et al. (2013) Prostate-specific kallikrein-related peptidases and their relation to prostate cancer biology and detection. Established relevance and emerging roles. Thromb Haemost 110:484-92|