bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The First-week Proliferative Response of Peripheral Blood PD-1+CD8+ T Cells Predicts the Response to Anti-PD-1 Therapy in Solid Tumors
Authors: Kim Kyung Hwan , Cho Jinhyun , Ku Bo Mi , Koh Jiae , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Cheon Jaekyung , Min Young Joo , Park Su-Hyung , Park Keunchil , Ahn Myung-Ju , Shin Eui-Cheol
Published: April 2023

AbstractPurpose:
To investigate blood-based dynamic biomarkers that predict responses to anti–programmed cell death protein 1 (PD-1) therapy in solid tumors.
Experimental Design:
Preplanned biomarker analysis was performed as part of a phase II clinical trial (NCT02607631) in patients with metastatic or refractory thymic epithelial tumors (TETs; n = 31) who received pembrolizumab. The biomarker was further tested in an independent cohort of prospectively recruited patients with metastatic non–small cell lung cancer (NSCLC) who received pembrolizumab or nivolumab (NSCLC cohort 1; n = 33) and validated in an independent cohort of patients with NSCLC (NSCLC cohort 2; n = 46). Peripheral blood samples were obtained immediately before treatment (D0) and 7 days after the first dose (D7) and analyzed using multi-color flow cytometry.
Results:
A higher fold-change in the percentage of Ki-67+ cells among PD-1+CD8+ T cells 7 days after the first dose (Ki-67D7/D0) significantly predicted durable clinical benefit (DCB; P < 0.001) and prolonged progression-free survival (PFS; P = 0.027) in patients with TETs. Ki-67D7/D0 ≥ 2.8 was also associated with better DCB, PFS, and overall survival (OS) in NSCLC cohort 1 (all P < 0.05). Ki-67D7/D0 was subsequently validated in NSCLC cohort 2, and Ki-67D7/D0 ≥ 2.8 significantly predicted better DCB (P = 0.001), PFS (P = 0.002), and OS (P = 0.037). Ki-67D7/D0 had a low correlation with tumor PD-L1 expression and combining both factors did not improve the predictive power of Ki-67D7/D0.
Conclusions:
The proliferative response of peripheral blood PD-1+CD8+ T cells, measured as the fold-change in the percentage of Ki-67+ cells 7 days after treatment (Ki-67D7/D0), may be a useful surrogate biomarker for predicting the response and prognosis to anti-PD-1 therapy in solid tumors.
Data from Unstable Genome and Transcriptome Dynamics during Tumor Metastasis Contribute to Therapeutic Heterogeneity in Colorectal Cancers
Authors: Cho Sung-Yup , Chae Jeesoo , Na Deukchae , Kang Wonyoung , Lee Ahra , Min Seoyeon , Kang Jinjoo , Choi Boram , Lee Jieun , Sung Chang Ohk , Chuang Jeffrey H. , Lee Charles , Lee Won-Suk , Park Hansoo , Kim Jong-Il
Published: April 2023

AbstractPurpose:
Genomic and transcriptomic alterations during metastasis are considered to affect clinical outcome of colorectal cancers, but detailed clinical implications of metastatic alterations are not fully uncovered. We aimed to investigate the effect of metastatic evolution on in vivo treatment outcome, and identify genomic and transcriptomic alterations associated with drug responsiveness.
Experimental Design:
We developed and analyzed patient-derived xenograft (PDX) models from 35 patients with colorectal cancer including 5 patients with multiple organ metastases (MOMs). We performed whole-exome, DNA methylation, and RNA sequencing for patient and PDX tumors. With samples from patients with MOMs, we conducted phylogenetic and subclonal analysis and in vivo drug efficacy test on the corresponding PDX models.
Results:
Phylogenetic analysis using mutation, expression, and DNA methylation data in patients with MOMs showed that mutational alterations were closely connected with transcriptomic and epigenomic changes during the tumor evolution. Subclonal analysis revealed that initial primary tumors with larger number of subclones exhibited more dynamic changes in subclonal architecture according to metastasis, and loco-regional and distant metastases occurred in a parallel or independent fashion. The PDX models from MOMs demonstrated therapeutic heterogeneity for targeted treatment, due to subclonal acquisition of additional mutations or transcriptomic activation of bypass signaling pathway during tumor evolution.
Conclusions:
This study demonstrated in vivo therapeutic heterogeneity of colorectal cancers using PDX models, and suggests that acquired subclonal alterations in mutations or gene expression profiles during tumor metastatic processes can be associated with the development of drug resistance and therapeutic heterogeneity of colorectal cancers.
Data from Neoadjuvant Therapy Remodels the Pancreatic Cancer Microenvironment via Depletion of Protumorigenic Immune Cells
Authors: Mota Reyes Carmen , Teller Steffen , Muckenhuber Alexander , Konukiewitz Björn , Safak Okan , Weichert Wilko , Friess Helmut , Ceyhan Güralp O. , Demir Ihsan Ekin
Published: April 2023

AbstractPurpose:
Neoadjuvant therapy (neoTx) has dramatically improved the prognosis of patients with locally advanced and borderline resectable pancreatic ductal adenocarcinoma, yet its mechanisms of action on tumor cells and the tumor microenvironment are still unknown. Here, we aimed to characterize the multiple facets of neoTx-induced alterations in the pancreatic cancer microenvironment.
Experimental Design:
We performed the currently most comprehensive histopathologic analysis of desmoplasia, angiogenesis, neural invasion, and immune cell infiltration at the tumor–host interface of pancreatic cancer after neoTx (n = 37) versus after primary resection (n = 37) through quantitative IHC and double immunofluorescence using automated and software-based quantification algorithms.
Results:
We demonstrate that, independently of the applied pretreatment, neoadjuvant regimes are able to reverse the immunosuppressive behavior of malignant cells on pancreatic cancer microenvironment. Here, neoTx-driven selective depletion of regulatory T cells and myeloid-derived suppressor cells was associated with enrichment of antitumor immune cells in the peritumoral niche, decreased stromal activation, and less neural invasion. Importantly, the degree of this antitumor immune remodeling correlates to the degree of histopathologic response to neoTx. Survival analysis revealed that the tumor proliferation rate together with the activation of the stroma and the intratumoral infiltration with CD4+ T cells and natural killer cells constitute as independent prognostic factors for neoadjuvantly treated pancreatic cancer.
Conclusions:
NeoTx is not only cytotoxic but has pleiotropic, beneficial effects on all cellular and noncellular components of pancreatic cancer. Combinational approaches including immunotherapy may unleash long-term and more effective antitumor responses and improve prognosis of pancreatic cancer.
Data from Functional Genomics Identifies Hepatitis-Induced STAT3–TYRO3–STAT3 Signaling as a Potential Therapeutic Target of Hepatoma
Authors: Tsai Chia-Liang , Chang Jeng-Shou , Yu Ming-Chin , Lee Chern-Horng , Chen Tse-Ching , Chuang Wen-Yu , Kuo Wei-Liang , Lin Chen-Chun , Lin Shi-Ming , Hsieh Sen-Yung
Published: April 2023

AbstractPurpose:
Hepatitis promotes the development and recurrence of hepatocellular carcinoma (HCC). Receptor tyrosine kinases (RTK) play critical roles in the development of many cancers. We explored the potential roles of RTKs in hepatitis-related liver cancers.
Experimental Design:
We conducted loss-of-function screening to elucidate the roles of RTKs in the development of HCC in vitro and in vivo.
Results:
Many RTKs were coexpressed in HCC and were involved in tumor development and growth. Of these, TYRO3 promoted tumor growth and was clinically associated with hepatitis activity and poor prognosis. In mice, chemical-induced hepatitis transcriptionally activated Tyro3 expression via IL-6/IL6R–STAT3 signaling. Moreover, hepatitis-associated apoptotic cells facilitated the presentation of GAS6, a TYRO3 ligand, to further activate TYRO3-mediated signaling. Furthermore, TYRO3 activation elicited intracellular SRC- and STAT3 signaling. In mice, hepatitis and Tyro3 synergistically promoted HCC development. Silencing TYRO3 expression or inhibiting its kinase activity suppressed xenograft HCC growth in nude mice.
Conclusions:
Many RTKs are simultaneously involved in HCC development. Hepatitis exerts dual effects on the activation of TYRO3-mediated signaling in HCC cells, which further elicits the “TYRO3–STAT3–TYRO3” signaling loop to facilitate tumor growth. Our findings unveil a previously unrecognized link between RTKs and hepatitis-associated HCC and suggest TYRO3 as a marker and therapeutic target for the HCCs with higher hepatitis activity.
Data from Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer
Authors: Lieu Christopher H. , Golemis Erica A. , Serebriiskii Ilya G. , Newberg Justin , Hemmerich Amanda , Connelly Caitlin , Messersmith Wells A. , Eng Cathy , Eckhardt S. Gail , Frampton Garrett , Cooke Matthew , Meyer Joshua E.
Published: April 2023

AbstractPurpose:
The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer.
Experimental Design:
DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSI-H) status established.
Results:
Overall genomic alteration rates in the younger (<40) and older (≥50) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular, TP53 (FDR < 0.01) and CTNNB1 (FDR = 0.01) alterations were more common in younger patients with colorectal cancer, and APC (FDR < 0.01), KRAS (FDR < 0.01), BRAF (FDR < 0.01), and FAM123B (FDR < 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in APC (FDR < 0.01), BRAF (FDR < 0.01), and KRAS (FDR < 0.01).
Conclusions:
Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer.
Data from Bevacizumab Reduces Permeability and Concurrent Temozolomide Delivery in a Subset of Patients with Recurrent Glioblastoma
Authors: Gerstner Elizabeth R. , Emblem Kyrre E. , Chang Ken , Vakulenko-Lagun Bella , Yen Yi-Fen , Beers Andrew L. , Dietrich Jorg , Plotkin Scott R. , Catana Ciprian , Hooker Jacob M. , Duda Dan G. , Rosen Bruce , Kalpathy-Cramer Jayashree , Jain Rakesh K. , Batchelor Tracy
Published: April 2023

AbstractPurpose:
Targeting tumor blood vessels is an attractive therapy in glioblastoma (GBM), but the mechanism of action of these agents and how they modulate delivery of concomitant chemotherapy are not clear in humans. We sought to elucidate how bevacizumab modulates tumor vasculature and the impact those vascular changes have on drug delivery in patients with recurrent GBM.
Experimental Design:
Temozolomide was labeled with [11C], and serial PET-MRI scans were performed in patients with recurrent GBM treated with bevacizumab and daily temozolomide. PET-MRI scans were performed prior to the first bevacizumab dose, 1 day after the first dose, and prior to the third dose of bevacizumab. We calculated tumor volume, vascular permeability (Ktrans), perfusion (cerebral blood flow), and the standardized uptake values (SUV) of [11C] temozolomide within the tumor.
Results:
Twelve patients were enrolled, resulting in 23 evaluable scans. Within the entire contrast-enhancing tumor volume, both temozolomide uptake and vascular permeability decreased after initiation of bevacizumab in most patients, whereas change in perfusion was more variable. In subregions of the tumor where permeability was low and the blood–brain barrier not compromised, increased perfusion correlated with increased temozolomide uptake.
Conclusions:
Bevacizumab led to a decrease in permeability and concomitant delivery of temozolomide. However, in subregions of the tumor where permeability was low, increased perfusion improved delivery of temozolomide, suggesting that perfusion may modulate the delivery of chemotherapy in certain settings. These results support exploring whether lower doses of bevacizumab improve perfusion and concomitant drug delivery.
Data from Reciprocal and Autonomous Glucocorticoid and Androgen Receptor Activation in Salivary Duct Carcinoma
Authors: Mitani Yoshitsugu , Lin Sue-Hwa , Pytynia Kristen B. , Ferrarotto Renata , El-Naggar Adel K.
Published: April 2023

AbstractPurpose:
To determine the expression of glucocorticoid receptor (GR) and androgen receptor (AR) in salivary duct carcinoma (SDC) and to analyze the role of these proteins in the development and management of this disease entity.
Experimental Design:
We performed a phenotypic assessment of GR and AR localization and expression, and determined their association with clinicopathologic factors in 67 primary SDCs. In vitro functional and response analysis of SDC cell lines was also performed.
Results:
Of the 67 primary tumors, 12 (18%) overexpressed GR protein, 30 (45%) had constitutive expression, and 25 (37%) had complete loss of expression. Reciprocal GR and AR expression was found in 32 (48%) tumors, concurrent constitutive GR and AR expression in 23 (34%), and simultaneous loss of both receptors and high GR with AR expressions were found in 12 (18%). GR overexpression was significantly associated with worse clinical outcomes. In vitro ligand-independent AR activation was observed in both male- and female-derived cell lines. GR antagonist treatment resulted in decreased cell proliferation and survival in GR-overexpressing cells, irrespective of AR status. Reciprocal GR- and AR-knockdown experiments revealed an independent interaction.
Conclusions:
Our study, for the first time, demonstrates differential GR and AR expressions, autonomous GR and AR activation, and ligand-independent AR expression and activation in SDC cells. The findings provide critical information on the roles of GR and AR steroid receptors in SDC tumorigenesis and development of biomarkers to guide targeted steroid receptor therapy trials in patients with these tumors.
Data from A Phase I/II Trial of Cetuximab in Combination with Interleukin-12 Administered to Patients with Unresectable Primary or Recurrent Head and Neck Squamous Cell Carcinoma
Authors: McMichael Elizabeth L. , Benner Brooke , Atwal Lakhvir S. , Courtney Nicholas B. , Mo Xiaokui , Davis Melanie E. , Campbell Amanda R. , Duggan Megan C. , Williams Kallan , Martin Kyle , Levine Kala , Olaverria Salavaggione Gonzalo N. , Noel Tiffany , Ganju Akaansha , Uppati Sarvani , Paul Bonnie , Olencki Thomas , Teknos Theodoros N. , Savvides Panos , Tridandapani Susheela , Byrd John C. , Caligiuri Michael A. , Liu Stephen V. , Carson William E.
Published: April 2023

AbstractPurpose:
mAbs including cetuximab can induce antibody-dependent cellular cytotoxicity (ADCC) and cytokine production mediated via innate immune cells with the ability to recognize mAb-coated tumors. Preclinical modeling has shown that costimulation of natural killer (NK) cells via the Fc receptor and the IL12 receptor promotes NK-cell–mediated ADCC and production of cytokines.
Patients and Methods:
This phase I/II trial evaluated the combination of cetuximab with IL12 for the treatment of EGFR-expressing head and neck cancer. Treatment consisted of cetuximab 500 mg/m2 i.v. every 2 weeks with either 0.2 mcg/kg or 0.3 mcg/kg IL12 s.c. on days 2 and 5 of the 2-week cycle, beginning with cycle 2. Correlative studies from blood draws obtained prior to treatment and during therapy included measurement of ADCC, serum cytokine, and chemokine analysis, determination of NK cell FcγRIIIa polymorphisms, and an analysis of myeloid-derived suppressor cell (MDSC) frequency in peripheral blood.
Results:
The combination of cetuximab and IL12 was well tolerated. No clinical responses were observed, however, 48% of patients exhibited prolonged progression-free survival (PFS; average of 6.5 months). Compared with patients that did not exhibit clinical benefit, patients with PFS >100 days exhibited increased ADCC as therapy continued compared with baseline, greater production of IFNγ, IP-10, and TNFα at the beginning of cycle 8 compared with baseline values and had a predominance of monocytic MDSCs versus granulocytic MDSCs prior to therapy.
Conclusions:
Further investigation of IL12 as an immunomodulatory agent in combination with cetuximab in head and neck squamous cell carcinoma is warranted.
Data from A Phase Ib/II Trial of the First-in-Class Anti-CXCR4 Antibody Ulocuplumab in Combination with Lenalidomide or Bortezomib Plus Dexamethasone in Relapsed Multiple Myeloma
Authors: Ghobrial Irene M. , Liu Chia-Jen , Redd Robert A. , Perez Raymond P. , Baz Rachid , Zavidij Oksana , Sklavenitis-Pistofidis Romanos , Richardson Paul G. , Anderson Kenneth C. , Laubach Jacob , Henrick Patrick , Savell Alexandra , Reyes Kaitlen , Hornburg Kalvis , Chuma Stacey , Sabbatini Peter , Robbins Michael D. , Becker Pamela S.
Published: April 2023

AbstractPurpose:
Ulocuplumab (BMS-936564) is a first-in-class fully human IgG4 monoclonal anti-CXCR4 antibody that inhibits the binding of CXCR4 to CXCL12.
Patients and Methods:
This phase Ib/II study aimed to determine the safety and tolerability of ulocuplumab alone and in combination with lenalidomide and dexamethasone (Arm A), or bortezomib and dexamethasone (Arm B), in patients with relapsed/refractory multiple myeloma.
Results:
Forty-six patients were evaluated (median age, 60 years; range, 53–67). The median number of prior therapies was 3 (range, 1–11), with 70% of subjects having received ≥3. This trial had a dose-escalation and a dose-expansion part. Using a 3+3 design on both arms of the trial, ulocuplumab's dose was escalated to a maximum of 10 mg/kg without reaching MTD. The most common treatment-related adverse events (AE) were neutropenia (13 patients, 43.3%) in Arm A and thrombocytopenia (6 patients, 37.5%) in Arm B. No deaths related to study drugs occurred. The combination of ulocuplumab with lenalidomide and dexamethasone showed a high response rate (PR or better) of 55.2% and a clinical benefit rate of 72.4%, even in patients who had been previously treated with immunomodulatory agents (IMiD).
Conclusions:
This study showed that blockade of the CXCR4–CXCL12 axis by ulocuplumab is safe with acceptable AEs and leads to a high response rate in combination with lenalidomide and dexamethasone in patients with relapsed/refractory myeloma, making CXCR4 inhibitors a promising class of antimyeloma drugs that should be further explored in clinical trials.
Data from Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma Patients
Authors: Duvvuri Umamaheswar , George Jonathan , Kim Seungwon , Alvarado Diego , Neumeister Veronique M. , Chenna Ahmed , Gedrich Richard , Hawthorne Thomas , LaVallee Theresa , Grandis Jennifer R. , Bauman Julie E.
Published: April 2023

AbstractPurpose:
ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A “window-of-opportunity” study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC.
Patients and Methods:
Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-week interval prior to tumor resection. The primary study objective was to achieve ≥50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed.
Results:
pErbB3 was detectable in all tumors prior to treatment and decreased for 10 of 12 (83%) patients following CDX-3379 dosing, with ≥50% reduction in 7 of 12 (58%; P = 0.04; 95% confidence interval, 27.7%–84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment–related toxicity was grade 1–2 and included diarrhea, fatigue, and acneiform dermatitis. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus–negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment.
Conclusions:
This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC.
Data from Phase II Study of Iniparib with Concurrent Chemoradiation in Patients with Newly Diagnosed Glioblastoma
Authors: Blakeley Jaishri O. , Grossman Stuart A. , Chi Andrew S. , Mikkelsen Tom , Rosenfeld Myrna R. , Ahluwalia Manmeet S. , Nabors L. Burt , Eichler April , Ribas Ignacio Garcia , Desideri Serena , Ye Xiaobu
Published: April 2023

AbstractPurpose:
Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (GBM).
Patients and Methods:
Adults meeting eligibility criteria were enrolled in this prospective, single-arm, open-label multi- institution phase II trial with median overall survival (mOS) compared with a historical control as the primary objective. A safety run-in component of radiotherapy + temozolomide + iniparib (n = 5) was followed by an efficacy study (n = 76) with the recommended phase II doses of iniparib (8.0 mg/kg i.v. twice/week with radiotherapy + daily temozolomide followed by 8.6 mg/kg i.v. twice/week with 5/28-day temozolomide).
Results:
The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was ≥ 80% in 87% of participants. The mOS was 22 months [95% confidence interval (CI), 17–24] and the HR was 0.44 (95% CI, 0.35–0.55) per-person-year of follow-up. The 2- and 3-year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AEs) occurred in 27% of patients; 9 patients had AEs requiring drug discontinuation including infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia.
Conclusions:
Iniparib is well tolerated with radiotherapy and temozolomide in patients with newly diagnosed GBM at up to 17.2 mg/kg weekly. The primary objective of improved mOS compared with a historical control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.
Data from The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy
Authors: Knepper Todd C. , Montesion Meagan , Russell Jeffery S. , Sokol Ethan S. , Frampton Garrett M. , Miller Vincent A. , Albacker Lee A. , McLeod Howard L. , Eroglu Zeynep , Khushalani Nikhil I. , Sondak Vernon K. , Messina Jane L. , Schell Michael J. , DeCaprio James A. , Tsai Kenneth Y. , Brohl Andrew S.
Published: April 2023

AbstractPurpose:
Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy, which has demonstrated sensitivity to immune checkpoint inhibitor therapy. Here, we perform the largest genomics study in MCC to date to characterize the molecular landscape and evaluate for clinical and molecular correlates to immune checkpoint inhibitor response.
Experimental Design:
Comprehensive molecular profiling was performed on 317 tumors from patients with MCC, including the evaluation of oncogenic mutations, tumor mutational burden (TMB), mutational signatures, and the Merkel cell polyomavirus (MCPyV). For a subset of 57 patients, a retrospective analysis was conducted to evaluate for clinical and molecular correlates to immune checkpoint inhibitor response and disease survival.
Results:
Genomic analyses revealed a bimodal distribution in TMB, with 2 molecularly distinct subgroups. Ninety-four percent (n = 110) of TMB-high specimens exhibited an ultraviolet light (UV) mutational signature. MCPyV genomic DNA sequences were not identified in any TMB-high cases (0/117), but were in 63% (110/175) of TMB-low cases. For 36 evaluable patients treated with checkpoint inhibitors, the overall response rate was 44% and response correlated with survival at time of review (100% vs. 20%, P < 0.001). Response rate was 50% in TMB-high/UV-driven and 41% in TMB-low/MCPyV-positive tumors (P = 0.63). Response rate was significantly correlated with line of therapy: 75% in first-line, 39% in second-line, and 18% in third-line or beyond (P = 0.0066). PD-1, but not PD-L1, expression was associated with immunotherapy response (77% vs. 21%, P = 0.00598, for PD-1 positive and negative, respectively).
Conclusions:
We provide a comprehensive genomic landscape of MCC and demonstrate clinicogenomic associates of immunotherapy response.
Data from Stratifin Inhibits SCFFBW7 Formation and Blocks Ubiquitination of Oncoproteins during the Course of Lung Adenocarcinogenesis
Authors: Shiba-Ishii Aya , Hong Jeongmin , Hirokawa Takatsugu , Kim Yunjung , Nakagawa Tomoki , Sakashita Shingo , Sakamoto Noriaki , Kozuma Yukinori , Sato Yukio , Noguchi Masayuki
Published: April 2023

AbstractPurpose:
Aberrant overexpression of SFN (stratifin) plays an oncogenic role in lung adenocarcinoma. We have shown previously that SKP1, an adapter component of E3 ubiquitin ligase forming an SCF complex, is a unique SFN-binding protein in lung adenocarcinoma cells.
Experimental Design:
In silico simulation and in vitro mutagenesis analysis were performed to identify the SFN-binding domain on SKP1. We examined expression, localization, and stability of SKP1 after knockdown of SFN using lung adenocarcinoma cells including A549. In silico library screening and experimental validation were used for drug screening. Daily oral administration of each candidate drugs to A549-injected tumor-bearing mice was performed to evaluate their in vivo antitumor efficacy.
Results:
Suppression of SFN upregulated the stability of SKP1 and accelerated its cytoplasm-to-nucleus translocation. Consistently, IHC analysis revealed that cytoplasmic expression of SKP1 was significantly associated with SFN positivity, tumor malignancy, and poorer patient outcome. After SFN suppression, ubiquitination of oncoproteins, including p-cyclin E1, p-c-Myc, p-c-Jun, and cleaved Notch 1, which are target proteins of SCFFBW7, was strongly induced. These results indicate that SFN–SKP1 binding results in SCFFBW7 dysfunction and allows several oncoproteins to evade ubiquitination and subsequent degradation. Because inhibition of SFN-SKP1 binding was expected to have antitumor efficacy, we next searched for candidate SFN inhibitors. Aprepitant and ticagrelor were finally selected as potential SFN inhibitors that dose dependently reduced SFN-SKP1 binding and tumor progression in vivo.
Conclusions:
As overexpression of SFN is detectable in most adenocarcinoma, we believe that SFN inhibitors would be novel and promising antitumor drugs for lung adenocarcinoma.
Data from Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy
Authors: Trendowski Matthew R. , El-Charif Omar , Ratain Mark J. , Monahan Patrick , Mu Zepeng , Wheeler Heather E. , Dinh Paul C. , Feldman Darren R. , Ardeshir-Rouhani-Fard Shirin , Hamilton Robert J. , Vaughn David J. , Fung Chunkit , Kollmannsberger Christian , Mushiroda Taisei , Kubo Michiaki , Hannigan Robyn , Strathmann Frederick , Einhorn Lawrence H. , Fossa Sophie D. , Travis Lois B. , Dolan M. Eileen
Published: April 2023

AbstractPurpose:
Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1–35 years after CBC and evaluate genetic contributions to these levels.
Experimental Design:
Eligible TCS given 300 or 400 (±15) mg/m2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a biexponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model.
Results:
Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P = 2.13 × 10−3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P = 6.58 × 10−3). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted ORhigh/low = 1.46; P = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low = 1.68, P = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (P = 4.6 × 10−8, a SNP intronic to MYH14).
Conclusions:
This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.
Data from Intratumoral Delivery of Plasmid IL12 Via Electroporation Leads to Regression of Injected and Noninjected Tumors in Merkel Cell Carcinoma
Authors: Bhatia Shailender , Longino Natalie V. , Miller Natalie J. , Kulikauskas Rima , Iyer Jayasri G. , Ibrani Dafina , Blom Astrid , Byrd David R. , Parvathaneni Upendra , Twitty Christopher G. , Campbell Jean S. , Le Mai H. , Gargosky Sharron , Pierce Robert H. , Heller Richard , Daud Adil I. , Nghiem Paul
Published: April 2023

AbstractPurpose:
IL12 promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer.
Patients and Methods:
Fifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected.
Results:
All patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months, respectively.
Conclusions:
I.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer.
Data from Methylation-dependent Tissue Factor Suppression Contributes to the Reduced Malignancy of IDH1-mutant Gliomas
Authors: Unruh Dusten , Mirkov Snezana , Wray Brian , Drumm Michael , Lamano Jonathan , Li Yuping D. , Haider Qazi F. , Javier Rodrigo , McCortney Kathleen , Saratsis Amanda , Scholtens Denise M. , Sarkaria Jann N. , James C. David , Horbinski Craig
Published: April 2023

AbstractPurpose:
Gliomas with isocitrate dehydrogenase 1 mutations (IDH1mut) are less aggressive than IDH1 wild-type (IDH1wt) gliomas and have global genomic hypermethylation. Yet it is unclear how specific hypermethylation events contribute to the IDH1mut phenotype. Previously, we showed that the gene encoding the procoagulant tissue factor (TF), F3, is among the most hypermethylated and downregulated genes in IDH1mut gliomas, correlating with greatly reduced thrombosis in patients with IDH1mut glioma. Because TF also increases the aggressiveness of many cancers, the current study explored the contribution of TF suppression to the reduced malignancy of IDH1mut gliomas.

Experimental Design: TF expression was manipulated in patient-derived IDH1mut and IDH1wt glioma cells, followed by evaluation of in vitro and in vivo behavior and analyses of cell signaling pathways.
Results:
A demethylating agent, decitabine, increased F3 transcription and TF-dependent coagulative activity in IDH1mut cells, but not in IDH1wt cells. TF induction enhanced the proliferation, invasion, and colony formation of IDH1mut cells, and increased the intracranial engraftment of IDH1mut GBM164 from 0% to 100% (P = 0.0001). Conversely, TF knockdown doubled the median survival of mice engrafted with IDH1wt/EGFRvIIIamp GBM6, and caused complete regression of IDH1wt/EGFRamp GBM12 (P = 0.001). In vitro and in vivo effects were linked to activation of receptor tyrosine kinases (RTK) by TF through a Src-dependent intracellular pathway, even when extracellular RTK stimulation was blocked. TF stimulated invasion predominately through upregulation of β-catenin.
Conclusions:
These data show that TF suppression is a component of IDH1mut glioma behavior, and that it may therefore be an attractive target against IDH1wt gliomas.
Data from Design and Evaluation of an External Control Arm Using Prior Clinical Trials and Real-World Data
Authors: Ventz Steffen , Lai Albert , Cloughesy Timothy F. , Wen Patrick Y. , Trippa Lorenzo , Alexander Brian M.
Published: April 2023

AbstractPurpose:
We discuss designs and interpretable metrics of bias and statistical efficiency of “externally controlled” trials (ECT) and compare ECT performance to randomized and single-arm designs.
Experimental Design:
We specify an ECT design that leverages information from real-world data (RWD) and prior clinical trials to reduce bias associated with interstudy variations of the enrolled populations. We then used a collection of clinical studies in glioblastoma (GBM) and RWD from patients treated with the current standard of care to evaluate ECTs. Validation is based on a “leave one out” scheme, with iterative selection of a single-arm from one of the studies, for which we estimate treatment effects using the remaining studies as external control. This produces interpretable and robust estimates on ECT bias and type I errors.
Results:
We developed a model-free approach to evaluate ECTs based on collections of clinical trials and RWD. For GBM, we verified that inflated false positive error rates of standard single-arm trials can be considerably reduced (up to 30%) by using external control data.
Conclusions:
The use of ECT designs in GBM, with adjustments for the clinical profiles of the enrolled patients, should be preferred to single-arm studies with fixed efficacy thresholds extracted from published results on the current standard of care.
Data from Genetic, Epigenetic, and Immunologic Profiling of MMR-Deficient Relapsed Glioblastoma
Authors: Indraccolo Stefano , Lombardi Giuseppe , Fassan Matteo , Pasqualini Lorenza , Giunco Silvia , Marcato Raffaella , Gasparini Alessandra , Candiotto Cinzia , Nalio Silvia , Fiduccia Pasquale , Fanelli Giuseppe Nicolò , Pambuku Ardi , Della Puppa Alessandro , D'Avella Domenico , Bonaldi Laura , Gardiman Marina Paola , Bertorelle Roberta , De Rossi Anita , Zagonel Vittorina
Published: April 2023

AbstractPurpose:
In-depth characterization of recurrent glioblastoma (rGBM) might contribute to a better understanding of the mechanisms behind tumor progression and enable rGBM treatment with targeted drugs.

Experimental Design: In this study, GBM samples were collected at diagnosis and recurrence from adult patients treated with Stupp protocol. Expression of mismatch repair (MMR) proteins was evaluated by IHC, followed by whole exome sequencing (WES) of tumor samples showing loss of MSH6 reactivity. Established genetic, epigenetic, and immunologic markers were assessed by standard methods and correlated with loss of MMR proteins and patient survival.
Results:
Expression of MMR proteins was partially or completely lost in 25.9% rGBM samples. Specifically, 12 samples showed partial or total MSH6 expression reduction. Conversely, 96.4% of GBM samples at diagnosis expressed MMR markers. WES disclosed lack of variants in MMR genes in primary samples, whereas two MSH6-negative rGBM samples shared a c.3438+1G>A* splicing MSH6 variant with a potential loss of function effect. MSH6-negative rGBM specimens had high tumor mutational burden (TMB), but no microsatellite instability. In contrast, GBM samples with partial loss of MMR proteins disclosed low TMB. MMR-deficient rGBM showed significant telomere shortening and MGMT methylation and are characterized by highly heterogeneous MHC class I expression.
Conclusions:
Multilevel profiling of MMR-deficient rGBM uncovered hypermutated genotype uncoupled from enriched expression of immune-related markers. Assessment of MHC class I expression and TMB should be included in protocols aiming to identify rGBM patients potentially eligible for treatment with drugs targeting immune-checkpoint inhibitors.
Data from Health-Related Quality of Life Impact from Adding Bevacizumab to Cisplatin-Pemetrexed in Malignant Pleural Mesothelioma in the MAPS IFCT-GFPC-0701 Phase III Trial
Authors: Eberst Guillaume , Anota Amélie , Scherpereel Arnaud , Mazieres Julien , Margery Jacques , Greillier Laurent , Audigier-Valette Clarisse , Moro-Sibilot Denis , Molinier Olivier , Léna Hervé , Rivière Frédéric , Monnet Isabelle , Gounant Valérie , Janicot Henri , Gervais Radj , Locher Chrystelle , Charton Emilie , Morin Franck , Zalcman Gérard , Westeel Virginie
Published: April 2023

AbstractPurpose:
The IFCT-GFPC-0701 MAPS phase III trial highlighted significant improvement in overall survival from adding bevacizumab to the standard first-line chemotherapy regimen [cisplatin plus pemetrexed (PC)] in advanced malignant pleural mesothelioma (MPM). We present the results of health-related quality of life (HRQoL), a secondary endpoint of MAPS.
Patients and Methods:
HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 and the lung cancer–specific module QLQ-LC13 at randomization and then every 9 weeks until disease progression.

HRQoL deterioration–free survival (QFS), used to analyze longitudinal HRQoL data, was defined as the interval between randomization and the occurrence of the first clinically relevant definitive deterioration compared with the HRQoL score at baseline, or death.
Results:
A total of 448 patients were included in the MAPS trial between 2008 and 2014. At baseline, 425 patients (94.8%) completed the HRQoL questionnaire. We report that adding bevacizumab to cisplatin and pemetrexed (PCB) significantly improved QFS for the peripheral neuropathy dimension, with a median QFS of 12.09 months [95% confidence interval (CI), 9.59–13.67] in the PCB arm versus 7.59 months (95% CI, 6.57–8.61) in the PC arm [HR (PCB vs. PC) = 0.74; 95% CI, 0.61–0.91; P = 0.004]. QFS was also longer in the PCB arm for the pain dimension (HR = 0.84; 95% CI, 0.69–1.02; P = 0.08).
Conclusions:
This study demonstrated that adding bevacizumab to standard chemotherapy in patients with advanced MPM had no negative impact on HRQoL. A significant improvement in the peripheral neuropathy and pain HRQoL dimensions was even observed.
Data from Broad Spectrum Activity of the Checkpoint Kinase 1 Inhibitor Prexasertib as a Single Agent or Chemopotentiator Across a Range of Preclinical Pediatric Tumor Models
Authors: Lowery Caitlin D. , Dowless Michele , Renschler Matthew , Blosser Wayne , VanWye Alle B. , Stephens Jennifer R. , Iversen Philip W. , Lin Aimee Bence , Beckmann Richard P. , Krytska Kateryna , Cole Kristina A. , Maris John M. , Hawkins Douglas S. , Rubin Brian P. , Kurmasheva Raushan T. , Houghton Peter J. , Gorlick Richard , Kolb E. Anders , Kang Min H. , Reynolds C. Patrick , Erickson Stephen W. , Teicher Beverly A. , Smith Malcolm A. , Stancato Louis F.
Published: April 2023

AbstractPurpose:
Checkpoint kinase 1 (CHK1) inhibitors potentiate the DNA-damaging effects of cytotoxic therapies and/or promote elevated levels of replication stress, leading to tumor cell death. Prexasertib (LY2606368) is a CHK1 small-molecule inhibitor under clinical evaluation in multiple adult and pediatric cancers. In this study, prexasertib was tested in a large panel of preclinical models of pediatric solid malignancies alone or in combination with chemotherapy.
Experimental Design:
DNA damage and changes in cell signaling following in vitro prexasertib treatment in pediatric sarcoma cell lines were analyzed by Western blot and high content imaging. Antitumor activity of prexasertib as a single agent or in combination with different chemotherapies was explored in cell line–derived (CDX) and patient-derived xenograft (PDX) mouse models representing nine different pediatric cancer histologies.
Results:
Pediatric sarcoma cell lines were highly sensitive to prexasertib treatment in vitro, resulting in activation of the DNA damage response. Two PDX models of desmoplastic small round cell tumor and one malignant rhabdoid tumor CDX model responded to prexasertib with complete regression. Prexasertib monotherapy also elicited robust responses in mouse models of rhabdomyosarcoma. Concurrent administration with chemotherapy was sufficient to overcome innate resistance or prevent acquired resistance to prexasertib in preclinical models of neuroblastoma, osteosarcoma, and Ewing sarcoma, or alveolar rhabdomyosarcoma, respectively.
Conclusions:
Prexasertib has significant antitumor effects as a monotherapy or in combination with chemotherapy in multiple preclinical models of pediatric cancer. These findings support further investigation of prexasertib in pediatric malignancies.
Data from Randomized Phase II Trial and Tumor Mutational Spectrum Analysis from Cabozantinib versus Chemotherapy in Metastatic Uveal Melanoma (Alliance A091201)
Authors: Luke Jason J. , Olson Daniel J. , Allred Jacob B. , Strand Carrie A. , Bao Riyue , Zha Yuanyuan , Carll Timothy , Labadie Brian W. , Bastos Bruno R. , Butler Marcus O. , Hogg David , Munster Pamela N. , Schwartz Gary K.
Published: April 2023

AbstractPurpose:
The surface receptor MET is highly expressed on primary uveal melanoma; MET inhibitors demonstrated early clinical signals of efficacy in slowing uveal melanoma growth. The primary objective of our study was to compare the progression-free survival rate at 4 months (PFS4) of patients with uveal melanoma treated with cabozantinib or chemotherapy.
Patients and Methods:
Patients with metastatic uveal melanoma and RECIST measurable disease were randomized 2:1 to receive either cabozantinib (arm 1) versus temozolomide or dacarbazine (arm 2) with restaging imaging every two cycles. Cross-over from arm 2 to cabozantinib after progression was allowed (arm 2X). Available tumor specimens were analyzed by whole-exome sequencing (WES) and results were correlated with outcome.
Results:
Forty-six eligible patients were accrued with 31, 15, and 9 in arms 1, 2, and 2X, respectively. Median lines of prior therapy, including hepatic embolization, were two. Rates of PFS4 in arm 1 and arm 2 were 32.3% and 26.7% (P = 0.35), respectively, with median PFS time of 60 and 59 days (P = 0.964; HR = 0.99). Median overall survival (OS) was 6.4 months and 7.3 months (P = 0.580; HR = 1.21), respectively. Grade 3–4 Common Terminology Criteria for Adverse Events were present in 61.3%, 46.7%, and 37.5% in arms 1, 2, and 2X, respectively. WES demonstrated a mean tumor mutational burden of 1.53 mutations/Mb and did not separate OS ≤ or >1 year (P = 0.14). Known mutations were identified by WES and novel mutations were nominated.
Conclusions:
MET/VEGFR blockade with cabozantinib demonstrated no improvement in PFS but an increase in toxicity relative to temozolomide/dacarbazine in metastatic uveal melanoma.
Data from Low-pass Whole-genome Sequencing of Circulating Cell-free DNA Demonstrates Dynamic Changes in Genomic Copy Number in a Squamous Lung Cancer Clinical Cohort
Authors: Chen Xiaoji , Chang Ching-Wei , Spoerke Jill M. , Yoh Kathryn E. , Kapoor Vidushi , Baudo Charles , Aimi Junko , Yu Mamie , Liang-Chu May M.Y. , Suttmann Rebecca , Huw Ling-Yuh , Gendreau Steven , Cummings Craig , Lackner Mark R.
Published: April 2023

AbstractPurpose:
We developed a method to monitor copy number variations (CNV) in plasma cell-free DNA (cfDNA) from patients with metastatic squamous non–small cell lung cancer (NSCLC). We aimed to explore the association between tumor-derived cfDNA and clinical outcomes, and sought CNVs that may suggest potential resistance mechanisms.
Experimental Design:
Sensitivity and specificity of low-pass whole-genome sequencing (LP-WGS) were first determined using cell line DNA and cfDNA. LP-WGS was performed on baseline and longitudinal cfDNA of 152 patients with squamous NSCLC treated with chemotherapy, or in combination with pictilisib, a pan-PI3K inhibitor. cfDNA tumor fraction and detected CNVs were analyzed in association with clinical outcomes.
Results:
LP-WGS successfully detected CNVs in cfDNA with tumor fraction ≥10%, which represented approximately 30% of the first-line NSCLC patients in this study. The most frequent CNVs were gains in chromosome 3q, which harbors the PIK3CA and SOX2 oncogenes. The CNV landscape in cfDNA with a high tumor fraction generally matched that of corresponding tumor tissue. Tumor fraction in cfDNA was dynamic during treatment, and increases in tumor fraction and corresponding CNVs could be detected before radiographic progression in 7 of 12 patients. Recurrent CNVs, such as MYC amplification, were enriched in cfDNA from posttreatment samples compared with the baseline, suggesting a potential resistance mechanism to pictilisib.
Conclusions:
LP-WGS offers an unbiased and high-throughput way to investigate CNVs and tumor fraction in cfDNA of patients with cancer. It may also be valuable for monitoring treatment response, detecting disease progression early, and identifying emergent clones associated with therapeutic resistance.