Citations

Abstract Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. Present management summarized here is focused on early diagnosis, assiduous avoidance of injury and iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function. Twenty-one members of the International Clinical Council on FOP (ICC) and seven consultants from 15 countries, chosen for their clinical expertise in FOP, developed this summary statement. Further advances in therapeutics will be based on rigorous clinical trials to assess novel and emerging treatment and prevention strategies. A detailed and updated exploration of the topics outlined in this brief perspective can be found in “The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations” which can be found on the International Clinical Council on FOP (ICC) website (www.iccfop.org).

Abstract Aging increases the vulnerability of kidneys to injury and impairs their regenerative capacity. SIRT3 expression declines with aging and is associated with multiple age‐related pathologies. The expression profile and functional role of SIRT3 in renal aging remain unclear. Here, SIRT3 expression in aging kidneys is assessed and analyzed for its promoter methylation patterns using methylation‐specific PCR (MSP). It is found that aging exacerbates UUO‐induced renal fibrosis, associated with downregulated SIRT3 expression. Mechanistically, age‐related SIRT3 downregulation is mediated by hypermethylation of its promoter region. SIRT3 knockout exacerbated renal fibrosis in young mice subjected to UUO, whereas SIRT3 overexpression attenuated fibrosis in aged UUO mice. Integration of RNA‐seq and immunoprecipitation‐mass spectrometry (IP‐MS) analyses revealed that SIRT3 deficiency leads to hyperacetylation of GSK3β at lysine 15 (K15). This K15 hyperacetylation inhibited GSK3β activity, consequently stabilizing its substrate β‐catenin. Furthermore, self‐assembled PEG‐PCL‐PEG micelles are designed and synthesized to encapsulate hydrophobic honokiol (HKL). These micelles significantly enhanced the aqueous solubility and oral bioavailability of free HKL, maintained stable blood concentrations, and ultimately improved its anti‐fibrotic efficacy. These findings propose novel therapeutic strategies for managing renal fibrosis in the aging population and provide a foundation for developing new drugs and combination therapies.

ImportanceEtiologic heterogeneity in breast carcinogenesis needs to be well characterized for targeted prevention. Associations between menopausal hormonal therapy (MHT) and oral contraceptive (OC) use and breast cancer intrinsic-like subtypes are not well understood.ObjectiveTo examine whether exogenous hormone use is differentially associated with breast cancer subtypes and to evaluate heterogeneity by intrinsic-like subtypes.Design, Setting, and ParticipantsThis study pooled data from 31 nested and population-based case-control studies involved in the Breast Cancer Association Consortium. The study population included individuals with breast cancer and control participants from 13 case-control studies nested in prospective cohorts (recruited between 1982 and 2011) and 18 population-based case-control studies (recruited between 1990 and 2013). Data analysis was performed in June 2024.ExposureMHT use (estrogen-progestin therapy [EPT] or estrogen-only therapy [ET]) in postmenopausal women and OC use in premenopausal women (never, past use, or current use).Main Outcomes and MeasuresBreast cancer intrinsic-like subtypes (luminal A–like, luminal B–like, luminal B–ERBB2 [formerly HER2 or HER2/neu]-like, ERBB2 enriched–like, or triple-negative) were determined by immunohistochemistry of tumor sections. Polytomous logistic regression was performed to estimate the association between exogenous hormones and risk of breast cancer by intrinsic-like subtypes. Analyses by subtypes were stratified by body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; healthy weight, 18.5-<25; overweight, 25-<30; or obesity, ≥30).ResultsThis study included 42 269 individuals with breast cancer (11 901 [28.2%] premenopausal and 30 368 [71.8%] postmenopausal; 23 353 [55.2%] had a known intrinsic-like subtype) and 71 072 control participants. The mean (SD) age of all participants was 57.9 (10.9) years. In postmenopausal women, associations between current MHT use (EPT or ET) and breast cancer differed by subtype. Current EPT users with healthy weight were more likely to be diagnosed with luminal A–like (odds ratio [OR], 2.51 [95% CI, 2.26-2.80]) or luminal B–ERBB2-like (OR, 1.95 [95% CI, 1.61-2.37]) subtypes. These associations were attenuated but remained for individuals with overweight (OR, 1.40 [95% CI, 1.02-1.92]) or obesity (OR, 1.68 [95% CI, 1.01-2.78]). EPT use increased the odds of being diagnosed with luminal B–like tumors solely in women with healthy weight (OR, 1.47 [95% CI, 1.17-1.86]). Current ET use was positively associated with luminal A–like disease in women with healthy weight only (OR, 1.16 [95% CI, 1.01-1.32]), showing inverse associations with higher BMI (obesity: OR, 0.65 [95% CI, 0.50-0.85]). In premenopausal women, recent OC use was associated with luminal B–ERBB2-like (OR, 1.50 [95% CI, 1.09-2.08]), ERBB2 enriched–like (OR, 2.33 [95% CI, 1.55-3.51]), and triple-negative (OR, 1.75 [95% CI, 1.33-2.29]; P < .04 for heterogeneity) tumors.Conclusions and RelevanceIn this study, clear differences were observed in associations between current EPT use and luminal-like breast cancer subtypes and other subtypes. EPT users with healthy weight were more likely to be diagnosed with luminal-like breast cancer compared with nonusers. Subtype heterogeneity was less apparent in associations of OC and ET use. Future studies on contemporary formulations, patterns of use, and routes of administration of exogenous hormone usage are warranted.

TPS5130 Background: Patients with prostate cancer and deleterious HRRa have poorer prognosis but derive benefit from poly (ADP-ribose) polymerase (PARP) inhibition. However, prevalence of HRRa and response to PARP inhibition are less well defined in racial/ethnic minorities. We designed the HARMONY trial to evaluate the efficacy of N/AA/P in HL and NHB patients with mHSPC and deleterious HRRa. Methods: This multicenter, open label, phase II study is open through the Hoosier Cancer Research Network in the United States. The trial enrolls patients who self-identify as HL or NHB and have mHSPC with HRRa including BRCA 1/2, BRIP1, CHEK2, FANCA, PALB2, RAD51B, and/or RAD54L. Eligible patients will have hormone sensitive, treatment naïve or minimally treated prostate cancer (i.e., bicalutamide ≤ 45 days, androgen deprivation therapy [ADT] ± AA plus P ≤ 45 days allowed). Prostate cancer variants, other therapy in mHSPC setting, or symptomatic brain metastases are exclusionary. Enrolled patients will receive 24 weeks (w) of ADT plus N/AA dual action tablet (DAT) plus P, followed by an adaptive approach based on prostate specific antigen (PSA) response. Subjects in Arm A (PSA > 4.0 ng/mL at 24 w) can continue ADT/N/AA/P for max 2 years or stop N and escalate therapy to ADT/AA/P plus 6 cycles of docetaxel followed by standard of care (SOC) therapy. Subjects in Arm B (PSA ≤ 4.0 ng/mL at 24 w) will continue ADT/N/AA/P for a total of 12 months. At 12 months in Arm B, subjects with PSA ≥ 0.2 ng/mL will continue ADT/N/AA/P for max 2 years, and subjects achieving PSA < 0.2 ng/mL have the option to continue ADT/N/AA/P for max 2 years or discontinue all therapy with the option to start SOC treatment at disease progression. PSA decline to < 0.2 ng/mL at 24w (primary endpoint) will be evaluated for each racial/ethnicity group against a historic rate of 50%. Thirty patients per racial/ethnic cohort will give 80% power at 0.1 significance to determine noninferiority with a no-inferiority margin of 0.185. Estimating 5% drop out, 64 patients will be enrolled (n=32 HL and n=32 NHB). Key secondary/exploratory endpoints include PSA reduction ≥ 90%, overall response rate, PSA/radiographic progression free survival, overall survival, time to subsequent anti-cancer therapy, quality of life and safety. Key genomic correlatives will be evaluated. ClinicalTrials.gov: NCT06392841. Study support of drug and funding: Janssen Scientific Affairs LLC. Clinical trial information: NCT06392841 .

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and the accumulation of Lewy bodies, leading to motor and nonmotor symptoms. While both genetic and environmental factors contribute to PD, recent studies highlight the crucial role of lipid metabolism disturbances in disease progression. Altered lipid homeostasis promotes protein aggregation and oxidative stress, with significant changes in lipid classes such as sphingolipids and glycerolipids observed in patients with PD. These disturbances are involved in key pathological processes, such as α-synuclein aggregation, organelle dysfunction, lipid-mediated neuroinflammation, and impaired lipid homeostasis. This review examines the relationship between lipid species and PD progression, focusing on the physiological roles of lipids in the central nervous system. It explores the mechanistic links between lipid metabolism and PD pathology, along with lipid-related genetic risk factors. Furthermore, this review discusses lipid-targeting therapeutic strategies to mitigate PD progression, emphasizing the potential of lipid modulation for effective treatment development.

Abstract Background: Leukocyte immunoglobulin-like receptor B2 (LILRB2) suppresses immune cell activation, particularly within myeloid cells in the tumor microenvironment (TME), while the PD-1/PD-L1 axis serves as a key immune checkpoint that inhibits T-cell function. SPX-303 is a novel bispecific antibody designed to simultaneously block LILRB2 and PD-L1, thereby revitalizing antitumor immune responses. Here, we present initial findings from the ongoing first-in-human Phase 1 trial of SPX-303 in patients with advanced solid tumors, including safety, pharmacokinetics (PK), and receptor occupancy (RO). Methods: This is an open-label, multicenter Phase 1 study for patients with advanced solid malignancies with 3+3 dose-escalation design, followed by an expansion cohort at the recommended Phase 2 dose (RP2D). SPX-303 is administered intravenously every three weeks and safety is assessed through CTCAE v5.0 criteria. Primary Objectives of this study are to determine the safety, tolerability, and RP2D of SPX-303. Secondary endpoints include antitumor activity as well as characterization of the PK and PD of SPX-303. This study is currently open and enrolling in escalation cohorts. Citation Format: Justin Moser, Hao Xie, Yujie Zhao, Yousef Zakharia, Dongdong Li, Brandon William, Dinh-Duc Nguyen, Jack Hovey, Tiffany Li, Robert Cai, Jichun Ma, Jingdong Qin, Martin Siekierzycki, Anthony Haight, Hua Jin, Weiwei Mao, Kevin Bin Li, Gui-Dong Zhu. A first-in-human phase 1 study on the safety, PK, receptor occupancy, and pharmacodynamic markers of SPX-303, a first-in-class LILRB2×PD-L1 bispecific antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT116.

Abstract Background: Effective treatments (Tx) are needed for MTAP-del cancers (10-15% of all cancers). BMS-986504 (formerly MRTX1719) is a potential first-in-class MTA-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor that selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP-del but not MTAP-wild-type cells. In the first-in-human phase 1/2 CA240-0007 study, BMS-986504 was well tolerated and showed clinical activity in heavily pretreated pts across multiple advanced solid tumors with homozygous MTAP-del. Here, we report results of exploratory PD analyses of PRMT5 inhibition with BMS-986504 in CA240-0007. Methods: Pts with advanced, unresectable or metastatic solid tumors with homozygous MTAP-del received BMS-986504 (50 to 800 mg) in 3-wk cycles. Symmetric dimethylarginine (SDMA) and intron retention are known PD BMs of PRMT5 inhibition. Therefore, PD effects of BMS-986504 were assessed via changes in plasma and tumor SDMA levels (mass spec and IHC), intron retention, and gene expression (RNASeq) based on samples collected at baseline (BL) and cycle 2 day 1 (C2D1). Additional analyses correlating efficacy outcomes with PD results and select mutations at BL were performed in clinically evaluable pts as of 19-SEP-24. Results: Robust PD modulation of the PRMT5 pathway was observed with BMS-986504. Among pts with matched samples (n = 63), median plasma SDMA levels were reduced by 56% from BL (122.6 ng/mL) to C2D1 (53.8 ng/mL). There were dose-dependent reductions in median plasma SDMA with the greatest reductions at 400 mg QD (59.7% [n = 20]), 400 mg BID (61.9% [n = 9]) and 600 mg QD (59.1% [n = 14]). These PD effects were corroborated in the tumor. Median tumor SDMA levels decreased from an HScore of 285 at BL to 0 at C2D1. Consistent with the SDMA decreases, increased intron retention was observed in 9/11 pts with matched samples. BMS-986504 led to downregulation of several gene pathways including DNA repair and mitotic spindle formation, and MYC and E2F targets, as assessed by RNASeq. There was no significant change in expression of MAT2A, PRMT5, or other PRMT genes, suggesting a lack of compensation for PRMT5 inhibition through these genes. Responses were observed with BMS-986504 across EGFR, KRAS, and TP53 mutation subgroups. Additional correlative analyses among BMs and efficacy outcomes will be presented. Conclusions: BMS-986504 demonstrated robust PD effects across multiple doses and solid tumors which is consistent with the proposed mechanism of action. There was a trend of increasing plasma SDMA reduction across doses, with the greatest reductions observed at 400 mg QD and above. Together these results support further investigation of BMS-986504 at 400 mg QD and higher doses as a potential first-in-class synthetic lethal Tx option in pts with advanced solid tumors with MTAP-del. Citation Format: Jordi Rodón, Tyler Simpson, Ben George, Pasi A. Jänne, Kathryn C. Arbour, Konstantinos Leventakos, Kyriakos P. Papadopoulos, Melissa L. Johnson, Alexander I. Spira, Cesar A. Perez, Hani M. Babiker, Richard Zuniga, Candace L. Haddox, Tapsi Kumar, Yidi Qin, Wen-Chi Chou, Peter Olson, Kenna Anderes, Alice Wozniak, Curtis Chin, Ming Lei, Jason T. Henry. Pharmacodynamic (PD) and exploratory biomarker (BM) analysis of the PRMT5 inhibitor BMS-986504 in patients (pts) with advanced solid tumors with homozygous MTAP deletion (MTAP-del) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT079.

Abstract Poly ADP ribose polymerase inhibitors (PARPi) are being investigated in combination with photon and proton radiotherapy in clinical trials of pediatric and adult malignancies. The precise mechanisms of PARPi radiosensitization, and whether differences in photon and proton-mediated relative efficacy exist, have not been fully elucidated. To study mechanisms of PARPi radiosensitization we investigated the effects of PARPi in combination with photons and two different ionizing densities of protons delivered at the entrance (ENT) or the Bragg peak (BP) of the profile (dose-averaged LET [LETd] 2.2 and 7.0 keV/µm, respectively) of a 76.8 MeV proton beam after observing an extreme tumor and normal tissue response in an 18-year-old female patient with high grade glioma treated veliparib and proton therapy in a Children’s Oncology Group clinical trial. BRCA1/2 wild-type hTERT RPE-1, U2OS, and MDA-MB-231 cells were hypersensitive to the combination of veliparib and proton BP, with enhanced relative biological effectiveness (RBE) at 2 Gy values of 1.7, 1.4, and 1.3, respectively. Similar findings were observed with talazoparib and olaparib, suggesting that PARP trapping efficiency was not a major influence on the proton BP RBE. Further, we did not observe differences in transcription replication conflict between the different proton ionizing densities. Unexpectedly, DNA fiber assays revealed more elongated replication fork tracks in PARPi treated cells 60 minutes after proton BP compared with proton ENT, indicative of accelerated replication fork progression. To assess gap formation in the vicinity of nascent DNA we treated cells with the ssDNA-specific S1 nuclease and found that the lengths of CldU-labeled tracks were significantly reduced in cells treated with the PARPi/proton BP combination, suggestive of greater gap formation at replication forks. We postulated that more ssDNA gaps were being converted to DSBs during replication as we further observed that PARPi/proton BP resulted in increased γH2AX foci at 4- and 24-hours after treatment. Consistent with increased DSB formation, a higher proportion of cells arrested in the G2/M phase of the cell cycle at 24 hours following PARPi/proton BP. Despite being arrested in G2/M when homologous recombination is active, there was a significant increase in 53BP1 and a decrease in RAD51 recruitment, indicative of upregulated repair by more error-prone non-homologous end-joining (NHEJ) repair pathway. The enhanced proton BP RBE in PARPi treated cells was abrogated upon knockdown of XRCC4, a critical component of NHEJ repair pathway, suggesting that toxic NHEJ may be contributing to the enhanced proton BP RBE. In conclusion, PARPi renders cells hypersensitive to high LET BP proton irradiation. Enhancing the LET in combination with PARPi warrants further investigation to overcome therapeutic resistance. Citation Format: Yiqun Han, Qin Zhou, Anna Olson, Cameron M. Callaghan, Bin Chen, Nicholas B. Remmes, Meng Xu Welliver, Zheming Wu, Daniel K. Ebner, Jake A. Kloeber, Zhenkun Lou, Robert W. Mutter. Poly ADP ribose polymerase inhibitors potentiate proton therapy end-of-range relative biological effective dose by increasing replication stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4689.

Immunosuppression within the tumor microenvironment (TME) poses a significant challenge to the efficacy of Chimeric Antigen Receptor (CAR) T-cell therapy in solid tumors, including glioblastoma (GBM), the most common and deadly primary brain tumor. Tumor and TME-residing immunosuppressive cells can hijack program death 1(PD1) pathway to evade antitumor T-cell immunity by upregulating its ligand, PD-L1. Thus, targeting PD-L1 emerges as a promising therapeutic strategy to simultaneously eliminate tumor cells and immunosuppressive components within the TME. We developed a novel PD-L1-targeting CAR T-cell therapy, MC9999, and investigated its therapeutic effects against GBM. The antigen-specific cytotoxicity of MC9999 CAR T-cells was firmly validated using a LN229 GBM cell line and its PD-L1-deficient variant, as well as patient-derived brain tumor-initiating cells (BTICs). Furthermore, in vivo therapeutic antitumor effects were confirmed in orthotopic GBM models through intracranial administration of MC9999 CAR T-cells. To pave the way to the translation of MC9999 CAR T-cell therapy to patient bedside, we established a unique experimental system using patient-specific CAR T-cells against their own tumor and immunosuppressive cells. High-quality, patient-specific MC9999 CAR T-cells were manufactured using T cells isolated from peripheral blood, while paired autologous BTICs were generated to serve as target cells. Autologous immunosuppressive cells include monocyte-derived M2 macrophages from patient’s peripheral blood and tumor-associated macrophages (TAMs) isolated from patient’s tumor. Data from multiple patients’ samples consistently demonstrated that these patient-specific MC9999 CAR T-cells elicited robust cytotoxicity against autologous GBM tumor and TME-residing immunosuppressive cells, supporting our hypothesis that targeting PD-L1 effectively address both tumor and its TME. Immunohistochemistry (IHC) staining of our GBM patients’ tissues showed that PD-L1 expression was restricted to tumor cells and macrophages /microglia within the tumor, with no expression detected in neurons, astrocytes, oligodendrocytes, or blood vessels. These findings suggest that MC9999 CAR T-cells can be safely delivered to the brain without compromising normal cell populations. Ongoing studies are underway to further validate the safety profile of MC9999 CAR T-cell therapy. Collectively, the data obtained from this preclinical study support the effectiveness, feasibility and safety of local administration of MC9999 CAR T-cells as a promising new approach for GBM treatment. These encouraging results have motivated us to prepare an Investigational New Drug application to initiate a phase I clinical trial. Citation Format: Yan Luo, Yaqing Qie, Maria J. Ulloa-Navas, Jesus E. Sanchez-Garavito, Vanessa K. Jones, Martha E. Gadd, Mieu M. Brooks, Tanya Hundal, Andrew D. Brim, Isas K. Vazquez-Rosario, Haidong Dong, Alfredo Quinones-Hinojosa, Hong Qin. Intracranial delivery of MC9999 CAR T-cell therapy: a novel strategy to simultaneously eliminate GBM tumors and immunosuppressive components in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4812.

Abstract Approximately two-thirds of hypopharyngeal squamous cell carcinoma (HPSCC) are diagnosed in advanced stage, with the worst prognosis among head and neck squamous cell carcinomas (HNSCCs). Identifying biomarkers for high-risk patients who need aggressive treatment is crucial. We present mutational, transcriptomic and proteomic studies of 103 Chinese HPSCC patients, observing a higher prevalence and poorer prognosis in males comparing to females. Genes in estrogen response pathways are up-regulated and proteins phosphorylated by protein kinase C (PKC) and Cyclin-dependent kinases (CDKs) are aberrantly regulated. We identify aberrant copy number regions including SOX2 (3q26.33), FGFR (8p11.23), CCND1 (11q13.3), CDKN2A/2B (9p21.3), and MYC (8q24.21). HPV status combined with highly mutated genes as predictive markers was assessed, including SYNE1 in HPV(-), MUC4 in HPV(+) patients. We confirm the presence of four known gene expression (GE) subtypes of HNSCC in our HPSCC cohort and present the genomic alterations, patient characteristics and survival status of each subtype. A predictive model involving clinical factors and transcriptomic expression of six genes was established and cross-site validated. The findings open new opportunities for stratifying high-risk patients and molecular targets for novel therapeutic strategies. Citation Format: Yanxin Ren, Wei Xiong, Chun Feng, Dan Yu, Xiaoyan Wang, Qing Yang, Siting Yu, Hongjiang Zhang, Bangyun Huo, Honglu Jiang, Zuli Li, Junlin Wang, Yu-Xiong Su, Ping Yang, Yong Liao, Qi Zhong, Junwen Wang. Multi-omics insights into the molecular signature and prognosis of hypopharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4999.