Citations

Abstract Men of African ancestry (MAA) have the highest global incidence and mortality of prostate cancer (PCa); however, the biology underlying this harsh disease presentation remains poorly understand, largely due to Africans and people within the African diaspora being under-represented in genomics research. MAA are younger at diagnosis, have higher tumor volume at diagnosis and have higher tumor aggression compared to European American men. Additionally, genomic profiling continues to show that PCa etiology and phenotype are influenced by higher amounts of African ancestry and that West African ancestry is associated with unique genomic alterations. Herein we utilize whole exome sequencing of a unique cohort of 45 advanced stage, treatment naïve Nigerian primary PCa tumors and 11 unmatched non-tumor tissue to compare genomic variants with African (AA) and European (EA) American TCGA PCa tumors. Nigerian samples were collected from 6 sites in central and southwest Nigeria. After whole exome sequencing, samples were processed using GATK best practices. Four genes [BRCA1 (100%), BARD1 (45%), BRCA2 (27%) and PMS2 (18%)] had germline variants in at least two Nigerian non-tumor samples. Across 111 germline variants, the AA cohort reflected a pattern [BRCA1 (68%), BARD1 (34%), BRCA2 (28%) and PMS2 (16%)] similar to Nigerian samples. Of the most frequently mutated genes, BRCA1 showed a statistically (p ≤ 0.05) higher mutation frequency in MAA. Disaggregating gene level mutation frequencies by variant revealed both ancestry linked and Nigerian specific germline variant patterns. Driven by rs799917, BRCA1 showed increasing mutation frequency as African admixture increased. BRCA2_rs11571831 was only present in MAA and BRCA2_rs766173 was increased in Nigerian men. 133 somatic variants were present in 26 PCa associated genes within the Nigerian tumor cohort. Nine genes [BRCA2 (27%), APC (20%), ATM (20%), BRCA1 (13%), DNAJC6 (13%), EGFR (13%), MAD1L1 (13%), MLH1 (11%) and PMS2 (11%)] showed mutation frequencies above 10%. Compared to TCGA cohorts, BRCA2, APC and BRCA1 showed statistically significant increases in Nigerian tumors. The Nigerian cohort variant pattern shared similarities (cosign similarities ≥ 0.734) with COSMIC signatures 5 and 6 and mutated genes showed significant (q < 0.001) GO and functional enrichment in mismatch repair and non-homologous repair deficiency (HRD) pathways. Here, we show that variants in DDR genes are increased in Nigerian PCa and that a portion of those variants correlate with increased African ancestry. Moreover, we identify variants of unknown significance that may contribute to population specific routes of tumorigenesis and treatment. These results present the most comprehensive characterization of the Nigerian PCa exome to date and further highlight the need to increase study population diversity. Citation Format: Jason A. White, Ernest Kaninjing, Kayode A. Adeniji, Paul Jibrin, John O. Obafunwa, Chidiebere N. Ogo, Mohammed Faruk, Solomon Rotimi, Ademola Popoola, Omolara A. Fatiregun, Olabode P. Oluwole, Balasubramanyam Karanam, Wei Tang, Stefan Ambs, Folake T. Odedina, Damali N. Martin, Clayton Yates. Tumor only analysis of whole exome sequencing from a multi-institutional Nigerian prostate cancer cohort reveals DNA repair genes associated with African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1507.

Abstract Glioblastoma (GBM) are inherently resistant to radiation therapy (RT), and development of radiosensitizers is one strategy to overcome this limitation. Repair of DNA double strand breaks induced by RT are mediated by the protein kinase Ataxia Telangiectasia mutated (ATM). In this study, the novel ATM inhibitor WSD-0628 was evaluated in combination with RT using GBM and melanoma models. In vitro evaluation of 10uM WSD-0628 binding to a panel of potential drug targets, including receptors, ion channels, enzymes, and transporters, indicated a satisfactory safety profile with low risk for off-target liability. WSD-0628 potently inhibits ATM-mediated phosphorylation of the DNA damage response protein KAP1 in MCF-7 cells at sub-nanomolar (nM) concentrations (IC50 0.42nM) in comparison to much less potent inhibition of the related kinases ATR (phosphorylation of CHK1, IC50 742nM) or DNA-PKcs (auto-phosphorylation of DNA-PK, IC50 169nM) in HT29 cells assessed by ELISA. In U251 GBM cells, 30 nM WSD-0628 potently inhibited RT-induced phospho-KAP1 and robustly reduced clonogenic survival by 5-fold when combined with 5 Gy irradiation (combination vs RT alone, p<0.01). Similar potent radiosensitizing effects were seen in a melanoma brain metastasis PDX line M12 (10nM WSD-0628+IR-5Gy 1% survival vs 5% survival with IR-5Gy alone. p<0.01), and the SV-40 transformed astrocyte line SVG-A (10nM WSD-0628 + IR-2.5Gy survival 0.2% vs 15% with IR-2.5Gy alone. p<0.01). Evaluation of the pharmacokinetic profile of WSD-0628 in mice 2h after a single 5 mg/kg oral dose reveals a high level of free drug availability in the brain (34nM) and in the CSF (50nM) with little to no Pgp/BCRP substrate liability. An initial in vivo dose finding study in orthotopic GBM43 PDX yielded significant benefit with WSD-0628 at either 5 or 10 mg/kg PO daily when combined with radiation (2Gy QD for 5 days); Median survival for sham RT (29d) or RT alone (34d) were significantly different from RT combinations with 5 mg/kg (54d) and 10 mg/kg (73d; p<0.01 for both dose levels), although the higher dose combination was poorly tolerated with body weight loss between 15-20% one week after RT completion. Dosing of WSD-0628 (7.5 mg/kg PO, QD) given just before and 24h after a single dose of RT (12.5Gy) in mice with orthotopic M12 was well tolerated and provided robust radiosensitizing effects with median survival for combination treatment of over 180d vs 17d for control and 49d with RT alone groups (combination vs RT alone, p=0.04). Collectively, these results suggest a promising role for WSD-0628 in combination with RT in GBM and melanoma metastatic to the brain. Citation Format: Ann Mladek Tuma, Wei Zhong, Lily Liu, Danielle M. Burgenske, Brett L. Carlson, Katrina K. Bakken, Zeng Hu, Margaret A. Connors, Jann N. Sarkaria. WSD-0628, a novel brain penetrant ATM inhibitor, radiosensitizes GBM and melanoma patient derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3305.

Background: Patients with advanced emphysema experience breathlessness due to impaired respiratory mechanics and diaphragm dysfunction. Bronchoscopic lung volume reduction (BLVR) is a minimally invasive bronchoscopic procedure done to reduce hyperinflation and air trapping, promoting atelectasis in the targeted lobe and allowing improved respiratory mechanics. Real-world data on safety and complications outside of clinical trials of BLVR are limited. Methods: We queried the US Food and Drug Administrations (FDA) Manufacturers and User Device Experience database from May 2019 to June 2020 for reports involving BLVR with endobronchial valve (EBV) placement. Events were reviewed for data analysis. Results: We identified 124 cases of complications during BLVR with EBV implantation. The most-reported complication was pneumothorax (110/124, 89%), all of which required chest tube placement. A total of 54 of these cases (54/110, 49%) were complicated by persistent air leak requiring additional interventions. Repeat bronchoscopy was needed to remove the valves in 28 patients, 12 were discharged with a Heimlich valve, and 10 had an additional pleural catheter placed. The other complications of BLVR with EBV placement included respiratory failure (6/124, 5%), pneumonia (4/124, 3%), hemoptysis (2/124, 1.6%), valve migration (1/124, 1%), and pleural effusion (1/124, 1%). A total of 14 deaths were reported during that year. Conclusion: Pneumothorax is the most-reported complication for BLVR with EBV placement, and in 65% of cases, pneumothorax is managed without removing valves. Importantly, 14 deaths were reported during that timeframe. Further studies are needed to estimate the true magnitude of the complications associated with BLVR.

11504 Background: Pazopanib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity in advanced soft tissue sarcoma. ARST1321 was a phase II study designed to compare the near complete pathologic response rate (≥ 90% necrosis) following preoperative chemoradiation +/- pazopanib in children and adults with intermediate/high risk chemotherapy-sensitive body wall/extremity NRSTS. Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary analysis of the study, we now report the outcome data for this cohort. Methods: ARST1321 was a jointly designed COG and NRG Oncology study open to enrollment July 2014-October 2018. Eligible adult (≥18 years) and pediatric (< 18 years) patients with newly-diagnosed unresected body wall/extremity NRSTS were enrolled into the Chemotherapy Cohort (> 5 cm, FNCLCC grade 2/3, protocol-designated chemotherapy-sensitive histology). Following a dose-finding phase, patients were randomized to receive (Regimen A) or not receive (Regimen B) pazopanib (< 18 years: 350 mg/m2/day; ≥ 18 years: 600 mg/day) in combination with ifosfamide (7.5 gm/m2/cycle) and doxorubicin (75 mg/m2/cycle) + 45 Gy preoperative RT followed by primary resection at week 13, then further chemotherapy to week 25. Results: Eighty-five eligible patients were enrolled in the Chemotherapy Cohort and randomized to receive or not receive pazopanib. Median age 22.1 years (range: 5.7-64.2 years); 30 patients < 18 years. Most common histologies were synovial sarcoma (n = 42) and undifferentiated pleomorphic sarcoma (n = 19). As of December 31, 2021, at a median survivor follow-up of 3.3 years (range: 0.1 – 5.8 years), the 3-year event-free survival (EFS) for all patients in the intent-to-treat analysis was 52.5% (95% CI: 34.8%-70.2%) for Regimen A and 50.6% (32%-69.2%) for Regimen B (p = 0.8677); 3-year overall survival (OS) was 75.7% (59.7%-91.7%) for Regimen A and 65.4% (48.1%-82.7%) for Regimen B (p = 0.1919). Conclusions: Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib to preoperative chemoradiation in children and adults with intermediate/high risk body wall/extremity NRSTS, outcomes were not statistically significantly different between the two regimens. Pathologic response could be a TKI-related phenomenon and may not be a good surrogate marker of outcome in future studies. Clinical trial information: NCT02180867.

TPS8068 Background: Elranatamab (PF-06863135) is a humanized bispecific antibody that targets both B cell maturation antigen (BCMA) on multiple myeloma (MM) cells and CD3 on T cells resulting in T cell- mediated cytotoxicity. In preclinical studies, elranatamab has demonstrated anti-myeloma activity and delayed disease progression. In the ongoing phase 1 MagnetisMM-1 study, elranatamab has demonstrated clinical efficacy and a manageable safety profile in patients with relapsed/refractory MM (Bahlis et al, J Clin Oncol 2021). Elranatamab maximum tolerated dose has not yet been reached. Subcutaneous (SC) elranatamab at the recommended dose of 76 mg QW on a 28-d cycle with a 2 step-up priming dose regimen administered during the first week is currently being evaluated in a phase 2 study, MagnetisMM-3 (Lesokhin et al, Blood, 2021). Methods: MagnetisMM-9 (start date: Oct 2021; estimated completion date: Apr 2025) is an open-label, multicenter, non-randomized phase 1/2 study evaluating an alternative priming regimen to further mitigate cytokine release syndrome (CRS) incidence and severity and to evaluate SC elranatamab Q2W and Q4W dosing regimens in patients with relapsed/refractory MM. In part 1 of the study, patients will receive premedications and 2 step-up priming doses on cycle 1 D1 (4 mg) and D4 (20 mg), followed by elranatamab 76 mg QW for 6 cycles, and a dose Q2W thereafter if partial response or better is achieved and maintained. In part 2, higher doses of elranatamab ( > 76 mg) at increased intervals between doses will be evaluated. The primary endpoint is grade ≥2 CRS rate during cycle 1. Secondary endpoints include dose-limiting toxicities (part 2 only), objective response rate, duration of response, progression-free survival, overall survival, minimal residual disease negativity rate, safety, and pharmacokinetics. Eligible patients should be ≥18 years of age with a MM diagnosis and measurable disease according to IMWG criteria, refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody, relapsed/refractory to their last treatment regimen, and have an ECOG performance status ≤1. Key exclusion criteria are smoldering MM, active plasma cell leukemia, amyloidosis, POEMS syndrome, stem cell transplant within 12 weeks of enrollment, active, uncontrolled bacterial, fungal, or viral infections, or any other active malignancy within 3 years prior to enrollment (except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ), or previous treatment with an anti-BCMA bispecific antibody. The study is open at centers in the USA, UK, Japan, and Taiwan. Clinical trial information: NCT05014412.

5002 Background: In the phase 3 VISION study, gallium (68Ga) gozetotide (68Ga-PSMA-11) PET/CT imaging was used to determine eligibility for lutetium (177Lu) vipivotide tetraxetan (177Lu-PSMA-617). Given that 177Lu-PSMA-617 targets PSMA, we assessed the association between quantitative PSMA imaging parameters and treatment outcomes. Methods: In VISION, adults with mCRPC with ≥ 1 PSMA-positive (+) and no PSMA-negative lesions meeting the exclusion criteria were enrolled. In this sub-study, the association between imaging data from pre-enrollment 68Ga-PSMA-11 PET/CT scans of pts in the 177Lu-PSMA-617 group and clinical outcomes was assessed. Imaging data meeting quality requirements were analyzed for 548/551 pts. PSMA expression was quantified by 5 PET parameters: PSMA+ lesions by region, mean standardized uptake value (SUVmean), maximum SUV (SUVmax), PSMA+ tumor volume, and tumor load (PSMA+ tumor volume × SUVmean). Parameters were extracted from the whole body and 4 regions. Association between PET parameters and radiographic progression-free survival (rPFS; primary objective), overall survival (OS), objective response rate (ORR), and prostate–specific antigen 50 (PSA50) response was assessed. Results: Most pts (92.7%) had PSMA uptake in bone. In both the whole-body and regional analyses, statistically significant associations of PSMA PET parameters to clinical outcomes were observed (whole-body data shown in Table). Higher whole-body SUVmean was associated with improved clinical outcomes; pts in the highest quartile (SUVmean: rPFS, ≥ 10.2; OS, ≥ 9.9) had a median rPFS and OS of 14.1 and 21.4 months, vs 5.8 and 14.5 months for those in the lowest quartile (< 6.0; < 5.7), respectively. Absence of PSMA+ lesions in bone, liver, and lymph node, and lower PSMA+ tumor load, were indicators of good prognosis. Conclusions: Higher SUVmean is strongly associated with improved outcomes with 177Lu-PSMA-617; clinical efficacy for different SUV levels vs the SoC arm is being assessed. Data support use of 68Ga-PSMA-11 PET/CT scan to identify pts who will benefit from PSMA-targeted radioligand therapy.[Table: see text]

4055 Background: Tumor microenvironmental (TME) features including tumor stroma ratio (TSR), tumor infiltrating lymphocytes (TILs) and tumor budding (TB), may be associated with tumor metastatic potential. We sought to identify the association of these features with prognosis of patients with resectable intestinal-type gastric cancer. Methods: Radical resection of gastric carcinoma (> 15 LNs removed) was performed in 493 patients (stage I, n=225; stage II, n=119; stage III, n=149) at two university hospitals between 2010 and 2016. Cutpoints were as follows: TSR (50%), TILs (median), and TB (Bd0-Bd3). TME features and their association with clinicopathological characteristics, time-to-recurrence (TTR) and overall survival (OS) were analyzed by univariate and multivariate Cox methods.. Results: Among 493 patients, high TSR, low TILs and high TB (Bd1-Bd3) were significantly associated with higher histological grade, larger tumor size, and increased T and N stages. Each of these features was significantly associated with poorer TTR and OS at 5 years. In Cox multivariable analysis, N stage and TSR were the only variables that were significantly associated with TTR and OS (Table). The relative contribution (%) of TSR to TTR ranked second (17.5%) behind N stage (49.2%) and ahead of TILs (7.2%) and TB (0.1%). Conclusions: Among TME features, TSR was the most robust and was significantly and independently associated with TTR and OS. The relative contribution of TSR to TTR was second only to nodal status. [Table: see text]

TPS11591 Background: Patients with high-risk rhabdomyosarcoma (HR-RMS) continue to have poor outcomes with 3-year event free survival (EFS) rates of 30% or less despite chemotherapy dose intensification on recent cooperative group RMS trials. Vinorelbine (VINO) has demonstrated clinical activity in RMS patients with relapsed/refractory disease and shown to provide a survival benefit when given with oral cyclophosphamide as maintenance chemotherapy for a select group of patients that achieved first complete remission. Methods: ARST2031 is a randomized Phase 3 trial with the primary aim to compare event-free survival (EFS) of patients with HR-RMS treated with vincristine, dactinomycin and cyclophosphamide (VAC) followed by maintenance with vinorelbine and oral cyclophosphamide (VINO-CPO) or vinorelbine, dactinomycin and cyclophosphamide (VINO-AC) followed by maintenance with VINO-CPO. Patients are stratified by histology and randomly assigned to VAC followed by VINO-CPO maintenance or VINO-AC followed by VINO-CPO maintenance. To be eligible, patients must be ≤ 50 years of age at the time of enrollment with newly diagnosed RMS except adult-type pleomorphic, based upon institutional histopathologic classification. All patients must have Stage 4 disease and patients diagnosed with embryonal RMS (ERMS) must be ≥ 10 years of age. Patients with malignant cytology in cerebrospinal fluid, intra-parenchymal brain metastases, or diffuse leptomeningeal disease are excluded. The study was activated on September 13, 2021 and is anticipated to enroll approximately 4 patients per month. The planned sample size is 100 patients, with approximately 50 patients randomized to each arm. Safety and feasibility of VINO-AC will be assessed in the first 8 patients prior to randomization. The study will have power of 0.8 to detect a hazard ratio of 0.61 (74 events in total) when the one-sided Type I error rate is 0.10, with 30 months of accrual and 2 years of follow-up. The hazard ratio of 0.61 was determined by assuming piecewise exponential distributions and specifying the 2-year EFS of 46% vs. 28% and long-term EFS of 32% vs. 16%, based on prior outcome data. Biospecimens will be collected and banked for future use. Clinical trial information: NCT04994132.

Abstract Background The AMP‐activated protein kinase (AMPK) is a central regulator of energy homeostasis, with deregulation leading to cancer and other diseases. However, how this pathway is dysregulated in cancer has not been well clarified. Methods Using a tandem affinity purification/mass‐spec technique and biochemical analyses, we identified tumor protein D52 (TPD52) as an AMPKα‐interacting molecule. To explore the biological effects of TPD52 in cancers, we conducted biochemical and metabolic assays in vitro and in vivo with cancer cells and TPD52 transgenic mice. Finally, we assessed the clinical significance of TPD52 expression in breast cancer patients using bioinformatics techniques. Results TPD52, initially identified to be overexpressed in many human cancers, was found to form a stable complex with AMPK in cancer cells. TPD52 directly interacts with AMPKα and inhibits AMPKα kinase activity in vitro and in vivo. In TPD52 transgenic mice, overexpression of TPD52 leads to AMPK inhibition and multiple metabolic defects. Clinically, high TPD52 expression predicts poor survival of breast cancer patients. Conclusion The findings revealed that TPD52 is a novel regulator of energy stress‐induced AMPK activation and cell metabolism. These results shed new light on AMPK regulation and understanding of the etiology of cancers with TPD52 overexpression.

Significance Eosinophils contribute to type 2 immunity against helminths and allergens. The small intestine harbors eosinophils with incompletely understood pathophysiological roles. Here, we show that intestinal eosinophils include two subsets. One expresses the inhibitory receptor Clec4a4 and the inhibitory ligand PD-L1 and is unique to the small intestine; the other manifests a proinflammatory phenotype. Both subsets are blood derived. Remarkably, Clec4a4 + eosinophils were instructed by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that imprints many gut immune cells. Selective AHR deletion in eosinophils depleted Clec4a4 + eosinophils, augmented innate lymphocytes producing type 2 cytokines, and enhanced helminth clearance. We conclude that Clec4a4 + eosinophils have immunomodulatory functions, which could be harnessed for the therapy of food allergies and eosinophilic gastrointestinal disorders.