[18F]FluorThanatrace PET imaging as a biomarker of response to PARP inhibitors in breast cancer

Communications Medicine · 2025-03-25 · 7 citations

Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for Breast Cancer gene (BRCA)-mutant HER2- breast cancer, and there is clinical interest in expanding indications to include homologous recombination deficient (HRD) breast cancers. Yet, response in these populations remains variable, suggesting clinical utility in developing a better biomarker to select patients for PARPi and predict response. Here, we evaluate a radiolabeled PARPi, [18F]FluorThanatrace ([18F]FTT), as a functional biomarker of PARPi response in breast cancer. A single-arm prospective observational trial was conducted at the University of Pennsylvania. [18F]FTT-PET uptake was measured in 24 women with untreated primary breast cancer and correlated with tumor HRD score. In a separate cohort of ten subjects with metastatic HER- breast cancer, [18F]FTT-PET uptake was measured at baseline and after a short interval on a PARPi (a measure of drug-target engagement) and correlated to progression free survival (PFS). Here we show that baseline [18F]FTT-PET uptake does not correlate to HRD tissue score, supporting that [18F]FTT provides distinct information from genetic features. Baseline [18F]FTT-PET uptake and the change in uptake from baseline to after PARPi initiation significantly correlates to PFS in woman with breast cancer who received a PARPi (ρ = 0.74, P = 0.023 and ρ = −0.86, P = 0.012, respectively). These early results suggest the potential of [18F]FTT-PET to select patients for PARPi treatment and monitor in vivo pharmacodynamics after therapy start. Absence of association with HRD scores supports [18F]FTT uptake as a novel measure that may be leveraged as a biomarker. Further studies are warranted. PARP inhibitors are an effective treatment for breast cancer; however, do not work in all patients. Our goal is to identify individuals with breast cancer who are likely to respond to this treatment, so we do not administer the drug to those who will not benefit and could experience side effects. We gave people a probe that is visible by imaging and that binds to the PARP protein in the body. We found that the amount of probe taken up by a person’s tumor was an indicator of whether they would respond well to PARP inhibitor treatment. Using such a probe could help doctors make decisions about whether to treat breast cancer patients with PARP inhibitors. Gitto, Pantel et al. evaluate a PARP-targeted PET imaging ligand, [18 F]FlourThanatrace, as a biomarker of response to PARP inhibitors in patients with breast cancer. There is [18 F]FlourThanatrace uptake in the tumor before treatment, and a decline in uptake after PARP inhibitor therapy initiation, correlating with patient progression free survival.

A biorthogonal chemistry approach for high-contrast antibody imaging of lymphoma at early time points

EJNMMI Research · 2025-03-24 · 2 citations

BACKGROUND: Monoclonal antibodies are highly specific for their targets making them effective for cancer therapy. However, their large molecular weight causes slow blood clearance, often requiring weeks to be removed from circulation. This limitation affects companion nuclear imaging and antibody-based diagnostics, necessitating delayed imaging. We report the expansion of a methodology improving positron emission tomography (PET) contrast of the lymphoma biomarker CD20 at early time points after radiolabeled antibody administration. Intact radioimmunoconjugates are allowed to stay in circulation long enough to accumulate in tumors, and then, using a chemical trigger, we induced rapid clearance of the radioactivity from non-target tissues by cleaving the linker between the antibody and the radioactivity. For brevity, we refer to the this as the Tetrazine KnockOut (TKO) method which uses the transcyclooctene-tetrazine (TCO-Tz) reaction, wherein an antibody is conjugated with linker containing TCO and a radioisotope. RESULTS: Zr]Zr-DFO-TCO-rituximab in a lymphoma model with PET imaging after Tz or vehicle administration. Treatment with Tz induced > 70% cleavage of the TCO linker in vitro within 30 min. Internalizing radioimmunoconjugates exhibited similar cellular uptake with Tz compared to vehicle, whereas decreased uptake was seen with slowly internalizing antibodies. In rodents, Tz rapidly liberated the radioactivity from the antibody, cleared from the blood, and accumulated in the bladder. TKO resulted in > 50% decreased radioactivity in non-target organs following Tz injection. No decrease in tumor uptake was observed when rate of antibody internalization is higher in a lymphoma model, and the target-to-background ratio increased by > twofold in comparison with Tz nontreated groups at 24 h. CONCLUSION: The TKO approach potentiates early imaging of rituximab radioimmunoconjugates and has translational potential for lymphoma imaging.

Abstract A029: PARP-targeted alpha therapy for the treatment of PARP inhibitor resistant ovarian cancer

Cancer Research · 2025-09-19

Abstract Background: While epithelial ovarian cancer (EOC) generally responds to frontline therapy, most tumors develop resistance to current treatments, prompting the need for innovative therapies. Homologous recombination deficient EOC with PARP inhibitor (PARPi) resistance are particularly difficult to treat. Here, we evaluate a novel theranostic approach for the treatment of drug-resistant EOC that leverages overexpression of PARP1 in EOC (even when PARPi resistant). Our platform is based on a small molecule similar to rucaparib labeled with 211At for alpha therapy ([211At]ParaThanatrace, PTT) and 18F for PET/CT ([18F]FluorThanatrace, FTT). Materials and Methods: PTT was synthesized and evaluated for cytotoxicity and binding properties in 16 human and 2 murine EOC cell lines with varying sensitivity to PARPi and chemotherapy. Maximum specific binding (Bmax), equilibrium dissociation constant (Kd), and half minimal effective concentration (EC50) were calculated. PTT efficacy was evaluated in a syngeneic mouse model of mouse oviduct secretory epithelial derived cells (MOSEC) engineered to include loss of Trp53 and Pten. Results: PTT had a 30-fold greater in vitro cytotoxicity than untargeted 211At. Comparing EOC OVCAR8 cells with endogenous PARP1 expression versus OVCAR8-PARP1KO cells, PTT activity was dependent on PARP1 expression (EC50 0.0079 vs. 0.027 MBq/mL, respectively). Human ovarian cancer cell lines had variable sensitivity with a range of EC50’s from 0.0021-0.80 MBq/mL (mean=0.011, median=0.007), concentrations that are safely achievable in vivo. Cytotoxicity was similar between PARPi-sensitive and -resistant cells (P=0.86). The number of PTT binding sites per cell (Bmax) ranged from 6.31x105-2.14x106 and the binding affinity was 2.0-11.4 nM. EC50 values significantly correlated to binding affinity (r=0.69, P=0.009), whereas no correlation was observed with Bmax, PARP1 expression, or tumor cell doubling time. To evaluate the anti-tumor efficacy in ovarian cancer in vivo, homologous proficient MOSECs were inoculated intraperitoneally into immunocompetent C57BL/6 mice. Four days following tumor inoculation; mice were treated intravenously with four fractionated doses of PTT at the MTD (48 MB/kg/fraction) or ½ MTD (24 MB/kg/fraction) over two weeks. PTT treatment was tolerable and significantly prolonged survival compared to untreated control mice (P=0.0027). In vitro cytotoxicity determined an IC50 of 0.97 mCi/mL in MOSEC, which is considerably higher than most of the evaluated human EOC cell lines, further supporting the efficacy of PTT in vivo. Conclusions: PTT cytotoxicity is largely independent of PARPi-sensitivity but reliant on PARPi binding affinity and line-specific radiation sensitivity. In vivo data supports the safety and efficacy of PTT. Overall, this study highlights a novel role for theranostic radiopharmaceutical therapy in drug-resistant EOC. Citation Format: Sarah B. Gitto, Aladdin Riad, Alastair McArthur, Fiona Simpkins, Daniel A. Pryma, Micheal D. Farwell. PARP-targeted alpha therapy for the treatment of PARP inhibitor resistant ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A029.

Abstract P2-07-04: [18F]FluorThanatrace PET imaging correlates with response to PARP inhibitors in breast cancer: a pilot study

Clinical Cancer Research · 2025-06-13

Abstract Introduction: PARP inhibitors (PARPi) are approved for BRCA-mutant HER2- breast cancer, and there is clinical interest in expanding indications to include homologous recombination deficient (HRD) breast cancers. Yet, response in these populations remains variable, suggesting clinical utility in developing a better biomarker to select patients for PARPi and predict response. Here, we evaluated the 18F-labeled PARPi, [18F]FluorThanatrace (FTT), as a functional biomarker of PARPi response in breast cancer. Methods: A single-arm prospective observational trial was conducted at the University of Pennsylvania from May 2017 to March 2022 (NCT03083288, NCT03846167). Subjects ≥18 years of age with known or suspected breast cancer, at least one lesion ≥1 cm on conventional imaging, and willing to undergo an FTT-PET prior to treatment initiation were enrolled. Participants provided written informed consent. Subjects were scanned on an Ingenuity TF PET/CT (Philips Healthcare) following injection of FTT. To evaluate if FTT uptake associated with PARPi response, primary and metastatic target lesions were selected based on anatomic CT imaging and RECIST 1.1 criteria. Maximum standardized uptake values (SUVmax) were recorded from the tumor with reference to CT scans. Spearman correlation estimated the strength of association between FTT uptake and progression free survival (PFS). Mann-Whitney test compared FTT uptake in subjects with < or ≥ 5-month PFS. For HRD correlation, somatic sequencing of the index tumor and germline sequencing were utilized and compared with SUV from the index malignancy on PET/CT. Participants: Twenty-four subjects with primary breast cancer underwent a baseline FTT-PET/CT scan prior to standard of care therapy. FTT uptake and genomic mutations were previously reported and showed a broad range of FTT uptake independent of genomic data. Here, untreated biopsy specimens were sequenced and HRD was calculated for correlation analysis with FTT uptake. A second cohort of 10 women with stage IV breast cancer underwent a baseline FTT-PET/CT scan prior to the start of a PARPi, and eight women received a second optional scan after a short interval after initiating PARPi treatment. Subjects ranged from 35 to 72 years of age and 3 self-reported as Black and 7 as White. All subjects had a germline or somatic pathogenic mutation in HR repair genes identified by a CLIA certified assay. Results: Baseline FTT-PET uptake did not correlate to HRD score, supporting that FTT provides distinct information from genetic features. In the PARPi cohort, 22 target lesions were identified across the 10 subjects. Target lesion diameter averaged 2.8 cm (range 1-6.5) and baseline FTT-PET imaging showed variable uptake (SUVmax range 0.5-6.9, mean 4.8). SUVmax did not correlate to tumor CT measurements, supporting that PARP expression or binding of PARPi to its target is not directly related to lesion size. Baseline average lesion uptake correlated to PFS (r=0.74, P=0.023, n=8), suggesting subjects with greater [18F]FTT uptake had longer survival. Dichotomizing subjects between those with a PFS >5 months and those with <5 months showed subjects with longer survival had higher SUVmax at baseline (P=0.04). All eight subjects imaged by FTT-PET/CT post-PARPi had a decline in FTT uptake (13%-61%), indicating variable drug-target engagement. A correlation was seen between PFS and subject-level percent change in SUVmax from baseline to post-PARPi imaging (r=-0.86, P=0.012, n=7), indicating larger declines in FTT uptake were associated with longer times-to-progression. Conclusion: These early results suggest the potential of FTT-PET to select patients for PARPi treatment and monitor in vivo pharmacodynamics after therapy start. The absence of association with HRD score supports FTT uptake as a novel measure from genomic biomarkers. Larger multicenter trials to evaluate FTT-PET as a biomarker of PARPi response in breast cancer are warranted. Citation Format: Austin R. Pantel, Kara Maxwell, Anthony Young, Daniel A. Pryma, Michael D. Farwell, Fang Liu, Quy Cao, Sophia R. O'Brien, Amy S. Clark, Payal D. Shah, Elizabeth S. McDonald. [18F]FluorThanatrace PET imaging correlates with response to PARP inhibitors in breast cancer: a pilot study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-07-04.

Influence of Subcellular Localization on the Cytotoxicity of Targeted α-Therapy

Journal of Nuclear Medicine · 2025-12-30 · 1 citations

Targeted α-therapy (TAT) is a promising approach for radiopharmaceutical therapy with various molecular targets, but uncertainty exists as to whether the subcellular location of a target influences its cytotoxicity. We used a model system that provides a subcellular “zip code” for TAT to determine whether localizing α-emitters closer to the DNA increases their cytotoxic effect. <b>Methods:</b> Human pleural mesothelioma (I45) and ovarian adenocarcinoma (SKOV3) cell lines were engineered to express a fusion <i>Escherichia coli</i> dihydrofolate reductase–yellow fluorescent protein localized to the DNA, nucleus, cytoplasm, and plasma membrane. Subcellular TAT was achieved by targeting <i>Escherichia coli</i> dihydrofolate reductase with [²¹¹At]At-trimethoprim (TMP), an analog of the antibiotic TMP labeled with α-emitting ²¹¹At. This model system was characterized using confocal microscopy, flow cytometry, and radioligand binding assays. In vitro cytotoxicity of subcellular [²¹¹At]At-TMP therapy was measured, followed by Monte Carlo subcellular dosimetry. In vivo biodistribution and antitumor efficacy of [²¹¹At]At-TMP were measured. <b>Results:</b> [²¹¹At]At-TMP targeted at the DNA, followed by the nucleus, yielded the highest in&nbsp;vitro cytotoxicity per ²¹¹At decay. The cytotoxic advantage persisted even after normalizing to α-particle nuclear dose deposition using subcellular dosimetry, suggesting a significant cytotoxic contribution by the α-recoil, which is not considered in standard subcellular dosimetry calculations. Targeting of the plasma membrane caused at least comparable cytotoxicity to cytoplasmic targeting, suggesting a potential role of membrane damage–induced cytotoxicity. In vivo xenografts responded similarly to nuclear versus cytoplasmic [²¹¹At]At-TMP, supported by subcellular dosimetry that predicted the relevance of subcellular TAT for the treatment of individual tumor cells and small tumor cell clusters. <b>Conclusion:</b> An α-emitter’s proximity to the DNA yields higher cytotoxicity, which can guide future TAT drug development for improved treatment of microscopic metastases in addition to macroscopic disease, potentially leading to better clinical outcomes.

Impact of geographic and demographic characteristics on treatment with Lu-PSMA for metastatic castrate-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology · 2025-02-10

153 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable and fatal disease. Administration of Lu-PSMA demonstrates improved progression free survival and overall survival in this population (1). Despite this, understanding patient access to and receipt of this therapy is understudied. We aim to characterize the demographics of patients receiving Lu-PSMA at a NCI-designated medical center in Philadelphia, PA after FDA approval. Methods: All patients treated at a single institutional center with Lu-PSMA from April 2023 to October 2024 were included. Demographic characteristics including age at first treatment, race, insurance status, and zip code were extracted from the medical record. Travel distance between a patient’s home and a treatment center was calculated using the Haversine formula as provided by the National Bureau of Economic Research. Median household income was obtained by US Census 2022 American Community Survey. All analyses were performed on Prism (GraphPad, v 10.3.1). Results: A total of 103 patients were included for analysis. The median age at time of first Lu-PSMA treatment was 73 years (range 50-92). 71.8% (n=74) were white and 28.2% were non-white (n=21 Black/African American; n=8 other/multiracial/unknown). All patients were non-Hispanic. All patients were insured (77.7%, n=80, Medicare/Managed Medicare; 3.9%, n=4, Medicaid/managed Medicaid; 18.4%, n=19, private/other insurance). Median distance travelled to a treatment center was 12 miles. About one quarter of patients travelled &gt;25 miles to reach their treatment center (42.7%, n=44, &lt;10 miles; 32.0%, n=33, 10-25 miles; 9.7%, n=10, 25-50 miles; 11.7%, n=12, 50-100 miles; and 3.9%, n=4, &gt;100 miles). Most patients resided in an urban zip code, with a minority (4.9%, n=5) residing in a rural zip code. The median household income by zip code varied from $30,946 to $233,194 (9.7%, n=10, $30-50K; 18.4%, n=19, $50-75K; 20.4%, n=21, $75-100K; 39.8%, n=41, $100-150K; 11.7%, n=12, &gt;150K). The number of Lu-PSMA treatments received was not correlated with distance travelled (F(4,98)=2.4, p=0.05), median household income (F(4,98)=0.5260, p=0.72), or race (p=0.83). There were no differences in travel distance between white and non-white patients (p=0.24). On Kaplan Meier, there were no differences in overall survival in patients that travelled &gt;12 miles for treatment versus those who resided &lt;12 miles from a treatment center (p=0.48). There were no differences in overall survival by race between white with non-white patients (p=0.66). Conclusions: Receipt of Lu-PSMA was not different in populations separated by race, distance to treatment center, or median household income. Increasing travel distance was not associated with receipt of fewer cycles of treatment. Further analysis is needed on whether these factors are associated with referral for and acceptance of Lu-PSMA. 1. Sartor NEJM 2021.

PARP1-targeted alpha therapy enhances target expression

EJNMMI Research · 2025-06-01

Abstract Graphical abstract

Space- and Time-Defined Monte Carlo Dosimetry Explains Ovarian Cancer Cell Viability in Targeted α-Particle Therapy With Astatine 211-ParaThanatrace

International Journal of Radiation Oncology*Biology*Physics · 2025-06-21

Kinetic Analysis and Metabolism of Poly(Adenosine Diphosphate–Ribose) Polymerase-1–Targeted¹⁸F-Fluorthanatrace PET in Breast Cancer

Journal of Nuclear Medicine · 2024-10-30 · 3 citations

The poly(adenosine diphosphate–ribose) polymerase inhibitors (PARPi) have demonstrated efficacy in ovarian, breast, and prostate cancers, but current biomarkers do not consistently predict clinical benefit. ¹⁸F-fluorthanatrace (¹⁸F-FTT) is an analog to rucaparib, a clinically approved PARPi, and is a candidate biomarker for PARPi response. This study intends to characterize ¹⁸F-FTT pharmacokinetics in breast cancer and optimize image timing for clinical trials. A secondary aim is to determine whether ¹⁸F-FTT uptake in breast cancer correlates with matched frozen surgical specimens as a reference standard for PARP-1 protein. <b>Methods:</b> Thirty prospectively enrolled women with a new diagnosis of breast cancer were injected with ¹⁸F-FTT and imaged dynamically 0–60 min after injection over the chest, with an optional static scan over multiple bed positions starting around 70 min. Kinetic analysis of lesion uptake was performed using blood-pool activity with population radiometabolite corrections. Normal breast and normal muscle reference tissue models were compared with PARP-1 protein expression in 10 patients with available tissue. Plasma radiometabolite concentrations and uptake in tumor and normal muscle were investigated in mouse xenografts. <b>Results:</b> Pharmacokinetics of ¹⁸F-FTT were well fit by Logan plot reference region models of reversible binding. However, fits of 2-tissue compartment models assuming negligible metabolite uptake were unstable. Rapid metabolism of ¹⁸F-FTT was demonstrated in mice, and similar uptake of radiometabolites was found in tumor xenografts and normal muscle. Tumor ¹⁸F-FTT distribution volume ratios relative to normal muscle reference tissue correlated with tissue PARP-1 expression (<i>P</i> &lt; 0.02, <i>n</i> = 10). The tumor–to–normal muscle ratio from a 5-min frame between 50 and 60 min after injection, a potential static scan protocol, closely corresponded to the distribution volume ratio relative to normal muscle and correlated to PARP-1 expression (<i>P</i> &lt; 0.02, <i>n</i> = 10). <b>Conclusion:</b> This study of PARPi analog ¹⁸F-FTT showed that uptake kinetics in&nbsp;vivo corresponded to expression of PARP-1 and that ¹⁸F-FTT quantitation is influenced by radiometabolites that are increasingly present late after injection. Radiometabolites can be controlled by using optimal image acquisition timing or normal muscle reference tissue modeling in dynamic imaging or a tumor–to–normal muscle ratio. Optimal image timing for tumor–to–normal muscle quantification in humans appears to be between 50 and 60 min after injection. Therefore, a clinically practical static imaging protocol commencing 45–55 min after injection may sufficiently balance ¹⁸F-FTT uptake with background clearance and radiometabolite interference for quantitative interpretation of PARP-1 expression in&nbsp;vivo.

Primary Results of NRG-RTOG1106/ECOG-ACRIN 6697: A Randomized Phase II Trial of Individualized Adaptive (chemo)Radiotherapy Using Midtreatment ¹⁸ F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Stage III Non–Small Cell Lung Cancer

Journal of Clinical Oncology · 2024-10-04 · 37 citations

PURPOSE NRG-RTOG0617 demonstrated a detrimental effect of uniform high-dose radiation in stage III non–small cell lung cancer. NRG-RTOG1106/ECOG-ACRIN6697 (ClinicalTrials.gov identifier: NCT01507428 ), a randomized phase II trial, studied whether midtreatment 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) can guide individualized/adaptive dose-intensified radiotherapy (RT) to improve and predict outcomes in patients with this disease. MATERIALS AND METHODS Patients fit for concurrent chemoradiation were randomly assigned (1:2) to standard (60 Gy/30 fractions) or FDG-PET–guided adaptive treatment, stratified by substage, primary tumor size, and histology. All patients had midtreatment FDG-PET/CT; adaptive arm patients had an individualized, intensified boost RT dose to residual metabolically active areas. The primary therapeutic end point was 2-year centrally reviewed freedom from local-regional progression (FFLP), defined as no progression in or near the planning target volume and/or regional nodes. FFLP was analyzed on a modified intent-to-treat population at a one-sided Z -test significance level of 0.15. The primary imaging end point was centrally reviewed change in SUV peak from baseline to midtreatment; its association with FFLP was assessed using the two-sided Wald test on the basis of Cox regression. RESULTS Of 138 patients enrolled, 127 were eligible. Adaptive-arm patients received a mean 71 Gy in 30 fractions, with mean lung dose 17.9 Gy. There was no significant difference in centrally reviewed 2-year FFLP (59.5% and 54.6% in standard and adaptive arms; P = .66). There were no significant differences in protocol-specified grade 3 toxicities, survival, or progression-free survival ( P &gt; .4). Median SUV peak and metabolic tumor volume (MTV) in the adaptive arm decreased 49% and 54%, from pre-RT to mid-RT PET. However, ΔSUV peak and ΔMTV were not associated with FFLP (hazard ratios, 0.997; P = .395 and .461). CONCLUSION Midtreatment PET-adapted RT dose escalation as given in this study was safe and feasible but did not improve efficacy outcomes.