Harnessing Preclinical Molecular Imaging to Inform Advances in Personalized Cancer Medicine

Clark, Peter M.; Ebiana, Victoria; Gosa, Laura; Cloughesy, Timothy F.; Nathanson, David

doi:10.2967/jnumed.116.181693

Cited by 15 publications

(11 citation statements)

References 87 publications

(125 reference statements)

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“…Given the breadth of potential adaptive mechanisms, coupled with the molecular heterogeneity of GBM, genetic biomarkers may alone be insufficient to predict responses to this approach. Our results emphasize the value of a functional biomarker, in this case changes in glucose uptake 46 , as a means to rapidly stratify metabolic responders and non-responders.…”

Section: Discussionmentioning

confidence: 53%

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma

Wilson

Gosa

Daniëls

et al. 2017

Nat Med

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Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for novel therapeutic strategies in cancer. Here we show that acute inhibition of EGFR-driven glucose metabolism induces minimal cell death, yet lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that, following attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, pharmacological stabilization of p53 with the brain-penetrant small molecule, Idasanutlin, in combination with targeting EGFR-driven glucose metabolism promoted synthetic lethality in orthotopic xenograft models. Notably, neither inhibition of EGFR signaling, nor genetic analysis of EGFR, was sufficient to predict sensitivity to this new therapeutic combination. Conversely, rapid changes in 18F-fluorodeoxyglucose (18F-FDG) uptake using non-invasive positron emission tomography was an effective predictive biomarker of response in vivo. Together, these studies identify a critical link between oncogene signaling, glucose metabolism, and cytoplasmic p53, which could be exploited for combination therapy in GBM and potentially, other malignancies.

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Section: Discussionmentioning

confidence: 53%

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma

Wilson

Gosa

Daniëls

et al. 2017

Nat Med

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“…One potential application for a PET strategy that can quantify liver-infiltrating CD4 and CD8 T lymphocytes is monitoring the response of these cells to immunosuppressive therapies, similar to the role of PET in other fields, including oncology (39). Studies suggest, and we found, that pretreatment of mice with the immunosuppressive drug dexamethasone can block ConA-induced autoimmune hepatitis (Fig.…”

Section: Changes In Hepatic 18 F-fac Accumulation Can Be Used To Monimentioning

confidence: 56%

¹⁸F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis

et al. 2018

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Immune cell-mediated attack on the liver is a defining feature of autoimmune hepatitis and hepatic allograft rejection. Despite an assortment of diagnostic tools, invasive biopsies remain the only method for identifying immune cells in the liver. We evaluated whether PET imaging with radiotracers that quantify immune activation (F-FDG and F-1-(2'-deoxy-2'-fluoro-arabinofuranosyl)cytosine [F-FAC]) and hepatocyte biology (F-2-deoxy-2-fluoroarabinose [F-DFA]) can visualize and quantify liver-infiltrating immune cells and hepatocyte inflammation, respectively, in a preclinical model of autoimmune hepatitis. Mice treated with concanavalin A (ConA) to induce a model of autoimmune hepatitis or vehicle were imaged withF-FDG, F-FAC, andF-DFA PET. Immunohistochemistry, digital autoradiography, and ex vivo accumulation assays were used to localize areas of altered radiotracer accumulation in the liver. For comparison, mice treated with an adenovirus to induce a viral hepatitis were imaged with F-FDG,F-FAC, and F-DFA PET.F-FAC PET was performed on mice treated with ConA and vehicle or with ConA and dexamethasone. Biopsy samples of patients with autoimmune hepatitis were immunostained for deoxycytidine kinase. Hepatic accumulation ofF-FDG and F-FAC was 173% and 61% higher, respectively, and hepatic accumulation ofF-DFA was 41% lower, in a mouse model of autoimmune hepatitis than in control mice. Increased hepatic F-FDG accumulation was localized to infiltrating leukocytes and inflamed sinusoidal endothelial cells, increased hepaticF-FAC accumulation was concentrated in infiltrating CD4 and CD8 cells, and decreased hepatic F-DFA accumulation was apparent in hepatocytes throughout the liver. In contrast, viral hepatitis increased hepaticF-FDG accumulation by 109% and decreased hepatic F-DFA accumulation by 20% but had no effect on hepaticF-FAC accumulation (nonsignificant 2% decrease). F-FAC PET provided a noninvasive biomarker of the efficacy of dexamethasone for treating the autoimmune hepatitis model. Infiltrating leukocytes in liver biopsy samples from patients with autoimmune hepatitis express high levels of deoxycytidine kinase, a rate-limiting enzyme in the accumulation ofF-FAC. Our data suggest that PET can be used to noninvasively visualize activated leukocytes and inflamed hepatocytes in a mouse model of autoimmune hepatitis.

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“…In other fields, PET imaging has proven effective for monitoring therapeutic responses (33). Approved therapies for acetaminophen overdose are limited but new treatments are in development (34,35).…”

Section: Pet Imaging With 18 F-dfa Can Monitor the Efficacy Of Treatmmentioning

confidence: 99%

Noninvasive Imaging of Drug-Induced Liver Injury with ¹⁸F-DFA PET

et al. 2018

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Drug-induced liver failure is a significant indication for a liver transplant, and unexpected liver toxicity is a major reason that otherwise effective therapies are removed from the market. Various methods exist for monitoring liver injury but are often inadequate to predict liver failure. New diagnostic tools are needed. We evaluate in a preclinical model whetherF-2-deoxy-2-fluoroarabinose (F-DFA), a PET radiotracer that measures the ribose salvage pathway, can be used to monitor acetaminophen-induced liver injury and failure. Mice treated with vehicle, 100, 300, or 500 mg/kg acetaminophen for 7 or 21 h were imaged with F-FDG andF-DFA PET. Hepatic radiotracer accumulation was correlated to survival and percentage of nonnecrotic tissue in the liver. Mice treated with acetaminophen and vehicle or -acetylcysteine were imaged withF-DFA PET. F-DFA accumulation was evaluated in human hepatocytes engrafted into the mouse liver. We show that hepatic F-DFA accumulation is 49%-52% lower in mice treated with high-dose acetaminophen than in mice treated with low-dose acetaminophen or vehicle. Under these same conditions, hepaticF-FDG accumulation was unaffected. At 21 h after acetaminophen treatment, hepatic F-DFA accumulation can distinguish mice that will succumb to the liver injury from those that will survive it (6.2 vs. 9.7 signal to background, respectively). HepaticF-DFA accumulation in this model provides a tomographic representation of hepatocyte density in the liver, with a between hepaticF-DFA accumulation and percentage of nonnecrotic tissue of 0.70. PET imaging with F-DFA can be used to distinguish effective from ineffective resolution of acetaminophen-induced liver injury with-acetylcysteine (15.6 vs. 6.2 signal to background, respectively). Human hepatocytes, in culture or engrafted into a mouse liver, have levels of ribose salvage activity similar to those of mouse hepatocytes. Our findings suggest that PET imaging withF-DFA can be used to visualize and quantify drug-induced acute liver injury and may provide information on the progression from liver injury to hepatic failure.

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Harnessing Preclinical Molecular Imaging to Inform Advances in Personalized Cancer Medicine

Cited by 15 publications

References 87 publications

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma

¹⁸F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis

Noninvasive Imaging of Drug-Induced Liver Injury with ¹⁸F-DFA PET

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Harnessing Preclinical Molecular Imaging to Inform Advances in Personalized Cancer Medicine

Cited by 15 publications

References 87 publications

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma

18F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis

Noninvasive Imaging of Drug-Induced Liver Injury with 18F-DFA PET

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¹⁸F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis

Noninvasive Imaging of Drug-Induced Liver Injury with ¹⁸F-DFA PET