المؤلفون: Murley, Grace Abigail, Pudakalakatti, Shivanand, Padron, William, Wang, Muxin, Armijo, Ryan, Delacerda, Jorge, Dominic, Abishai, Chin, Renee, Schuler, William, Rai, Kunal, Pagel, Marty, Bhattacharya, Pratip

المصدر: Journal of Clinical and Translational Science ; volume 8, issue s1, page 130-130 ; ISSN 2059-8661

الوصف: OBJECTIVES/GOALS: Acidity and the lactate-to-pyruvate ratio correlate with immunotherapy resistance. AcidoCEST MRI and hyperpolarized magnetic resonance spectroscopy (HP-MRS) measure extracellular pH and lactate-to-pyruvate ratio. We will establish a baseline for these biomarkers then observe changes after combination esomeprazole and immunotherapy. METHODS/STUDY POPULATION: We used multiple melanoma models created via serial in vivo passage under immunotherapeutic pressure (FVAX, CTLA-4, PD-1, PD-L1). We used four of these corresponding to 25%, 50%, 75% and 100% resistance (TMT, F2, F3, and F4, respectively). HP-MRS was performed two weeks post implantation in male BL6 mice with AcidoCEST MRI 2-3 days later. Tumors were implanted in additional mice and grown for 1 week. We used esomeprazole as a possible immunotherapy sensitizer. Esomeprazole (or PBS) alone and in combination with immune checkpoint blockade (ICB; αCTLA-4, αPD-1) was then conducted every 3 days for 3 doses. ICB was administered 3h after esomeprazole. AcidoCEST MRI was performed the day after the final dose of combination therapy and 3h after esomeprazole (or PBS) alone. HP-MRS was performed 2-3 days after acidoCEST MRI. RESULTS/ANTICIPATED RESULTS: There was a statistical increase in the lactate-to-pyruvate ratio of the F4 group compared with TMT, F2, and F3 groups (p < 0.05). The TMT, F2, and F3 groups did not differ significantly. The extracellular pH (pHe) of the TMT group was statistically lower than the F2 and F4 groups (p < 0.05). The pHe did not differ significantly between the TMT and F3 groups nor the F2, F3, and F4 groups. The lactate-to-pyruvate ratio and pHe after combination treatment with esomeprazole and ICB did not differ compared to PBS+ICB control. Treatment with esomeprazole alone generated higher lactate-to-pyruvate ratio compared with PBS alone. Tumor volume curves and survival curves of mice bearing F4 tumors treated with esomeprazole combination with ICB showed no difference compared with PBS+ICB, PBS alone, and ...

الإتاحة: https://doi.org/10.1017/cts.2024.376Test
https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S2059866124003765Test

المؤلفون: Li, Tianzhe^1,2,3 (AUTHOR), Murley, Grace A.^1,2 (AUTHOR), Liang, Xiaofei¹ (AUTHOR), Chin, Renee L.^1,2 (AUTHOR), de la Cerda, Jorge¹ (AUTHOR), Schuler, F. William¹ (AUTHOR), Pagel, Mark D.^1,4 (AUTHOR) mdpagel2@wisc.edu

المصدر: Molecular Imaging & Biology. Jun2024, Vol. 26 Issue 3, p448-458. 11p.

مصطلحات موضوعية: *ELECTRON paramagnetic resonance, *PATHOLOGICAL physiology, *CONTRAST media, *RESPIRATION, *PARTIAL pressure, *RADIOTHERAPY

مستخلص: Purpose: Electron Paramagnetic Resonance Imaging (EPRI) can image the partial pressure of oxygen (pO2) within in vivo tumor models. We sought to develop Oxygen Enhanced (OE) EPRI that measures tumor pO2 with breathing gases of 21% O2 (pO221%) and 100% O2 (pO2100%), and the differences in pO2 between breathing gases (ΔpO2). We applied OE EPRI to study the early change in tumor pathophysiology in response to radiotherapy in two tumor models of pancreatic cancer. Procedures: We developed a protocol that intraperitoneally administered OX071, a trityl radical contrast agent, and then acquired anatomical MR images to localize the tumor. Subsequently, we acquired two pO221% and two pO2100% maps using the T1 relaxation time of OX071 measured with EPRI and a R1-pO2 calibration of OX071. We studied 4T1 flank tumor model to evaluate the repeatability of OE EPRI. We then applied OE EPRI to study COLO 357 and Su.86.86 flank tumor models treated with 10 Gy radiotherapy. Results: The repeatability of mean pO2 for individual tumors was ± 2.6 Torr between successive scans when breathing 21% O2 or 100% O2, representing a precision of 9.6%. Tumor pO221% and pO2100% decreased after radiotherapy for both models, although the decreases were not significant or only moderately significant, and the effect sizes were modest. For comparison, ΔpO2 showed a large, highly significant decrease after radiotherapy, and the effect size was large. MANOVA and analyses of the HF10 hypoxia fraction provided similar results. Conclusions: EPRI can evaluate tumor pO2 with outstanding precision relative to other imaging modalities. The change in ΔpO2 before vs. after treatment was the best parameter for measuring the early change in tumor pathophysiology in response to radiotherapy. Our studies have established ΔpO2 from OE EPRI as a new parameter, and have established that OE EPRI is a valuable new methodology for molecular imaging. [ABSTRACT FROM AUTHOR]