John Laurence Humm

Background/Objectives: The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by an enriched stroma, hampering the effectiveness of therapy. This co-clinical study aimed to (1) provide insight into early post-treatment changes in the TME using multiparametric magnetic resonance imaging (mpMRI)-derived quantitative imaging biomarkers (QIBs) in a preclinical PDAC model treated with radiotherapy and correlate these QIBs with histology; (2) evaluate the feasibility of obtaining these QIBs in patients with PDAC using clinically approved mpMRI data acquisitions. Methods: Athymic mice (n = 12) at pre- and post-treatment as well as patients with PDAC (n = 11) at pre-treatment underwent mpMRI including diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) data acquisition sequences. DW and DCE data were analyzed using monoexponential and extended Tofts models, respectively. DeepLIIF quantified the total percentage (%) of tumor cells in hematoxylin and eosin (H&E)-stained tissues from athymic mice. Spearman correlation and Wilcoxon signed rank tests were performed for statistical analysis. Results: In the preclinical PDAC model, mean pre- and post-treatment ADC and K^trans values differed significantly (p < 0.01), changing by 20.50% and 20.41%, respectively, and the median total tumor cells quantified by DeepLIIF was 24% (range: 15–53%). Post-treatment ADC values and relative change in v_e (rΔv_e) showed a significant negative correlation with total tumor cells (ρ = −0.77, p < 0.014 for ADC and ρ = −0.77, p = 0.009 for rΔv_e). In patients with PDAC, pre-treatment mean ADC and K^trans values were 1.76 × 10⁻³ (mm²/s) and 0.24 (min⁻¹), respectively. Conclusions: QIBs in both preclinical and clinical settings underscore their potential for future co-clinical research to evaluate emerging drug combinations targeting both tumor and stroma.

This study compares the subcellular dosimetry of 161 Tb and 177Lu, focusing on β⁻ particles, conversion electrons, and Auger electrons, and their relative contributions to cellular and subcellular damage. We aim to evaluate whether the higher emission yields of 161 Tb provide a therapeutic advantage, particularly for non-internalizing targeting agents in radiopharmaceutical therapy. A stochastic radionuclide decay model was implemented in MATLAB, incorporating internal conversion and Auger cascades and validated against ICRP 107. Geant4 track code simulations modeled electron transport in single-cell and voxelized membrane geometries. Energy deposition was assessed in the membrane, cytoplasm, and nucleus for 10,000 decays of each radionuclide. 161 Tb achieved similar nuclear energy deposition as 177Lu with about 25% of the decays, due to its higher yield of internal conversion. These conversion electrons contribute to nuclear damage playing a crucial role in cell damage. Auger electrons from 161 Tb additionally produced highly localized energy deposition at the cell membrane, that could also contribute to cell death. However, when normalizing for equivalent radiotoxicity to the bone marrow, around 75% of the 161 Tb decays provide a similar marrow absorbed dose as 177Lu, while still increasing the absorbed dose to the nucleus by approximately 18%. 161 Tb offers a more efficient subcellular energy deposition profile than 177Lu. It enables either similar therapeutic effect with fewer decays or enhanced nuclear absorbed dose under equivalent bone marrow toxicity. These results support the use of 161 Tb in targeted radiopharmaceutical therapy, particularly for isolated tumor cells and micrometastases.

Background: DNA repair inhibitors may safely enhance targeted radiotherapy if they can be administered when radioisotope has cleared from critical normal tissues. We investigated whether the kinetics of [ ¹⁷⁷ Lu]Lu-PSMA-617 (Pluvicto) would be consistent with such a strategy in metastatic castrate resistant prostate cancer (mCRPC). Materials and Methods: Pluvicto effective t _1/2 was measured for organs-at-risk (kidneys, parotid and submandibular glands) and lesions from 60 mCRPC patients. Based on this, a safe strategy for DDR inhibition was defined, and its potential benefit to the lesion was calculated, using published in vitro radiosensitivity data. Results: Pluvicto clearance is almost 3× faster in normal organs-at-risk compared to lesions. Using pre-clinical estimates of DDRi sensitization, a meaningful increase in lesion effective treatment dose could be achieved with minor additional risk to normal organs.

Preserving the integrity of the genome is critical to healthy cellular growth and development. Under normal circumstances, the eukaryotic mismatch repair (MMR) machinery is effective at detecting DNA polymerase errors and maintaining the fidelity of the genome. However, cells with inactivated MMR machinery are prone to the accumulation of mutations and tumorigenesis. This study explores the theoretical potential of rhodium-99- and iodine-123-labeled DNA metalloinsertors as Auger electron-emitting radiotherapeutics for cancers characterized by MMR deficiency. A Monte Carlo code was developed in MATLAB^® to obtain Auger electron energy spectra for ⁹⁹Rh and ¹²³I. Using Geant4 track structure simulations, we determined the difference in effectiveness of these two Auger electron-emitting radionuclides in direct damage to DNA and the ability to produce double strand break damage (dsb) to the DNA comparing two different constructors 'G4EmDNAPhysics_option2' and 'G4EmDNAPhysics_option4'. Differences in the Auger electron emission spectra of ⁹⁹Rh and ¹²³I arise from their electronic structure: ¹²³I favors more complex cascades and ultra-low-energy electrons, while ⁹⁹Rh produces electrons with energies more suited to DNA damage. Despite similar total electron yields, the emissions of ⁹⁹Rh are more effective at causing dsb (0.71 vs. 0.60 dsb/decay for ⁹⁹Rh and ¹²³I, respectively, using constructor 'G4EmDNAPhysics_option2' and 0.81 dsb/decay for ⁹⁹Rh vs. 0.71 dsb/decay for ¹²³I when using 'G4EmDNAPhysics_option4'. This theoretical study leverages both simulation and comparative analyses to identify ⁹⁹Rh as a promising Auger electron-emitting nuclide for radiotheranostics, as it offers superior DNA damage efficacy compared to ¹²³I.

This phase 1, dose-escalation study examined the use of the radiolabeled antibody ¹²⁴I-Omburtamab delivered directly to brain-stem tumors via convection-enhanced delivery (CED). CED bypasses the blood–brain barrier by injecting the agent under the pressure of a peristaltic pump to convectively drive the therapeutic agent through the brain tissue and tumor compartment, enabling high concentrations at the target site. We evaluated ¹²⁴I-Omburtamab’s potential to deliver therapeutic radiation doses to diffuse intrinsic pontine glioma in children. PET and MRI were used to assess the alignment between the intended and actual distribution of the agent, with an analysis of tumor coverage and radiation absorbed doses. Methods:¹²⁴I-Omburtamab doses ranging from 9.25 to 370 MBq were administered to 36 patients. Tumor distribution volumes were derived from PET images by placing volumes of interest over lesions and overlaying them onto T2-weighted fluid-attenuated inversion recovery MRI-delineated tumor volumes. Dosimetry metrics evaluated after CED included dose-volume histograms, tumor coverage percentage, and the Dice similarity coefficient between the antibody distribution and tumor volume. A 4-quadrant scatter plot of Dice similarity versus tumor coverage was used to classify treatment variations among patients. Results: Serial PET scans showed ¹²⁴I-Omburtamab localization in brain-stem lesions from 1 h to 7 d ± 1 d after dose administration. Coverage analysis revealed that 29 patients had tumor volume coverage greater than 50%, and 28 had a Dice similarity coefficient over 50%. The 4-quadrant statistical analysis—percentage of coverage versus Dice similarity coefficient—showed that 27 patients had acceptable coverage for treatment, and 4 patients experiencing suboptimal tumor coverage. Conclusion: CED of ¹²⁴I-Omburtamab is a novel approach for delivering radiolabeled therapies into brain-stem tumors. Imaging enabled quantification of radiation dose coverage within the MRI-defined tumor target, highlighting the importance of precise alignment between therapeutic agent distribution and tumor volume. Visual Abstract

Background The small molecule radiotracer ¹²⁴I-PU-H71 is an imaging biomarker of epichaperome formation. The tracer has been established to localize in tissues under chronic stress, specifically in cancer cells and neurodegenerative brain cells. A first-in-human imaging trial using positron emission tomography (PET) in cancer patients revealed unexpected tracer accumulation in the myocardium. Purpose To describe human ¹²⁴I-PU-H71 myocardial biodistribution and pharmacokinetics in a series of cancer patients with no history of cardiovascular disease. Methods 25 cancer patients (age 22–75 years, M:F − 7:18) with no history of cardiovascular disease received intravenous injections with microdose ¹²⁴I-PU-H71 while at rest, followed by dynamic and gated/non-gated PET image data acquisitions. Region-of-interest (ROI) analysis of left ventricular myocardium (LVmyo) and background left atrium quantified tracer concentrations as standardized uptake value (SUV) and uptake ratios. Kinetic rate constants were evaluated by a two-tissue compartment model. Results Myocardial accumulation of ¹²⁴I-PU-H71 was prominent in all patients, with median LVmyo SUVmean (interquartile range, IQR) of 2.8 (IQR, 2.13–3.29), 2.5 (IQR, 1.94–2.98), 2.4 (IQR, 1.73–3.31) and 1.0 (IQR, 0.61–2.45), and median LVmyo/blood-pool ratios of 1.9 (IQR, 1.57–2.38), 2.0 (IQR, 1.53–2.32), 3.6 (IQR, 2.91–4.06) and 3.9 (IQR, 2.62–5.08) at 1–9 min, 14–23 min, 3–4 h and 21–25 h, respectively on non-gated PET images. Myocardium showed peak uptake within 2 min post-injection, with sustained myocardial tracer-concentration at 4 h post-injection. Pharmacokinetic modeling revealed median K₁ = 0.45 ml/min/g (IQR, 0.38–0.62); k₂ = 0.47 min^− 1 (IQR, 0.27–0.71); k₃ = 0.16 min^− 1 (IQR, 0.09–0.26); and k₄ = 0.0038 min^− 1 (IQR, 0.0015–0.0057). Regional assessment demonstrated essentially uniform tracer uptake in LV and myocardial segments; with normal LVEF in all patients (mean 57.7 ± 3.5%); and no patients suffered cardiac events over subsequent 12-month period. Conclusion Our study finds human myocardial epichaperome expression, as quantified by ¹²⁴I-PU-H71 PET. Our data indicates PU-H71 PET merits further study as a myocardial epichaperome biomarker, with potential application in drug development, possibly as a biomarker in subclinical cardiac dysfunction.