Theranostics has its roots with the first radioiodine therapy for thyroid diseases in about 80 years ago. More recently the field has experienced a remarkable renascence with the regulatory approval of paired imaging and radiopharmaceutical therapy agents in gastroenteropancreatic neuroendocrine tumours and metastatic castration-resistant prostate cancer that are now employed in routine clinical practice. The momentum is strong for identification and testing of new theranostic agents for use in various cancers and finding new clinical indications of the available agents. There are currently numerous preclinical, first-in-human studies, large-scale prospective registries, and clinical trials including randomized trials underway in cancer theranostics that target a variety of germane biological targets. The results of these investigations, if successful, will undoubtedly impact the future of cancer management which is anticipated to improve patient outcome. Multi-targeted theranostics may also provide opportunities for synergistic efficacy to tackle the inherent complexities driven by the heterogeneity of cancer. In this article, we review the currently active recruiting phase 2 and phase 3 clinical trials in cancer theranostics that are targeted to the prostate-specific membrane antigen, gastrin-releasing peptide receptor, and fibroblast activation protein, with the anticipated potential near-term (<5 years) impact on clinical practice.

1059 Background: Second line treatment options for patients with ER+/HER2- metastatic breast cancer (MBC) after progression on 1 st line endocrine therapy (ET) continue to expand with novel endocrine agents (oral SERDs) and combination therapies (PIK3CA/AKTi, CDKi). However, short median PFS reported in clinical trials show that many patients do not benefit from 2 nd line ET. Identifying endocrine-resistant MBC at time of progression on 1 st line ET can help place patients on potentially more effective non-ET options (e.g., chemotherapy / antibody-drug conjugates). FES PET/CT has been approved for clinical use in the U.S. and allows whole-body evaluation of ER expression in MBC. Difference in FES uptake across lesions may reflect ER loss/downregulation, a mechanism of endocrine resistance. Goal of this clinical trial was to evaluate the impact of FES PET/CT results on 2 nd line therapeutic management decisions. Methods: In this multicenter trial in the U.S. [NCT05068726], patients with progression of ER+/HER2- MBC on 1 st line ET were prospectively enrolled to undergo FES PET/CT in addition to standard of care (SOC) imaging (CT + bone scan / FDG PET/CT). Treating oncologists completed questionnaires before and after FES PET/CT, detailing therapeutic management plans plus their confidence in the plans. FES PET/CT scans were compared with SOC imaging to assess FES uptake in MBC lesions. An FES uptake score (number of FES-positive lesions divided by total number of lesions per patient) was calculated to evaluate ER expression heterogeneity by central blinded image evaluation. Results: 45 patients underwent FES PET/CT. FES PET/CT results led to a change in therapeutic management in 17/45 patients (37.8%; 95% CI 23.8% - 53.5%). Revised management plan was ET in 5/17 and non-ET in 12/17 patients. FES uptake score was 1 (all lesions FES-positive) in 14/45 patients and < 1 (with FES-negative lesions, indicating ER expression heterogeneity) in 31/45 patients. Of 14 patients with FES uptake score of 1, 11 received 2 nd line ET. Of 31 patients with FES uptake score < 1, 15 were treated with ET and 16 with non-ET, based on guidelines suggesting that an FES-negative lesion is predictive of lack of endocrine response. FES PET/CT results led to 25/45 patients avoiding additional tests (20 biopsies, 5 scans) and 7/45 patients receiving further testing (4 biopsies, 1 scan, 2 other). Treating oncologist’s confidence in 2 nd line treatment decision (measured in n = 45 on 10-point scale with 10 being fully confident) increased on average with 2 points from 6.6 (SD = 1.7) pre-FES PET/CT to 8.6 (SD = 1.8) post-FES PET/CT. Conclusions: FES PET/CT is a clinically useful tool in the post-first line ER+/HER2- MBC setting. FES PET/CT results led to a change in management in 37.8% of patients and increased oncologist’s confidence in 2 nd line treatment decision. Clinical trial information: NCT05068726 .

5048 Background: Ra-223, an alpha-emitting radionuclide, is the first agent of its kind approved for the treatment of mCRPC. Although a pivotal phase 3 study evaluated its short-term safety, there is a need to investigate its long-term safety. The REASSURE study prospectively examined the long-term safety of Ra-223, including secondary primary malignancies (SPMs), in a large patient (pt) population enrolled across Europe, the United States, Israel, and Latin America. Methods: We report final analyses (data cut-off Oct 24, 2024) of REASSURE (NCT02141438), a global, noninterventional study (enrolment 2014–2017). Primary outcomes were the incidence of SPMs, short- (30 days) and long-term (7 years) safety events, and bone marrow suppression (BMS) management in pts who had ≥1 Ra-223 dose. Secondary outcomes included overall survival (OS). Results: Analyses included 1472 pts; median follow-up was 17 months (range 0.3–95.4). Median age was 73 years and 80% of pts had an ECOG PS of 0/1. In evaluable pts, median alkaline phosphatase, prostate-specific antigen, and lactate dehydrogenase levels were 133 U/L, 59 ng/mL, and 266 U/L, respectively. Overall, 81% of pts had bone-only metastases at baseline; 19% of pts had metastases in the bone plus other sites (mostly lymph nodes). Prior treatments included abiraterone (48% of pts), enzalutamide (39%), docetaxel (39%), and cabazitaxel (9%). Pts received a median of 6 Ra-223 doses; 67% received ≥5 doses. SPMs occurred in 2% of pts (25 SPMs in 24 pts). Of these pts, 16 (67%) and 1 (4%) had received prior or concomitant radiotherapy, respectively. Overall, 3% of pts had drug-related serious adverse events >30 days after completing Ra-223. Fractures were reported in 10% of pts and were less common in pts with (7% of 605) than without (12% of 867) concomitant BHA use. During Ra-223 and up to 30 days after the last dose, there was no notable difference in the incidence of abnormal platelet counts between pts with (3%) or without (2%) prior chemotherapy; similar findings were seen for abnormal neutrophil counts (5% and 5%, respectively). BMS treatments, assessed from the start of Ra-223, were more common in pts who had received prior taxanes (38%) than in those who had not (26%). The most common life-prolonging therapies received after Ra-223 were docetaxel (18%), enzalutamide (15%), abiraterone (11%), and cabazitaxel (11%). Median OS was 15.6 months (95% CI, 14.6, 16.4); pt subgroups that survived the longest will be characterized and presented. Conclusions: This real-world safety analysis of pts with mCRPC is the longest follow-up of a radiopharmaceutical reported to date and supports the well-established favorable safety profile of Ra-223. The incidence of SPMs was low. The rate of fracture was low, especially in the presence of BHAs. Prior taxane chemotherapy use had no impact on hematological toxicity. Clinical trial information: NCT02141438 .

106 Background: In the Phase 3 ALSYMPCA trial, radium-223 (Ra-223) demonstrated an overall survival (OS) benefit and a favorable safety profile in patients with metastatic castration-resistant prostate cancer (mCRPC). REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of Ra-223 use in patients with mCRPC with bone metastases within routine clinical settings. Utilizing data from the second planned interim analysis, we evaluated safety outcomes in patients with mCRPC treated with Ra-223 following external beam radiation therapy (EBRT) in the US. Methods: In this descriptive analysis (data cutoff 3-20-2019), we included patients who received EBRT to bone prior to Ra-223 (≤2 years prior to Ra-223 first dose); results are presented relative to the overall US subset of patients enrolled into REASSURE. The focus of this abstract is on incidence of hematological toxicities, bone fractures, and second primary malignancies (SPM). Results: Of N=498 patients in the US subset, 118 patients received prior EBRT to bone. Median duration of observation was 11.7 months among patients who received EBRT and 11.9 months for the overall US subset. Any-grade drug-related hematological treatment-emergent adverse events (TEAEs) occurred in 8% (10/118) and 9% (47/498) of patients who received EBRT and the overall subset, respectively (Table). Grade ≥3 drug-related hematological TEAEs occurred in 5% (6/118) and 6% (32/498) of patients who received EBRT and the overall subset, respectively. Bone fractures occurred in 7% (8/118) and 4% (19/498) of patients who received EBRT and the overall subset, respectively. Six SPMs occurred in 5/118 patients who received EBRT (4%), and 11 SPMs occurred in 10/498 patients in the overall subset (2%). Results of bone fracture events by bone health agent use will be included in the full presentation. Conclusions: In this descriptive analysis of real-world data, patients who received EBRT prior to Ra-223 did not demonstrate an increased incidence of hematological toxicities relative to the overall US subset. Although percent of SPMs and bone fractures seems higher among patients treated with EBRT relative to the overall US subset, the real-world incidence of these events remains low. [Table: see text]

e17040 Background: Our aim was to evaluate two distinct clinical settings catering to US patients with metastatic castration-resistant prostate cancer (mCRPC): academic (A) and community (C) practice. We used data from a real-world non-interventional study (REASSURE; NCT02141438) examining the use of 223Ra. Methods: Patients with mCRPC who received at least one dose of 223Ra in the US were included. Enrolment occurred between 2014 and 2017; median follow-up was nearly 12 months. Our analysis included patient disease characteristics, treatment history, short- and long-term safety of 223Ra, patient overall survival (OS), and patient-reported pain (Brief Pain Inventory – Short Form [BPI–SF] scores). A clinically meaningful pain response was a ≥2-point decrease from a baseline score of ≥2 in the BPI-SF worst pain item during treatment until last dose. Results: Analysis included 498 patients (A: 147; C: 351). Comparing A with C, the median ages were 70 and 76 years, respectively, and the majority of patients (74% and 84%) had bone-only metastases. A higher percentage of patients in A (69%) than in C (49%) had completed at least one life-prolonging therapy (LPT) prior to 223Ra; these included abiraterone (A: 38%; C: 19%), enzalutamide (A: 32%; C:17%), docetaxel (A: 38%; C: 19%), and sipuleucel-T (A: 18%; C: 25%). Most patients received 5–6 223Ra injections in both settings (A: 65%; C: 71%). 223Ra was used concomitantly with LPTs in 48% of patients in A and 57% in C, predominantly with abiraterone (A: 25%; C: 25%) or enzalutamide (A: 25%; C: 36%); fewer patients in A (35%) received concomitant bone health agents than in C (52%). For safety outcomes, refer to the table. During treatment, 47% and 62% of patients with a baseline BPI-SF ≥2 had a clinically meaningful pain response in A and C, respectively. The median OS was 17.2 months (95% CI 14.0–19.4) in A and 18.4 months (14.8–21.0) in C. More patients in A (42%) than in C (26%) received a LPT after 223Ra, most commonly docetaxel (A: 25%; C: 12%). Conclusions: Patients treated in A tended to be younger and more heavily treated, as evidenced by a higher number of patients receiving LPTs prior to and following 223Ra treatment. Bone health agents were more frequently used in C. Additionally, more patients in C had a clinically meaningful pain response and more drug-related AEs were reported in A. Despite the observed differences, overall survival was comparable for both practice settings. Clinical trial information: NCT02141438 . [Table: see text]

Abstract Background: REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of Ra-223 use in patients with mCRPC with bone metastases within routine clinical settings. Using data from the second planned interim analysis, we compared baseline characteristics, survival, and safety outcomes among White, Black, and Asian patients treated with Ra-223 in the US subset of REASSURE. Methods: In this descriptive analysis (data collection 8-20-2014 to 3-20-2019), we examined baseline characteristics, OS, and safety outcomes for the US subset enrolled into REASSURE stratified by race (White, Black, Asian). Results: Of the 498 men in the US subset, 414 (83.1%) reported as White, 58 (11.7%) as Black, and 10 (2.0%) as Asian; race was not reported for 16 (3.2%) patients. Median age at study entry was 74.0, 69.5, and 71.0 years for White, Black, and Asian men, respectively. The proportion of patients whose prostate cancer was American Joint Committee on Cancer (AJCC) 7th edition stage III or IV at initial diagnosis was 45.2%, 58.6%, and 60.0% for White, Black, and Asian patients, respectively. The proportion of patients who completed 6 Ra-223 injections was similar across groups. Median duration of observation from the start of Ra-223 treatment was 11.3 months (range 0.4-41.3 months) for White patients, 14.9 months (range 0.7-39.1 months) for Black patients, and 20.5 months (range 4-27.7 months) for Asian patients. Median OS for White, Black, and Asian patients was 17.3 months (95% CI, 15.2-19.2 months), 19.5 months (95% CI, 12.9-27.1 months), and 21.8 months (95% CI, 3.58 months-not applicable), respectively. Any treatment-emergent drug related AE, treatment-emergent SAE, or drug-related SAE occurred in 45.2%, 41.4%, and 10.0% of White, Black, and Asian patients, respectively. Any-grade and grade ≥3 drug-related hematological TEAEs occurred in 8.4% and 5.3% of White patients, respectively, 15.5% and 12.1% of Black patients, respectively, and were not observed in Asian patients. Incidence of bone fractures was 4.1%, 3.4%, and 0% in White, Black and Asian patients respectively. Conclusions: This descriptive analysis of REASSURE found that Black patients were younger and presented with later-stage disease at diagnosis compared with White patients. A trend toward longer OS was seen in Black and Asian patients compared with White patients. AEs occurred at similar rates among groups. Drug-related hematological TEAEs, which have been reported with Ra-223 treatment, were more common in Black patients compared with White and Asian patients. Given the very small number of Asian patients enrolled in REASSURE, comparisons with this group should be interpreted with caution. Citation Format: Peter S. Conti, Oliver Sartor, Mary-Ellen Taplin, Daniel Y. Song, Saby George, Jeffrey Tomaszewski, John Sylvester, Constantine Mantz, Robert W. Given, Robert Brookland, Jeff Meltzer, Matthew J. Korn, Richard Andres, Svetlana Babajanyan, Celestia Higano. Baseline characteristics, safety, and efficacy of Radium-223 in metastatic castration resistant prostate cancer by race: Insights from the REASSURE US subset [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C160.

Background and Objective: Positron emission tomography (PET) imaging has been useful in delineating tumor volumes and allowing for improved radiation treatment. The field of PET-guided radiotherapy is rapidly growing and will have significant impact on radiotherapy delivery in the future. This narrative review provides an overview of the current state of PET-guided radiotherapy as well as the future directions of the field. Methods: For this narrative review, PubMed was searched for articles from 2010-2023. A total of 18 keywords or phrases were searched to provide an overview of PET-guided radiotherapy, radiotracers, the role of PET-guided radiotherapy in oligometastatic disease, and biology-guided radiotherapy (BgRT). The first 300 results for each keyword were searched and relevant articles were extracted. The references of these articles were also reviewed for relevant articles. Key Content and Findings: In radiotherapy, 18F-2-fluoro-2-deoxy-D-glucose (F-FDG or FDG) is the major radiotracer for PET and when combined with computed tomography (CT) scan allows for anatomic visualization of metabolically active malignancy. Novel radiotracers are being explored to delineate certain cell types and numerous tumor metrics including metabolism, hypoxia, vascularity, and cellular proliferation. This molecular and functional imaging will provide improved tumor characterization. Through these radiotracers, radiation plans can employ dose painting by creating different dose levels based upon specific risk factors of the target volume. Additionally, biologic imaging during radiotherapy can allow for adaptation of the radiation plan based on response to treatment. Dose painting and adaptive radiotherapy should improve the therapeutic ratio through more selective dose delivery. The novel PET-linear accelerator hopes to combine these techniques and more by using radiotracers to deliver BgRT. The areas of radiotracer uptake will serve as fiducials to guide radiotherapy to themselves. This technique may prove promising in the growing area of oligometastatic radiation treatment. Conclusions: Significant challenges exist for the future of PET-guided radiotherapy. However, with the advancements being made, PET imaging is set to change the delivery of radiotherapy. painting; adaptive radiotherapy

Supplementary Methods from Smad3 Deficiency Promotes Tumorigenesis in the Distal Colon of <i>Apc^Min/+</i> Mice

Supplementary Table 1 from Smad3 Deficiency Promotes Tumorigenesis in the Distal Colon of <i>Apc^Min/+</i> Mice

PDF file - 62K, Table S1. Humanized MAb159 Pharmacokinetics in mouse. Table S2. Toxicology study of humanized MAb159 in mouse.

Background Radium-223, a targeted alpha therapy, is approved to treat bone-dominant metastatic castration-resistant prostate cancer (mCRPC), based on significantly prolonged overall survival versus placebo and a favourable safety profile in the phase 3 ALSYMPCA study. ALSYMPCA was conducted when few other treatment options were available, and prospectively collected data are limited on the use of radium-223 in the current mCRPC treatment landscape. We sought to understand long-term safety and treatment patterns in men who received radium-223 in real-world clinical practice. Methods REASSURE (NCT02141438) is a global, prospective, observational study of radium-223 in men with mCRPC. Primary outcomes are adverse events (AEs), including treatment-emergent serious AEs (SAEs) and drug-related AEs during and <30 days after radium-223 completion, grade 3/4 haematological toxicities <6 months after last radium-223 dose, drug-related SAEs after radium-223 therapy completion, and second primary malignancies. Findings Data collection commenced on Aug 20, 2014, and the data cutoff date for this prespecified interim analysis was Mar 20, 2019 (median follow-up 11.5 months [interquartile range 6.0-18.6]), 1465 patients were evaluable. For second primary malignancies, 1470 patients were evaluable, 21 (1%) of whom had a total of 23 events. During radium-223 therapy, 311 (21%) of 1465 patients had treatment-emergent SAEs, and 510 (35%) had drug-related AEs. In the 6 months after completion of radium-223 therapy, 214 (15%) patients had grade 3/4 haematological toxicities. Eighty patients (5%) had post-treatment drug-related SAEs. Median overall survival was 15.6 months (95% confidence interval 14.6-16.5) from radium-223 initiation. Patient-reported pain scores declined or stabilised. Seventy (5%) patients had fractures. Interpretation REASSURE offers insight into radium-223 use in global real-world clinical practice with currently available therapies. At this interim analysis, with a median follow-up of almost 1 year, 1% of patients had second primary malignancies, and safety and overall survival findings were consistent with clinical trial experience. Final analysis of REASSURE is due in 2024.

PDF file - 736K, Fig. S1. Generation and characterization of MAb159. Fig. S2. MAb159 induces GRP78 endocytosis through clathrin mediated pathway. Fig. S3. MAb159 induces apoptosis of tumor cells in vitro. Fig. S4. Surface GRP78 Forms Complex with PI3K. Fig. S5. Surface GRP78 level in cancer cell lines. Fig. S6. MAb159 treatment of xenograft tumor leads to reduced vessel density and mTOR signaling. Fig. S7. MAb159 shows no toxicity to normal organs in tumor xenograft study. Fig. S8. Inhibition of primary tumor growth and metastasis by MAb159 in 4T1 orthotopic model. Fig. S9. MAb159 inhibits the growth of hormone refractory mouse prostate cancer cell CE1 in vivo.

5050 Background: 223 Ra improved overall survival (OS) and quality of life and demonstrated a favorable safety profile in pts with mCRPC in the phase 3 ALSYMPCA trial. REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of 223 Ra use in pts with mCRPC and bone metastases in routine clinical practice. Here, we present clinical outcomes from the second planned interim analysis of REASSURE for pts treated in the US. Methods: This analysis included pts with confirmed mCRPC with bone metastases scheduled to receive 223 Ra in the US. All pts received ≥1 dose of 223 Ra. Primary endpoints are short- and long-term safety, including incidence of bone marrow suppression and second primary malignancies (SPM). Secondary endpoints included OS and pt-reported pain (Brief Pain Inventory – Short Form [BPI–SF] scores). A clinically meaningful pain response was defined as a decrease from baseline of ≥2 points in BPI-SF worst pain item. Results: Pts were enrolled from 2014–2017. Overall, 498 pts were included in this analysis. At the data cut-off (20 March 2019), the median duration of observation was 11.9 months (0.4–41.3). Most pts (81%) had bone metastases only; 69% of pts received 5–6 223 Ra injections. Overall, 77% of pts had received ≥1 prior life-prolonging therapies: abiraterone (45%), enzalutamide (48%), docetaxel (25%), cabazitaxel (6%), or sipuleucel-T (24%). Concomitant enzalutamide was received by 31% of pts, and 47% received concomitant bone health agents. After 223 Ra, 31% of pts received ≥1 life prolonging therapies. During treatment, 208/358 (58%) pts with a baseline BPI-SF ≥2 had a clinically meaningful pain response. Any-grade and grade ≥3 drug-related treatment-emergent adverse events (TEAEs) occurred in 32% and 10% of pts, respectively. Drug-related TEAEs resulted in 223 Ra discontinuation in 4% of pts. Treatment-emergent and drug-related serious AEs (SAEs) occurred in 21% and 6% of pts, respectively. The most common (>5% of pts) any-grade drug-related TEAEs were diarrhea (10%), fatigue (9%), anemia (8%) and nausea (7%). Overall, 4% of pts had fractures; 2% of pts developed bone disorders. Eleven SPMs occurred in 10 pts (2%). In total, 60% of pts died during study follow-up. Median OS was 17.8 months (95% CI 15.6–19.4). Conclusions: Within the current treatment landscape in routine clinical practice in the US, median OS after 223 Ra treatment was close to 18 months. A majority of pts completed 5–6 223 Ra injections. The known safety profile of 223 Ra was confirmed with no new safety signals. Over half of pts with pain at baseline had a clinically meaningful pain response during 223 Ra treatment. Clinical trial information: NCT02141438 .

Diet-induced obesity is a major risk factor for metabolic syndrome, diabetes and cardiovascular disease. Here, we show that a 5-d fasting-mimicking diet (FMD), administered every 4 weeks for a period of 2 years, ameliorates the detrimental changes caused by consumption of a high-fat, high-calorie diet (HFCD) in female mice. We demonstrate that monthly FMD cycles inhibit HFCD-mediated obesity by reducing the accumulation of visceral and subcutaneous fat without causing loss of lean body mass. FMD cycles increase cardiac vascularity and function and resistance to cardiotoxins, prevent HFCD-dependent hyperglycaemia, hypercholesterolaemia and hyperleptinaemia and ameliorate impaired glucose and insulin tolerance. The effect of monthly FMD cycles on gene expression associated with mitochondrial metabolism and biogenesis in adipocytes and the sustained ketogenesis in HFCD-fed mice indicate a role for fat cell reprogramming in obesity prevention. These effects of an FMD on adiposity and cardiac ageing could explain the protection from HFCD-dependent early mortality.

Objective In patients with a history of lymphoma who demonstrate palatine tonsil uptake on posttreatment PET/CT (positron emission tomography/computed tomography), tonsillectomy is often performed to evaluate for lymphoma recurrence. However, predictive clinical and imaging factors for true tonsil recurrence in this setting are not well established; this will be explored herein. Study Design Retrospective case series. Setting Patients treated at a tertiary medical center from January 2008 to May 2020. Methods Chart review was performed on all patients with a history of treated lymphoma in clinical remission who presented for evaluation of abnormal PET/CT imaging findings and subsequently underwent tonsillectomy. Results Among 15 patients who met inclusion criteria, 14 had benign findings on surgical pathology, yielding a false-positive rate of 93%. The patient with malignancy was identified on biopsy after inconclusive surgical pathology and is the only documented case of recurrence in this specific patient population throughout the literature. The patient presented with B symptoms, irregularly shaped tonsils, increased lymph node activity on PET/CT, and uptrending bilateral tonsil activity but with one of the lowest maximum standardized uptake values of the cohort. The singular distinguishing feature for the patient with recurrent disease was a prior tonsil biopsy suspicious for recurrence, which prompted the otolaryngology referral. Conclusion PET/CT lacks specificity in identifying lymphoma recurrence in the oropharynx. Clinical and radiographic features that were previously considered concerning for recurrence are most likely not indicative of malignancy in this patient population. Our findings call into question whether tonsillectomy should be routinely performed in this patient population.

1601 Objectives: ATP-binding cassette transporter A1 (ABCA1) is a viable therapeutic target in Alzheimer’s disease for treatment with peptides such as CS-6253. CS-6253 is a 26-residue peptide derived from the C-terminus of Apolipoprotein E (ApoE) that has been shown to increase ABCA1-mediated cholesterol efflux. Radiolabeling CS-6253 will allow for monitoring of ABCA1 activity in the brain using PET imaging. Methods: CS-6253 contains a lysine residue (Lys-25) at the C-terminal side that can be modified while retaining the bioactivity of the peptide, which allows for radiolabeling. An azide-modified amino acid was incorporated into CS-6253 by solid-phase peptide synthesis to form the radiolabeling precursor (Azido-CS-6253). 18F-CS-6253 was radiosynthesized via a CuAAC reaction strategy, using Azido-CS-6253 and an 18F-containing alkyne. The stability of 18F-CS-6253 in mouse serum was determined at 1 and 2 hours after incubation. PET-CT images were performed in normal nude mice (n = 3) at 1 and 2 hours after tail vein injection of 18F-CS-6253. Biodistribution of 18F-CS-6253 in major organs was measured using PET. Results: 18F-CS-6253 was radiosynthesized with a radiochemical purity of ≥ 99%. The stability results show that 18F-CS-6253 is stable in mouse serum after 2 h incubation. PET imaging shows that brain uptake of 18F-CS-6253 at 1 h post-injection (pi) was 2.10 ± 0.08 %ID/g and 1.93 ± 0.05 %ID/g after 2 h. Uptake of 18F-CS-6253 in the liver was 12.93 ± 1.60 %ID/g at 1 h pi and 12.40 ± 1.35 %ID/g at 2 h pi. Kidney uptake was 11.43 ± 0.68 and 10.10 ± 0.81 %ID/g at 1 h and 2 h, respectively, and muscle uptake was 1.43 ± 0.12 %ID/g at 1 h and 1.67 ± 0.09 %ID/g at 2 h. The brain-to-muscle uptake ratio of 18F-CS-6253 was measured to be 1.47 ± 0.14 at 1 h and 1.16 ± 0.04 at 2 h, respectively. Conclusions: 18F-CS-6253 has been successfully synthesized with excellent radiochemical purity. Brain uptake of 18F-CS-6253 was observed by PET in normal mice. Tests of 18F-CS-6253 in animal disease models are underway to demonstrate the potential of 18F-CS-6253 as an ABCA1 imaging agent in various phenotypes. Research Support: This work was supported by R01AG067063 and R21AG056518 from the National Institute of Aging.

Vascular contributions to dementia and Alzheimer’s disease are increasingly recognized1–6. Recent studies have suggested that breakdown of the blood–brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer’s disease5,8–10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer’s disease11–14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15–19, which maintain BBB integrity20–22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target in APOE4 carriers. Breakdown of the blood–brain barrier in individuals carrying the ε4 allele of the APOE gene, but not the ε3 allele, increases with and predicts cognitive impairment and is independent of amyloid β or tau pathology.

Radium-223 (Ra-223) improved overall survival (OS) and demonstrated a favorable safety profile in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 ALSYMPCA trial. REASSURE (NCT02141438) is a global, prospective, single-arm, observational study investigating the safety of Ra-223 in routine clinical practice in pts with mCRPC over 7 years. The objective of this investigation, using data from the second prespecified interim analysis, was to assess safety and clinical outcomes in pts from REASSURE, including the subgroups who received radiotherapy concomitant with Ra-223, or investigational 177Lu-PSMA subsequent to Ra-223. Results of this analysis may help to inform future treatment decisions in pts with mCRPC. This analysis (data cut-off: March 20, 2019) was conducted for the entire cohort and two subsets of pts treated with either concomitant radiotherapy or with subsequent 177Lu-PSMA. Incidence of second primary malignancy (SPM), pain response, incidence of adverse events (AEs), and OS are described. In total, 1465 pts with mCRPC were included. Median follow-up was 11.5 months, and a median of 6 Ra-223 injections was received. Overall, 14 pts (1%) developed a SPM. At Cycle 6, 222/657 pts (34%) had a clinically meaningful pain response (decrease ≥2 points from baseline) in the Brief Pain Inventory worst pain item. Overall, median OS was 15.6 months (95% CI 14.6, 16.5). The most frequent treatment-emergent serious AEs (any grade; ≤30 days after Ra-223) were anemia (n = 27; 2%), physical health deterioration (n = 14; 1%), and pneumonia (n = 13; 1%). Grade 3–4 hematologic AEs occurred in 214 pts (15%); 70 pts (5%) had fractures. 160/1465 pts (11%) had concomitant radiotherapy, mainly external beam radiation therapy (n = 117; 73%), brachytherapy (n = 14; 9%), and gamma knife or stereotactic therapy (n = 8; 5% for each). Of these 160 pts, 1 (<1%) developed a SPM. Safety, including hematologic toxicity fracture rate, and pain response in this pt group was acceptable and will be presented. 26/1465 pts (2%) received 177Lu-PSMA treatment after Ra-223. Median duration of 177Lu-PSMA was 3.5 months. 3/26 pts (12%) had drug-related serious AEs; 9/26 pts (35%) had grade 3–4 hematologic AEs. 2/26 pts (8%) had fractures. Median OS was 28.0 months (95% CI 19.5, 32.7) from start of Ra-223 and 13.2 months (8.4, 16.2) from start of 177Lu-PSMA. There was a low incidence of SPM, low rate of grade 3–4 hematologic AEs, and low incidence of fractures in this second interim analysis of REASSURE, in a real-life clinical practice setting. A pain response was observed in about one-third of pts. Treatment with 177Lu-PSMA in pts who had prior Ra-223 may be feasible in selected pts based on the subset analyzed.