bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Additional Oncogenic Alterations in RAS-Driven Differentiated Thyroid Cancers Associate with Worse Clinicopathologic Outcomes
Authors: Bikas Athanasios , Ahmadi Sara , Pappa Theodora , Marqusee Ellen , Wong Kristine , Nehs Matthew A. , Cho Nancy L. , Haase Jacob , Doherty Gerard M. , Sehgal Kartik , Barletta Justine A. , Alexander Erik K. , Landa Iñigo
Published: September 2024

Abstract
Purpose: RAS mutations occur across the spectrum of thyroid neoplasms, and more tools are needed for better prognostication. The objective of this study was to evaluate how additional genetic events affecting key genes modify prognosis in patients with RAS-mutant thyroid cancers, and specifically differentiated thyroid cancers (DTC). Experimental Design: We performed a clinical–genomic analysis of consecutive patients with DTC, poorly differentiated (PDTC), or anaplastic thyroid cancer (ATC) between January 2014 and December 2021, in whom a custom-targeted next generation sequencing assay was performed. Patients harboring RAS mutations were included, and we compared their clinical features and outcomes based upon the presence of additional oncogenic alterations. Results: Seventy-eight patients were identified, with 22% (17/78) harboring a driver RAS mutation plus an additional oncogenic alteration. All six (100%) ATCs had an additional mutation. Compared to DTCs harboring a solitary RAS mutation, DTC patients with RAS and additional mutation(s) were more likely to be classified as American Thyroid Association high-risk of recurrence (77% vs. 12%; P<0.001), have larger primary tumors (4.7 vs. 2.5 cm; P=0.002) and advanced stage (III or IV) at presentation (67% vs. 3%; P<0.001). Importantly, over an average 65-month follow-up, DTC-specific-mortality was more than 10-fold higher (20% vs. 1.8%, P=0.011) when additional mutations were identified. Conclusions: Identification of key additional mutations in patients with RAS-mutant thyroid cancers confers a more aggressive phenotype, increases mortality risk in DTC, and can explain the diversity of RAS-mutated thyroid neoplasia. These data support genomic profiling of DTCs to inform prognosis and clinical decision making.
Data from Subsets of interferon signaling predict response to immune checkpoint blockade in melanoma patients
Authors: Horowitch Brooke , Lee Daniel Y. , Ding Min , Martinez-Morilla Sandra , Aung Thazin Nwe. , Ouerghi Feriel , Wang Xueting , Wei Wei , Damsky William , Sznol Mario , Kluger Harriet , Rimm David L. , Ishizuka Jeffrey
Published: September 2024

Abstract
Purpose: Interferon (IFN) signaling in the tumor microenvironment is a critical determinant of both response and resistance of cancer to immune checkpoint inhibitors (ICIs). We hypothesized that distinct patterns of IFN signaling in melanoma are associated with clinical response or resistance to ICIs. Experimental Design: Two Tissue Microarrays (TMAs) containing samples from 97 patients with metastatic melanoma who received nivolumab, pembrolizumab, or a combination of ipilimumab and nivolumab at Yale New Haven Hospital between 2011-2017 were randomized into discovery and validation cohorts. Samples were stained and visualized using multiplexed immunofluorescence microscopy for STAT1, STAT1 phosphorylated at Y701 (pSTAT1Y701), and PD-L1, and signals were quantified using the AQUA method of quantitative immunofluorescence. Treatment response was assessed using RECIST criteria, and overall survival was analyzed. For in vitro studies, human melanoma cell lines were stimulated with IFNγ and IFNβ, and Western blotting was performed. Results: Pre-treatment STAT1 levels were higher in responders to ICIs (CR/PR/SD for > 6 months) than in non-responders (SD < 6 months/PD). Higher pre-treatment STAT1 levels were associated with improved survival after ICIs in both the discovery and validation cohorts. Western blot analysis of human melanoma cell lines stimulated with IFN demonstrated distinct patterns of upregulation of STAT1 compared with pSTAT1Y701 and PD-L1. When combining STAT1 and PD-L1 markers, patients with STAT1highPD-L1low tumors had improved survival compared with those with STAT1lowPD-L1high tumors. >Conclusions: STAT1 may better predict melanoma response to ICIs than current strategies, and combined STAT1 and PD-L1 biomarkers may provide insight into IFN-responsive versus IFN-resistant states.
Data from An open-label phase I study of GDC-0927 in postmenopausal women with locally advanced or metastatic estrogen receptor positive breast cancer
Authors: Chandarlapaty Sarat , Dickler Maura N. , Perez Fidalgo Jose Alejandro , Villanueva-Vázquez Rafael , Giltnane Jennifer , Gates Mary , Chang Ching-Wei , Cheeti Sravanthi , Fredrickson Jill , Wang Xiaojing , Collier Ann , Moore Heather M. , Metcalfe Ciara , Lauchle Jennifer , Humke Eric W. , Bardia Aditya
Published: September 2024

Abstract
Background: GDC-0927 is a novel, potent, non-steroidal, orally bioavailable, selective estrogen receptor (ER) degrader (SERD) that induces tumor regression in ER+ breast cancer xenograft models. Methods: This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2- metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans. Results: Forty-two patients received GDC-0927 once daily. The maximum tolerated dose was not reached. The most common adverse events (AEs) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and a ~40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and PR protein and mutant ESR1 ctDNA did not correlate with clinical benefit. Conclusions: GDC-0927 appeared to be well-tolerated with pharmacokinetics supporting once daily dosing. There was evidence of target engagement and preliminary evidence of anti-tumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2- breast cancer with and without ESR1 mutations.
Data from Maveropepimut-S, a DPX-based immune-educating therapy, shows promising and durable clinical benefit in patients with recurrent ovarian cancer, a phase 2 trial
Authors: Dorigo Oliver , Oza Amit M. , Pejovic Tanja , Ghatage Prafull , Ghamande Sharad , Provencher Diane , MacDonald Lisa D. , Torrey Heather , Kaliaperumal Valarmathy , Ebrahimizadeh Walead , Hirsch Heather A. , Bramhecha Yogesh , Villella Jeannine , Fiset Stephan
Published: September 2024

Abstract
Purpose: Patients with platinum resistant ovarian cancer (OvCa) respond poorly to existing therapies. Hence there is a need for more effective treatments. Methods: The DeCidE1 trial is a multicenter, randomized, open-label, single-arm phase 2 study to evaluate the safety and effectiveness of maveropepimut-S (MVP-S) with cyclophosphamide (CPA) in patients with recurrent ovarian cancer. Median follow-up for evaluable subjects was 4.4 months. Data were collected from March 2019 to June 2021. Subjects received two injections of 0.25 mL MVP-S 3 weeks apart, followed by one 0.1 mL doses, every 8 weeks up to progression. Oral CPA, 50 mg twice daily, was administered in repeating weekly on and off cycles. Results: Twenty-two patients were enrolled. Median age was 58 years (38-78 years). Among the evaluable population, ORR was 21% (90% CI, 7.5%-41.9%), with a DCR of 63% (90% CI, 41.8%-81.3%), including 4 (21%) patients with partial responses, 8 (42%) stable disease, and 7 (37%) progressive disease. The ORRs were consistent across subgroups based on platinum-sensitivity, and DCR was higher in the platinum-resistant subpopulation. Four stable disease patients maintained clinical benefit up to 25 months. Most treatment related adverse events (TRAEs) were grade 1 and 2 (87% of unique events). Most common AEs were injection site reactions. Eight subjects reported grade 3 and no grade 4 AEs. Survivin-specific T cell responses were observed in treated patients with clinical benefit. Conclusions: MVP-S with intermittent low-dose CPA is well-tolerated, with clinical benefit for patients with recurrent OvCa. Observed responses are irrespective of the platinum status.
Data from Spatial Immunoprofiling of Adenoid Cystic Carcinoma Reveals B7-H4 Is a Therapeutic Target for Aggressive Tumors
Authors: de Sousa Luana G. , McGrail Daniel J. , Lazar Neto Felippe , Li Kaiyi , Marques-Piubelli Mario L. , Ferri-Borgogno Sammy , Dai Hui , Mitani Yoshitsugu , Spardy Burr Nicole , Cooper Zachary A. , Kinneer Krista , Cortez Maria Angelica. , Lin Shiaw-Yih , Bell Diana , El-Naggar Adel , Burks Jared , Ferrarotto Renata
Published: September 2024

Abstract
Purpose: Adenoid cystic carcinoma (ACC) is a heterogeneous malignancy, and no effective systemic therapy exists for metastatic disease. We previously described two prognostic ACC molecular subtypes with distinct therapeutic vulnerabilities, ACC-I and ACC-II. In this study, we explored the ACC tumor microenvironment (TME) using RNA-sequencing and spatial biology to identify potential therapeutic targets. Experimental Design: Tumor samples from 62 ACC patients with available RNA-sequencing data that had been collected as part of previous studies were stained with a panel of 28 validated metal-tagged antibodies. Imaging mass cytometry (IMC) was performed using the Fluidigm Helios CyTOF instrument and analyzed with Visiopharm software. The B7-H4 antibody-drug conjugate AZD8205 was tested in ACC patient–derived xenografts (PDXs). Results: RNA deconvolution revealed that most ACCs are immunologically “cold”, with approximately 30% being “hot”. ACC-I tumors with a poor prognosis harbored a higher density of immune cells; however, spatial analysis by IMC revealed that ACC-I immune cells were significantly restricted to the stroma, characterizing an immune-excluded TME. ACC-I tumors overexpressed the immune checkpoint B7-H4, and the degree of immune exclusion was directly correlated with B7-H4 expression levels, an independent predictor of poor survival. Two ACC-I/B7-H4-high PDXs obtained 90% complete responses to a single dose of AZD8205, but none were observed with isotype-conjugated payload or in an ACC-II/B7-H4 low PDX. Conclusions: Spatial analysis revealed that ACC subtypes have distinct TMEs, with enrichment of ACC-I immune cells that are restricted to the stroma. B7-H4 is highly expressed in poor-prognosis ACC-I subtype and is a potential therapeutic target.
Data from Comparative Genomic Analysis of Pancreatic Acinar Cell Carcinoma (PACC) and Pancreatic Ductal Adenocarcinoma (PDAC)Unveils New Actionable Genomic Aberrations in PACC
Authors: Florou Vaia , Elliott Andrew , Bailey Matthew H. , Stone David , Affolter Kajsa , Soares Heloisa P. , Nevala-Plagemann Chris , Scaife Courtney , Walker Phillip , Korn W. Michael , Lou Emil , Shroff Rachna T. , Hosein Peter J. , Garrido-Laguna Ignacio
Published: September 2024

Abstract
Purpose: Pure pancreatic acinar cell carcinomas (PACC) are rare malignancies with no established treatment. PACC demonstrates significant genetic intertumoral heterogeneity with multiple pathways involved, suggesting using targeted cancer therapeutics to treat this disease. We aggregated one of the largest datasets of pure PACC to examine the genomic variability and explore patient-specific therapeutic targets. Experimental Design: PACC specimens (n=51) underwent next-generation sequencing (NGS) of DNA (n=29) or whole exome [n=22]) and RNA (whole transcriptome, n=29) at a commercial laboratory. We performed comparative analyses of a genomic cohort of pancreatic ductal adenocarcinomas (PDAC, n=4205). In parallel, we conducted a retrospective review patients with PACC treated at Huntsman Cancer Institute (HCI). Results: The real-world dataset included samples from 51 patients with PACC. We found key molecular differences between pure PACC and PDAC, highlighting the unique characteristics of pure PACC. Major differences in PACC include lower MAPK signaling and less stromal cell abundance compared to PDAC. Pure PACC showed genomic loss-of-heterozygosity to largely coincide with mutations in BRCA1, BRCA2, and PALB2. Of the seven patients treated at HCI, one had a tumor that harbored a BRAF-V600E mutation. Leveraging precision oncology, this patient is being treated with encorafenib plus binimetinib, achieving an exceptionally durable and ongoing complete response of more than three years. Conclusions: There are major differences between PACC and PDAC, including downregulation of the MAPK signaling pathway, and less stromal cell abundance. In addition, genomic characterization of pure PACC revealed frequent targetable alterations, which can guide patient treatment.
Data from MEK inhibition sensitizes pancreatic cancer to STING agonism by tumor-cell intrinsic amplification of type I interferon signaling
Authors: Ghukasyan Razmik , Liang Keke , Chau Kevin , Li Luyi , Chan Charlotte , Abt Evan R. , Le Thuc , Park Joon Y. , Wu Nanping , Premji Alykhan , Damoiseaux Robert , Luu Tony , Labora Amanda , Rashid Khalid , Link Jason M. , Radu Caius G. , Donahue Timothy R.
Published: September 2024

Abstract
Purpose: STING (Stimulator of Interferon Genes) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor-cell intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity. Experimental Design: We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo. Results: We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce Type I interferon-dependent cell death in vitro and tumor regression in vivo. We parsed NF-κB-dependent and independent mechanisms that mediate STING-driven Type I interferon production and show that MEK signaling inhibits this effect by suppressing NF-κB activation. Conclusions: Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity, and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.
Data from A bi-functional PARP-HDAC inhibitor with activity in Ewing sarcoma
Authors: Ramos Louise , Truong Sarah , Zhai Beibei , Joshi Jay , Ghaidi Fariba , Lizardo Michael M. , Shyp Taras , Kung Sonia H.Y. , Rezakhanlou Alireza M. , Oo Htoo Zarni , Adomat Hans , Le Bihan Stephane , Collins Colin , Bacha Jeffrey , Brown Dennis , Langlands John , Shen Wang , Lallous Nada , Sorensen Poul H. , Daugaard Mads
Published: September 2024

Abstract
Purpose: Histone deacetylase (HDAC) inhibition has been shown to induce pharmacological “BRCAness” in cancer cells with proficient DNA repair activity. This provides a rationale for exploring combination treatments with HDAC and poly-(ADP-ribose)-polymerase (PARP) inhibition in cancer types that are insensitive to single-agent PARP inhibitors. Here, we report the concept and characterization of a novel bi-functional PARP inhibitor (kt-3283) with dual activity towards PARP1/2 and HDAC enzymes in Ewing sarcoma cells. Experimental Design: Inhibition of PARP1/2 and HDACs was measured using PARP1/2, HDAC activity, and PAR formation assays. Cytotoxicity was assessed by IncuCyte live cell imaging, CellTiter-Glo®, and spheroid assays. Cell cycle profiles were determined using propidium iodide staining and flow cytometry. DNA damage was examined by γH2AX expression and comet assay. Inhibition of metastatic potential by kt-3283 was evaluated via ex vivo pulmonary metastasis assay (PuMA). Results: Compared to FDA-approved PARP (olaparib) and HDAC (vorinostat) inhibitors, kt-3283 displayed enhanced cytotoxicity in Ewing sarcoma models. The kt-3283-induced cytotoxicity was associated with strong S and G2/M cell cycle arrest in nanomolar concentration range and elevated DNA damage as assessed by γH2AX tracking and comet assays. In three-dimensional spheroid models of Ewing sarcoma, kt-3283 showed efficacy in lower concentrations than olaparib and vorinostat and kt-3283 inhibited colonization of Ewing sarcoma cells in the ex vivo PuMA model. Conclusion: Our data demonstrates the preclinical justification for studying the benefit of dual PARP and HDAC inhibition in the treatment of Ewing sarcoma in a clinical trial and provides proof-of-concept for a bi-functional single-molecule therapeutic strategy.
Data from Thyroid cancers exhibit oncogene-enhanced macropinocytosis that is restrained by IGF1R and promotes albumin-drug-conjugate response
Authors: Hu Huiyu , Ng Thomas S.C. , Kang Mikyung , Scott Ella , Li Ran , Quintana Jeremy M. , Matvey Dylan , Vantaku Venkata R. , Weissleder Ralph , Parangi Sareh , Miller Miles A.
Published: September 2024

Abstract
Purpose: Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK-ERK and PI3K pathway mutations remains unclear. We hypothesized that understanding links between thyroid cancer signaling and macropinocytosis might uncover new therapeutic strategies. Experimental Design: Macropinocytosis was assessed across cells derived from papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), non-malignant follicular thyroid, and aggressive anaplastic thyroid cancer (ATC), by imaging fluorescent dextran and serum albumin. The impacts of ectopic BRAF V600E and mutant RAS, genetic PTEN silencing, and inhibitors targeting RET, BRAF, and MEK kinases were quantified. Braf V600E p53-/- ATC tumors in immunocompetent mice were used to measure efficacy of an albumin-drug-conjugate comprising microtubule-destabilizing monomethyl auristatin E (MMAE) linked to serum albumin via a cathepsin-cleavable peptide (Alb-vc-MMAE). Results: FTC and ATC cells showed greater macropinocytosis than non-malignant and PTC cells. ATC tumors accumulated albumin at 8.8% injected dose per gram tissue. Alb-vc-MMAE, but not MMAE alone, reduced tumor size by >90% (P<0.01). ATC macropinocytosis depended on MAPK/ERK activity and nutrient signaling, and increased by up to 230% with metformin, phenformin, or inhibition of insulin-like growth factor 1 receptor (IGF1Ri) in monoculture but not in vivo. Macrophages also accumulated albumin and express the cognate IGF1R ligand, IGF1, which reduced ATC responsiveness to IGF1Ri. Conclusions: These findings identify regulated oncogene-driven macropinocytosis in thyroid cancers and demonstrate the potential of designing albumin-bound drugs to efficiently treat them.
Data from Preclinical Characterization and Phase 1 Trial Results of INBRX-109, a Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma
Authors: Subbiah Vivek , Chawla Sant P. , Conley Anthony P. , Wilky Breelyn A. , Tolcher Anthony , Lakhani Nehal J. , Berz David , Andrianov Vasily , Crago William , Holcomb Monica , Hussain Abrahim , Veldstra Carson , Kalabus James , O’Neill Brianne , Senne Lane , Rowell Emily , Heidt Analeah B. , Willis Katelyn M. , Eckelman Brendan P.
Published: September 2024

Abstract
Purpose: Patients with unresectable/metastatic chondrosarcoma have poor prognoses; conventional chondrosarcoma is associated with a median progression-free survival (PFS) of <4 months after first-line chemotherapy. No standard targeted therapies are available. We present the preclinical characterization of INBRX-109, a third-generation death receptor 5 (DR5) agonist, and clinical findings from a phase 1 trial of INBRX-109 in unresectable/metastatic chondrosarcoma (NCT03715933). Patients and Methods: INBRX-109 was first characterized preclinically as a DR5 agonist, with binding specificity and hepatotoxicity evaluated in vitro and antitumor activity evaluated both in vitro and in vivo. INBRX-109 (3 mg/kg every 3 weeks) was then evaluated in a phase 1 study of solid tumors that included a cohort with any subtype of chondrosarcoma and a cohort with IDH1/IDH2-mutant conventional chondrosarcoma. The primary endpoint was safety. Efficacy was an exploratory endpoint, with measures including objective response, disease control rate, and PFS. Results: In preclinical studies, INBRX-109 led to antitumor activity in vitro and in patient-derived xenograft models, with minimal hepatotoxicity. In the phase 1 study, INBRX-109 was well tolerated and demonstrated antitumor activity in unresectable/metastatic chondrosarcoma. INBRX-109 led to a disease control rate of 87.1% (27/31; durable clinical benefit, 40.7% [11/27]), including 2 partial responses, and median PFS of 7.6 months. Most treatment-related adverse events, including liver-related events, were low grade (grade ≥3 events in chondrosarcoma cohorts, 5.7%). Conclusions: INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase 2 trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.
Data from Early changes in circulating cell free KRAS G12C predicts response to adagrasib in KRAS mutant non-small cell lung cancer patients
Authors: Paweletz Cloud P. , Heavey Grace A. , Kuang Yanan , Durlacher Emily , Kheoh Thian , Chao Richard C. , Spira Alexander I. , Leventakos Konstantinos , Johnson Melissa L. , Ou Sai-Hong Ignatius. , Riely Gregory J. , Anderes Kenna , Yang Wenjing , Christensen James G. , Janne Pasi A.
Published: September 2024

Abstract
Purpose: Non-invasive monitoring of circulating tumor DNA (ctDNA) has the potential to be a readily available measure for early prediction of clinical response. Here we report on early ctDNA changes of KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C mutant lung cancer. Experimental Design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRASG12C-mutant lung cancer patients that participated in cohort A of the KRYSTAL-1 clinical trial. We analyzed the change in ctDNA at 2 specific intervals: between cycles 1 and 2 and at cycle 4. Changes in ctDNA were compared to clinical and radiographic response. Results: We found that, in general, a maximal response in KRAS G12C ctDNA levels could be observed during the initial ~3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in KRAS G12C cfDNA >90% and 33 pts (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared to patients with incomplete ctDNA clearance (60.6% vs 33.3%). Furthermore, complete ctDNA clearance at cycle 4 was associated with an improved overall survival (14.7 months vs 5.4 months) and progression free survival (HR 0.3). Conclusion: These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.
Data from Bavituximab decreases immunosuppressive myeloid-derived suppressor cells in newly diagnosed glioblastoma patients
Authors: Ly K. Ina , Richardson Leland G. , Liu Mofei , Muzikansky Alona , Cardona Jonathan , Lou Kevin , Beers Andrew L. , Chang Ken , Brown James M. , Ma Xiaoyue , Reardon David A. , Arrillaga-Romany Isabel C. , Forst Deborah A. , Jordan Justin T. , Lee Eudocia Q. , Dietrich Jorg , Nayak Lakshmi , Wen Patrick Y. , Chukwueke Ugonma , Giobbie-Hurder Anita , Choi Bryan D. , Batchelor Tracy T. , Kalpathy-Cramer Jayashree , Curry William T. , Gerstner Elizabeth R.
Published: September 2024

Abstract
Purpose: We evaluated the efficacy of bavituximab – a monoclonal antibody with anti-angiogenic and immunomodulatory properties – in newly diagnosed glioblastoma (GBM) patients who also received radiation and temozolomide. Perfusion MRI and myeloid-related gene transcription and inflammatory infiltrates in pre-and post-treatment tumor specimens were studied to evaluate on-target effects (NCT03139916). Patients and Methods: Thirty-three adults with isocitrate-dehydrogenase-wild-type GBM received 6 weeks of concurrent chemoradiation, followed by 6 cycles of temozolomide (C1-C6). Bavituximab was given weekly, starting week 1 of chemoradiation, for at least 18 weeks. The primary endpoint was proportion of patients alive at 12 months (OS-12). The null hypothesis would be rejected if OS-12 was ≥72%. Relative cerebral blood flow (rCBF) and vascular permeability (Ktrans) were calculated from perfusion MRIs. Peripheral blood mononuclear cells (PBMCs) and tumor tissue were analyzed pre-treatment and at disease progression using RNA transcriptomics and multispectral immunofluorescence for myeloid-derived suppressor cells (MDSCs) and macrophages. Results: The study met its primary endpoint with an OS-12 of 73% (95% CI 59-90%). Decreased pre-C1 rCBF (HR 4.63, p=0.029) and increased pre-C1 Ktrans were associated with improved OS (HR 0.09, p=0.005). Pre-treatment, overexpression of myeloid-related genes in tumor tissue was associated with longer survival. Post-treatment, tumor specimens contained fewer immunosuppressive MDSCs (p=0.01). Discussion: Bavituximab has activity in newly diagnosed GBM and resulted in on-target depletion of intratumoral immunosuppressive MDSCs. Elevated pre-treatment expression of myeloid-related transcripts in GBM may predict response to bavituximab.
Data from Discovery and targeting of a noncanonical mechanism of sarcoma resistance to ADI-PEG20 mediated by the microenvironment
Authors: Rogers Leonard C. , Kremer Jeff C. , Brashears Caitlyn B. , Lin Zongtao , Hu Zhixian , Bastos Alliny C. S. , Baker Adriana , Fettig Nicole , Zhou Dong , Shoghi Kooresh I. , Dehner Carina A. , Chrisinger John S. A. , Bomalaski John S. , Garcia Benjamin A. , Oyama Toshinao , White Eileen P. , Van Tine Brian A.
Published: September 2024

Abstract
Purpose: Many cancers lack argininosuccinate synthetase 1 (ASS1), the rate limiting enzyme of arginine biosynthesis. This deficiency causes arginine auxotrophy, targetable by extracellular arginine-degrading enzymes such as ADI-PEG20. Long-term tumor resistance has thus far been attributed solely to ASS1 re-expression. This study examines the role of ASS1 silencing on tumor growth and initiation and identifies a noncanonical mechanism of resistance, aiming to improve clinical responses to ADI-PEG20. Experimental Design: Tumor initiation and growth rates were measured for a spontaneous Ass1 knockout (KO) murine sarcoma model. Tumor cell lines were generated, and resistance to arginine deprivation therapy was studied in vitro and in vivo. Results: Conditional Ass1 KO affected neither tumor initiation nor growth rates in a sarcoma model, contradicting the prevalent idea that ASS1 silencing confers a proliferative advantage. Ass1 KO cells grew robustly through arginine starvation in vivo, while ADI-PEG20 remained completely lethal in vitro, evidence that pointed toward a novel mechanism of resistance mediated by the microenvironment. Co-culture with Ass1-competent fibroblasts rescued growth through macropinocytosis of vesicles and/or cell fragments, followed by recycling of protein-bound arginine through autophagy/lysosomal degradation. Inhibition of either macropinocytosis or autophagy/lysosomal degradation abrogated this growth support effect in vitro and in vivo. Conclusions: Noncanonical, ASS1-independent tumor resistance to ADI-PEG20 is driven by the microenvironment. This mechanism can be targeted by either the macropinocytosis inhibitor imipramine or the autophagy inhibitor chloroquine. These safe, widely available drugs should be added to current clinical trials to overcome microenvironmental arginine support of tumors and improve patient outcomes.
Data from Safety and efficacy of tucatinib, letrozole and palbociclib in patients with previously treated HR+/HER2+ breast cancer
Authors: Shagisultanova Elena , Gradishar William , Brown-Glabberman Ursa , Chalasani Pavani , Brenner Andrew J. , Stopeck Alison , Parris Hannah , Gao Dexiang , Mcspadden Tessa , Mayordomo Jose , Diamond Jennifer R. , Kabos Peter , Borges Virginia F.
Published: September 2024

Abstract
Purpose: To overcome resistance to anti-hormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor Tucatinib, aromatase inhibitor Letrozole, and CDK4/6 inhibitor Palbociclib (TLP) for treatment of HR+/HER2+ metastatic breast cancer (MBC). Patients and Methods: Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary end point was safety of the regimen evaluated by NCI CTCAE version 4.3. The phase II primary endpoint was efficacy by median progression free survival (mPFS). Results: 42 women aged 22-81 years were enrolled. Patients received a median of 2 lines of therapy in the metastatic setting, 71.4% had visceral disease, 35.7% had CNS disease. The most common treatment-emergent adverse events (AEs) of grade≥3 were neutropenia (64.3%), leukopenia (23.8%) diarrhea (19.0%), and fatigue (14.3%). Tucatinib increased AUC 10-19 hours of palbociclib 1.7-fold, requiring palbociclib dose reduction from 125 to 75mg daily. In 40 response-evaluable patients, mPFS was 8.4 months, with similar mPFS in non-CNS and CNS cohorts (10.0 versus 8.2 months; p=0.9). Overall response rate was 44.5%, median duration of response was 13.9 months, clinical benefit rate was 70.4%; 60% of patients were on treatment for ≥6 months, 25% for ≥1 year, and 10% for ≥2 years. In CNS cohort, 26.6% of patients remained on study for ≥1 year. Conclusions: TLP combination was safe and tolerable. AEs were expected and manageable with supportive therapy and dose reductions. TLP showed excellent efficacy for an all-oral chemotherapy-free regimen warranting further testing.
Data from Clinical and Genomic Characteristics of Patients with HR+, HER2- Metastatic Breast Cancer Following Progression on a CDK4 and 6 Inhibitor
Authors: Rao Xi , Chen Yongmei , Beyrer Julie , Nash Smyth Emily , Morato Guimaraes Claudia , Litchfield Lacey M. , Bowman Lee , Lawrence Garreth W. , Aggarwal Amit , Andre Fabrice
Published: September 2024

Abstract
Purpose: We explored the clinical and genomic characteristics of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) after progression on cyclin-dependent kinase 4 and 6 inhibitors (CDK4 & 6i) +/- endocrine therapy (ET) to understand potential resistance mechanisms that may aid in identifying treatment options. Experimental Design: US patients with HR+, HER2- MBC had tumor biopsies collected from metastatic site during routine care following progression on a CDK4 & 6i +/- ET (CohortPost) or prior to initiating CDK4 & 6i treatment (CohortPre) and analyzed using a targeted mutation panel and RNA-seq. Clinical and genomic characteristics were described. Results: The mean age at MBC diagnosis was 59 years in CohortPre (n=133) and 56 years in CohortPost (n=223); 14% and 45% of patients had prior chemotherapy/ET and 35% and 26% had de novo stage IV MBC, respectively. The most common biopsy site was liver (CohortPre, 23%; CohortPost, 56%). CohortPost had significantly higher tumor mutational burden (TMB), (median 3.16 vs 1.67 Mut/Mb, P<0.0001), ESR1 alteration frequency (mutations: 37% vs 10%, FDR<0.0001; fusions: 9% vs 2%, P=0.0176), and higher copy number amplification of genes on chr12q15, including MDM2, FRS2, and YEATS4 versus CohortPre patients. Additionally, CDK4 copy number gain on chr12q13 was significantly higher in CohortPost vs. CohortPre (27% vs. 11%, P=0.0005). Conclusions: Distinct mechanisms potentially associated with resistance to CDK4 & 6i +/- ET, including alterations in ESR1 and amplification of chr12q15 and CDK4 copy number gain, were identified.
Data from Dissecting the Mechanisms Underlying the Cytokine Release Syndrome (CRS) Mediated by T-Cell Bispecific Antibodies
Authors: Leclercq-Cohen Gabrielle , Steinhoff Nathalie , Albertí Servera Llucia , Nassiri Sina , Danilin Sabrina , Piccione Emily , Yángüez Emilio , Hüsser Tamara , Herter Sylvia , Schmeing Stephan , Gerber Petra , Schwalie Petra , Sam Johannes , Briner Stefanie , Jenni Sylvia , Bianchi Roberta , Biehl Marlene , Cremasco Floriana , Apostolopoulou Katerina , Haegel Hélène , Klein Christian , Umaña Pablo , Bacac Marina
Published: September 2024

AbstractPurpose:
Target-dependent TCB activity can result in the strong and systemic release of cytokines that may develop into cytokine release syndrome (CRS), highlighting the need to understand and prevent this complex clinical syndrome.
Experimental Design:
We explored the cellular and molecular players involved in TCB-mediated cytokine release by single-cell RNA-sequencing of whole blood treated with CD20-TCB together with bulk RNA-sequencing of endothelial cells exposed to TCB-induced cytokine release. We used the in vitro whole blood assay and an in vivo DLBCL model in immunocompetent humanized mice to assess the effects of dexamethasone, anti-TNFα, anti-IL6R, anti-IL1R, and inflammasome inhibition, on TCB-mediated cytokine release and antitumor activity.
Results:
Activated T cells release TNFα, IFNγ, IL2, IL8, and MIP-1β, which rapidly activate monocytes, neutrophils, DCs, and NKs along with surrounding T cells to amplify the cascade further, leading to TNFα, IL8, IL6, IL1β, MCP-1, MIP-1α, MIP-1β, and IP-10 release. Endothelial cells contribute to IL6 and IL1β release and at the same time release several chemokines (MCP-1, IP-10, MIP-1α, and MIP-1β). Dexamethasone and TNFα blockade efficiently reduced CD20-TCB–mediated cytokine release whereas IL6R blockade, inflammasome inhibition, and IL1R blockade induced a less pronounced effect. Dexamethasone, IL6R blockade, IL1R blockade, and the inflammasome inhibitor did not interfere with CD20-TCB activity, in contrast to TNFα blockade, which partially inhibited antitumor activity.
Conclusions:
Our work sheds new light on the cellular and molecular players involved in cytokine release driven by TCBs and provides a rationale for the prevention of CRS in patients treated with TCBs.

See related commentary by Luri-Rey et al., p. 4320
Data from Impact of Frontline Ivosidenib on Volumetric Growth Patterns in Isocitrate Dehydrogenase (IDH) mutant Astrocytic and Oligodendroglial Tumors
Authors: Kamson David Olayinka. , Puri Sushant , Sang Yingying , Shi Meihui Jessica. , Blair Lindsay , Blakeley Jaishri O. , Laterra John
Published: September 2024

Abstract
Purpose: Isocitrate dehydrogenase (IDH) mutant gliomas are usually treated with radiotherapy and chemotherapy, which increases the risk for neurocognitive sequelae during patients’ most productive years. We report our experience using off-label first-inclass IDH1mut-inhibitor ivosidenib and its impact on tumor volume in IDHmut gliomas. Experimental Design: We retrospectively analyzed patients aged ≥18 years with radiation/chemotherapy-naïve, IDH1mut, non-enhancing, radiographically active, grade 2/3 gliomas, and ≥2 pretreatment and ≥2 on-ivosidenib MRIs. T2/FLAIR-based tumor volumes, growth rates and PFS were analyzed. Log-linear mixed-effect modeling of growth curves adjusted for grade, histology and age was performed. Results: We analyzed 116 MRIs of 12 patients (median age 46years [range:26-60]) 10 males, 8 astrocytomas (50% grade 3), 4 grade 2 oligodendrogliomas. Median on-drug follow-up was 13.2 months (interquartile range[IQR]:9.7-22.2). Tolerability was 100%. 50% of patients experienced ≥20% tumor volume reduction on treatment and absolute growth-rate was lower during treatment (-1.2±10.6cc/year) than before treatment (8.0±7.7cc/year; p≤0.05). Log-linear models in the Stable group (n=9) showed significant growth before treatment (53%/year; p=0.013), and volume reduction (- 34%/year; p=0.037) after 5-months on treatment. After-treatment volume curves were significantly lower than before treatment (after/before treatment ratio 0.5; p<0.01). Median-time-to-Best Response was 11.2(IQR:1.7-33.4) months, and 16.8(IQR:2.6-33.5) months in patients on drug for ≥1 year. PFS-9mo was 75%. Conclusions: Ivosidenib was well-tolerated and induced a high volumetric response rate. Responders had significant reduction in tumor growth rates and volume reductions observed after a 5-month delay. Thus, ivosidenib appears useful to control tumor growth and delay more toxic therapies in IDH-mutant non-enhancing indolently growing gliomas.
Data from Genomic Profiling of Metastatic Castration-Resistant Prostate Cancer Samples Resistant to Androgen Receptor Pathway Inhibitors
Authors: Menssouri Naoual , Poiraudeau Loïc , Helissey Carole , Bigot Ludovic , Sabio Jonathan , Ibrahim Tony , Pobel Cédric , Nicotra Claudio , Ngo-Camus Maud , Lacroix Ludovic , Rouleau Etienne , Tselikas Lambros , Chauchereau Anne , Blanc-Durand Félix , Bernard-Tessier Alice , Patrikidou Anna , Naoun Natacha , Flippot Ronan , Colomba Emeline , Fuerea Alina , Albiges Laurence , Lavaud Pernelle , van de Wiel Paul , den Biezen Eveline , Wesseling-Rozendaal Yvonne , Ponce Santiago , Michiels Stefan , Massard Christophe , Gautheret Daniel , Barlesi Fabrice , André Fabrice , Besse Benjamin , Scoazec Jean-Yves , Friboulet Luc , Fizazi Karim , Loriot Yohann
Published: September 2024

AbstractPurpose:
The androgen receptor axis inhibitors (ARPI; e.g., enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown.
Experimental Design:
In the prospective trial MATCH-R (NCT02517892), 59 patients with mCRPC underwent whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 patients with mCRPC underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher exact tests.
Results:
WES analysis indicated that no single-gene genomic alterations were strongly associated with primary resistance. RNA-seq analysis showed that androgen receptor (AR) gene alterations and expression levels were similar between responders and nonresponders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples.
Conclusions:
Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs’ resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation.

See related commentary by Slovin, p. 4323
Data from Early Clearance of Plasma Epidermal Growth Factor Receptor Mutations as a Predictor of Outcome on Osimertinib in Advanced Non-Small Cell Lung Cancer; Exploratory Analysis from AURA3 and FLAURA
Authors: Gray Jhanelle E. , Ahn Myung-Ju , Oxnard Geoffrey R. , Shepherd Frances A. , Imamura Fumio , Cheng Ying , Okamoto Isamu , Cho Byoung Chul , Lin Meng-Chih , Wu Yi-Long , Majem Margarita , Gautschi Oliver , Boyer Michael , Bulusu Krishna C. , Markovets Aleksandra , Barrett J. Carl. , Hodge Rachel , McKeown Astrid , Hartmaier Ryan J. , Chmielecki Juliann , Papadimitrakopoulou Vassiliki A. , Ramalingam Suresh S.
Published: September 2024

Abstract
Purpose: Plasma circulating tumor DNA (ctDNA) analysis is used for genotyping advanced non-small cell lung cancer (NSCLC); monitoring dynamic ctDNA changes may be used to predict outcomes. Experimental design: This was a retrospective, exploratory analysis of two phase III trials (AURA3 [NCT02151981], FLAURA [NCT02296125]). All patients had epidermal growth factor receptor mutation-positive (ex19del or L858R; EGFRm) advanced NSCLC; AURA3 also included T790M-positive NSCLC. Osimertinib (FLAURA, AURA3), or comparator EGFR-TKI (gefitinib/erlotinib; FLAURA), or platinum-based doublet chemotherapy (AURA3) was given. Plasma EGFRm was analyzed at baseline and Weeks 3/6 by droplet digital polymerase chain reaction. Outcomes were assessed by detectable/non-detectable baseline plasma EGFRm and plasma EGFRm clearance (non-detection) at Weeks 3/6. Results: In AURA3 (n=291), non-detectable versus detectable baseline plasma EGFRm had longer median progression-free survival (mPFS) (hazard ratio [HR] 0.48; 95% confidence interval [CI], 0.33–0.68; P<0.0001). In patients with Week 3 clearance versus non-clearance (n=184), respectively, mPFS (months; 95% CI) was 10.9 (8.3–12.6) versus 5.7 (4.1–9.7) with osimertinib and 6.2 (4.0–9.7) versus 4.2 (4.0–5.1) with platinum-pemetrexed. In FLAURA (n=499), mPFS was longer with non-detectable versus detectable baseline plasma EGFRm (HR 0.54; 95% CI, 0.41–0.70; P<0.0001). For Week 3 clearance versus non-clearance (n=334), respectively, mPFS was 19.8 (15.1 to not calculable) versus 11.3 (9.5–16.5) with osimertinib and 10.8 (9.7–11.1) versus 7.0 (5.6–8.3) with comparator EGFR-TKI. Similar outcomes were observed by Week 6 clearance/non-clearance. Conclusions: Plasma EGFRm analysis as early as 3 weeks on-treatment has the potential to predict outcomes in EGFRm advanced NSCLC.
Data from De novo and histologically transformed small cell lung cancer is sensitive to lurbinectedin treatment through the modulation of EMT and NOTCH signaling pathways.
Authors: Chakraborty Subhamoy , Coleman Charles , Manoj Parvathy , Demircioglu Deniz , Shah Nisargbhai , de Stanchina Elisa , Rudin Charles M. , Hasson Dan , Sen Triparna
Published: September 2024

Abstract
Purpose: Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor with dismal prognosis and limited treatment options. Lurbinectedin, conditionally approved as a second-line treatment for metastatic SCLC, drives clinical responses in about 35% of patients and the overall survival of those who benefit from it remains very low (~9.3 months). This highlights the need to develop improved mechanistic insight and predictive biomarkers of response. Experimental Design: We used human and PDX-derived SCLC cell lines to evaluate the effect of lurbinectedin in vitro. We also demonstrate the anti-tumor effect of lurbinectedin in multiple de novo and transformed SCLC PDX models. Changes in gene and protein expression pre- and post-lurbinectedin treatment was assessed by RNA sequencing and western blot analysis. Results: Lurbinectedin markedly reduced cell viability in majority of SCLC models with the best response on POU2F3-driven SCLC cells. We further demonstrate that lurbinectedin, either as a single agent or in combination with osimertinib, causes an appreciable anti-tumor response in multiple models of EGFR-mutant lung adenocarcinoma with histologic transformation to SCLC. Transcriptomic analysis identified induction of apoptosis, repression of EMT, modulation of PI3K/AKT, NOTCH signaling associated with lurbinectedin response in de novo and transformed SCLC models. Conclusion: Our study provides a mechanistic insight into lurbinectedin response in SCLC and the first demonstration that lurbinectedin is a potential therapeutic target after SCLC transformation.
Data from Combined CDK4/6 and ERK1/2 inhibition enhances anti-tumor activity in NF1-associated plexiform neurofibroma
Authors: Flint Alyssa C. , Mitchell Dana K. , Angus Steven P. , Smith Abbi E. , Bessler Waylan , Jiang Li , Mang Henry , Li Xiaohong , Lu Qingbo , Rodriguez Brooke , Sandusky George E. , Masters Andi R. , Zhang Chi , Dang Pengtao , Koenig Jenna , Johnson Gary L. , Shen Weihua , Liu Jiangang , Aggarwal Amit , Donoho Gregory P. , Willard Melinda D. , Bhagwat Shripad V. , Clapp D. Wade , Rhodes Steven D.
Published: September 2024

Abstract
Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental Design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced anti-tumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusion: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.