bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Mast Cell Activation and KSHV Infection in Kaposi Sarcoma
Authors: Ayers Leona W. , Barbachano-Guerrero Arturo , McAllister Shane C. , Ritchie Julie A. , Asiago-Reddy Elizabeth , Bartlett Linda C. , Cesarman Ethel , Wang Dongliang , Rochford Rosemary , Martin Jeffrey N. , King Christine A.
Published: April 2023

Abstract
Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS–associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV.

Experimental Design: Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine.

Results: In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore, MC activation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions.

Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS. Clin Cancer Res; 24(20); 5085–97. ©2018 AACR.
Data from Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity
Authors: Baro Marta , Lopez Sambrooks Cecilia , Quijano Amanda , Saltzman W. Mark , Contessa Joseph
Published: April 2023

AbstractPurpose:
Parallel signaling reduces the effects of receptor tyrosine kinase (RTK)–targeted therapies in glioma. We hypothesized that inhibition of protein N-linked glycosylation, an endoplasmic reticulum co- and posttranslational modification crucial for RTK maturation and activation, could provide a new therapeutic approach for glioma radiosensitization.

Experimental Design: We investigated the effects of a small-molecule inhibitor of the oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, and FGFR1. The influence of glycosylation state on tumor cell radiosensitivity, chemotherapy-induced cell toxicity, DNA damage, and cell-cycle arrest were determined and correlated with glioma cell receptor expression profiles. The effects of NGI-1 on xenograft tumor growth were tested using a nanoparticle formulation validated by in vivo molecular imaging. A mechanistic role for RTK signaling was evaluated through the expression of a glycosylation-independent CD8-EGFR chimera.
Results:
NGI-1 reduced glycosylation, protein levels, and activation of most RTKs. NGI-1 also enhanced the radiosensitivity and cytotoxic effects of chemotherapy in those glioma cells with elevated ErbB family activation, but not in cells without high levels of RTK activation. NGI-1 radiosensitization was associated with increases in both DNA damage and G1 cell-cycle arrest. Combined treatment of glioma xenografts with fractionated radiotherapy and NGI-1 significantly reduced tumor growth compared with controls. Expression of the CD8-EGFR eliminated the effects of NGI-1 on G1 arrest, DNA damage, and cellular radiosensitivity, identifying RTK inhibition as the principal mechanism for the NGI-1 effect.
Conclusions:
This study suggests that oligosaccharyltransferase inhibition with NGI-1 is a novel approach to radiosensitize malignant gliomas with enhanced RTK signaling.

See related commentary by Wahl and Lawrence, p. 455
Data from The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study
Authors: Stamatopoulos Basile , Smith Thomas , Crompot Emerence , Pieters Karlien , Clifford Ruth , Mraz Marek , Robbe Pauline , Burns Adam , Timbs Adele , Bruce David , Hillmen Peter , Meuleman Nathalie , Mineur Philippe , Firescu Radu , Maerevoet Marie , De Wilde Virginie , Efira André , Philippé Jan , Verhasselt Bruno , Offner Fritz , Sims David , Heger Andreas , Dreau Hélène , Schuh Anna
Published: April 2023

Abstract
Purpose: Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21.

Experimental Design: We performed total RNA sequencing in 32 patients and investigated IgLV3-21 prognostic impact in terms of treatment-free survival (TFS) and overall survival (OS) in 3 other independent cohorts for a total of 813 patients. IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing.

Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients express higher levels of genes responsible for ribosome biogenesis and translation initiation (P < 0.0001) as well as MYC target genes (P = 0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P < 0.05), particularly those with IgHV mutation. In each of the three independent validation cohorts, we showed that IgLV3-21 rearrangements—similar to UM IgHV status—conferred poor prognosis compared with mutated IgHV (P < 0.0001). Importantly, we confirmed by multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (P < 0.0001).

Conclusions: We have demonstrated for the first time that a light chain can affect CLL prognosis and that IgLV3-21 light chain usage defines a new subgroup of CLL patients with poor prognosis. Clin Cancer Res; 24(20); 5048–57. ©2018 AACR.
Data from Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma
Authors: Amin-Mansour Ali , George Suzanne , Sioletic Stefano , Carter Scott L. , Rosenberg Mara , Taylor-Weiner Amaro , Stewart Chip , Chevalier Aaron , Seepo Sara , Tracy Adam , Getz Gad , Hornick Jason L. , Nucci Marisa R. , Quade Bradley , Demetri George D. , Raut Chandrajit P. , Garraway Levi A. , Van Allen Eliezer M. , Wagner Andrew J.
Published: April 2023

AbstractPurpose:
Leiomyosarcoma and liposarcoma are common subtypes of soft tissue sarcoma (STS). Patients with metastatic leiomyosarcoma or dedifferentiated liposarcoma (DDLPS) typically have worse outcomes compared with localized leiomyosarcoma or well-differentiated liposarcoma (WDLPS). A better understanding of genetic changes between primary/metastatic leiomyosarcoma and between WDLPS/DDLPS may provide insight into their genetic evolution.
Experimental Design:
We interrogated whole-exome sequencing (WES) from “trios” of normal tissue, primary tumor, and metastatic tumor from individual patients with leiomyosarcoma (n = 9), and trios of normal tissue, well-differentiated tumor, and dedifferentiated tumor from individual patients with liposarcoma (n = 19). Specifically, we performed mutational, copy number, and tumor evolution analyses on these cohorts and compared patterns among leiomyosarcoma and liposarcoma trios.
Results:
Leiomyosarcoma cases harbored shared drivers through a typical parent/child relationship where the metastatic tumor was derived from the primary tumor. In contrast, while all liposarcoma cases shared the characteristic focal chromosome 12 amplicon, most paired liposarcoma cases did not share additional mutations, suggesting a divergent evolutionary pattern from a common precursor. No highly recurrent genomic alterations from WES were identified that could be implicated as driving the progression of disease in either sarcoma subtype.
Conclusions:
From a genomic perspective, leiomyosarcoma metastases contain genetic alterations that are also found in primary tumors. WDLPS and DDLPS, however, appear to divergently evolve from a common precursor harboring 12q amplification, rather than as a transformation to a higher-grade tumor. Further efforts to identify specific drivers of these distinct evolutionary patterns may inform future translational and clinical research in STS.
Data from Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy
Authors: Marciscano Ariel E. , Ghasemzadeh Ali , Nirschl Thomas R. , Theodros Debebe , Kochel Christina M. , Francica Brian J. , Muroyama Yuki , Anders Robert A. , Sharabi Andrew B. , Velarde Esteban , Mao Wendy , Chaudhary Kunal R. , Chaimowitz Matthew G. , Wong John , Selby Mark J. , Thudium Kent B. , Korman Alan J. , Ulmert David , Thorek Daniel L.J. , DeWeese Theodore L. , Drake Charles G.
Published: April 2023

Abstract
Purpose: In the proper context, radiotherapy can promote antitumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), affects adaptive immune responses and combinatorial efficacy of radiotherapy with immune checkpoint blockade (ICB).

Experimental Design: We developed a preclinical model to compare stereotactic radiotherapy (Tumor RT) with or without ENI to examine immunologic differences between radiotherapy techniques that spare or irradiate the DLN.

Results: Tumor RT was associated with upregulation of an intratumoral T-cell chemoattractant chemokine signature (CXCR3, CCR5-related) that resulted in robust infiltration of antigen-specific CD8+ effector T cells as well as FoxP3+ regulatory T cells (Tregs). The addition of ENI attenuated chemokine expression, restrained immune infiltration, and adversely affected survival when combined with ICB, especially with anti-CLTA4 therapy. The combination of stereotactic radiotherapy and ICB led to long-term survival in a subset of mice and was associated with favorable CD8 effector-to-Treg ratios and increased intratumoral density of antigen-specific CD8+ T cells. Although radiotherapy technique (Tumor RT vs. ENI) affected initial tumor control and survival, the ability to reject tumor upon rechallenge was partially dependent upon the mechanism of action of ICB; as radiotherapy/anti-CTLA4 was superior to radiotherapy/anti-PD-1.

Conclusions: Our results highlight that irradiation of the DLN restrains adaptive immune responses through altered chemokine expression and CD8+ T-cell trafficking. These data have implications for combining radiotherapy and ICB, long-term survival, and induction of immunologic memory. Clinically, the immunomodulatory effect of the radiotherapy strategy should be considered when combining stereotactic radiotherapy with immunotherapy. Clin Cancer Res; 24(20); 5058–71. ©2018 AACR.
Data from Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors
Authors: Gebreyohannes Yemarshet K. , Wozniak Agnieszka , Zhai Madalina-Elena , Wellens Jasmien , Cornillie Jasmien , Vanleeuw Ulla , Evans Erica , Gardino Alexandra K. , Lengauer Christoph , Debiec-Rychter Maria , Sciot Raf , Schöffski Patrick
Published: April 2023

AbstractPurpose:
Gastrointestinal stromal tumors (GIST) are commonly treated with tyrosine kinase inhibitors (TKI). The majority of patients with advanced GIST ultimately become resistant to TKI due to acquisition of secondary KIT mutations, whereas primary resistance is mainly caused by PDGFRA p.D842V mutation. We tested the activity of avapritinib, a potent and highly selective inhibitor of mutated KIT and PDGFRA, in three patient-derived xenograft (PDX) GIST models carrying different KIT mutations, with differential sensitivity to standard TKI.

Experimental Design: NMRI nu/nu mice (n = 93) were transplanted with human GIST xenografts with KIT exon 11+17 (UZLX-GIST9KIT 11+17), exon 11 (UZLX-GIST3KIT 11), or exon 9 (UZLX-GIST2BKIT9) mutations, respectively. We compared avapritinib (10 and 30 mg/kg/once daily) versus vehicle, imatinib (50 mg/kg/bid) or regorafenib (30 mg/kg/once daily; UZLX-GIST9KIT11+17); avapritinib (10, 30, 100 mg/kg/once daily) versus vehicle or imatinib [UZLX-GIST3KIT11]; and avapritinib (10, 30, 60 mg/kg/once daily) versus vehicle, imatinib (50, 100 mg/kg/twice daily), or sunitinib (40 mg/kg/once daily; UZLX-GIST2BKIT9).
Results:
In all models, avapritinib resulted in reduction of tumor volume, significant inhibition of proliferation, and reduced KIT signaling. In two models, avapritinib led to remarkable histologic responses, increase in apoptosis, and inhibition of MAPK-phosphorylation. Avapritinib showed superior (UZLX-GIST9KIT 11+17 and -GIST2BKIT 9) or equal (UZLX-GIST3KIT 11) antitumor activity to the standard dose of imatinib. In UZLX-GIST9KIT 11+17, the antitumor effects of avapritinib were significantly better than with imatinib or regorafenib.
Conclusions:
Avapritinib has significant antitumor activity in GIST PDX models characterized by different KIT mutations and sensitivity to established TKI. These data provide strong support for the ongoing clinical trials with avapritinib in patients with GIST (NCT02508532, NCT03465722).
Data from DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway
Authors: Adam Liana , San Lucas F. Anthony , Fowler Richard , Yu Yao , Wu Wenhui , Liu Yulun , Wang Huamin , Menter David , Tetzlaff Michael T. , Ensor Joe , Manyam Ganiraju , Arold Stefan T. , Huff Chad , Kopetz Scott , Scheet Paul , Overman Michael J.
Published: April 2023

AbstractPurpose:
Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease.

Experimental Design: Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with ERBB2 kinase activating mutations were tested for sensitivity to anti-ERBB2 agents in vivo and in vitro. Biochemical changes were measured by reverse-phase protein arrays.
Results:
WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although APC mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. ERBB2 mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank HR = 2.4, P = 0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC50 < 2.5 nmol/L). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, whereas it had no effect in an SBA wild-type ERBB2 model.
Conclusions:
The in vitro and in vivo models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating ERBB2 mutations in patients with SBA that harbor these alterations.
Data from Phase I Study of Rapid Alternation of Sunitinib and Regorafenib for the Treatment of Tyrosine Kinase Inhibitor Refractory Gastrointestinal Stromal Tumors
Authors: Serrano César , Leal Alessandro , Kuang Yanan , Morgan Jeffrey A. , Barysauskas Constance M. , Phallen Jillian , Triplett Olivia , Mariño-Enríquez Adrián , Wagner Andrew J. , Demetri George D. , Velculescu Victor E. , Paweletz Cloud P. , Fletcher Jonathan A. , George Suzanne
Published: April 2023

AbstractPurpose:
Polyclonal emergence of KIT secondary mutations is a main mechanism of imatinib progression in gastrointestinal stromal tumor (GIST). Approved KIT inhibitors sunitinib and regorafenib have complementary activity against KIT resistance mutations. Preclinical evidence suggests that rapid alternation of sunitinib and regorafenib broadens the spectrum of imatinib-resistant subclones targeted.
Patients and Methods:
Phase Ib study investigating continuous treatment with cycles of sunitinib (3 days) followed by regorafenib (4 days) in patients with tyrosine kinase inhibitor (TKI)-refractory GIST. A 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Plasma samples were analyzed for pharmacokinetics and circulating tumor DNA (ctDNA) studies using targeted error correction sequencing (TEC-seq) and droplet digital PCR (ddPCR).
Results:
Of the 14 patients enrolled, 2 experienced dose-limiting toxicities at dose level 2 (asymptomatic grade 3 hypophosphatemia). Sunitinib 37.5 mg/day and regorafenib 120 mg/day was the RP2D. Treatment was well-tolerated and no unexpected toxicities resulted from the combination. Stable disease was the best response in 4 patients, and median progression-free survival was 1.9 months. Combined assessment of ctDNA with TEC-seq and ddPCR detected plasma mutations in 11 of 12 patients (92%). ctDNA studies showed that KIT secondary mutations remain the main mechanism of resistance in TKI-refractory GIST, revealing effective suppression of KIT-mutant subpopulations in patients benefiting from the combination.
Conclusions:
Sunitinib and regorafenib combination is feasible and tolerable. Rapid alternation of TKIs with complementary activity might be effective when combining drugs with favorable pharmacokinetics, potentially allowing active doses while minimizing adverse events. Serial monitoring with ctDNA may guide treatment in patients with GIST.
Data from Serum- and Glucocorticoid-induced Kinase Sgk1 Directly Promotes the Differentiation of Colorectal Cancer Cells and Restrains Metastasis
Authors: Lee Lennard Y.W. , Woolley Connor , Starkey Thomas , Biswas Sujata , Mirshahi Tia , Bardella Chiara , Segditsas Stefania , Irshad Shazia , Tomlinson Ian
Published: April 2023

AbstractPurpose:
The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, because in colorectal cancer, the degree of differentiation of a tumor is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer, there is marked downregulation of SGK1 compared with normal tissue.

Experimental Design: An inducible SGK1 viral overexpression system was utilized to induce reexpression of SGK1 in colorectal cancer cell lines. Transcriptomic and phenotypic analyses of these colorectal cancer lines was performed and validation in mouse and human cohorts was performed.
Results:
We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Reexpression of SGK1 in colorectal cancer cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated, in part, by SGK1-induced PKP3 expression and increased degradation of MYC.
Conclusions:
Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit colorectal cancer metastasis.
Data from T-Cell Dynamics in Chronic Lymphocytic Leukemia under Different Treatment Modalities
Authors: Vardi Anna , Vlachonikola Elisavet , Papazoglou Despoina , Psomopoulos Fotis , Kotta Kostantia , Ioannou Nikolaos , Galigalidou Chrysi , Gemenetzi Katerina , Pasentsis Kostantinos , Kotouza Maria , Koravou Evdoxia , Scarfó Lydia , Iskas Michail , Stavroyianni Niki , Ghia Paolo , Anagnostopoulos Achilles , Kouvatsi Anastasia , Ramsay Alan G. , Stamatopoulos Kostas , Chatzidimitriou Anastasia
Published: April 2023

AbstractPurpose:
Using next-generation sequencing (NGS), we recently documented T-cell oligoclonality in treatment-naïve chronic lymphocytic leukemia (CLL), with evidence indicating T-cell selection by restricted antigens.
Experimental Design:
Here, we sought to comprehensively assess T-cell repertoire changes during treatment in relation to (i) treatment type [fludarabine-cyclophosphamide-rituximab (FCR) versus ibrutinib (IB) versus rituximab-idelalisib (R-ID)], and (ii) clinical response, by combining NGS immunoprofiling, flow cytometry, and functional bioassays.
Results:
T-cell clonality significantly increased at (i) 3 months in the FCR and R-ID treatment groups, and (ii) over deepening clinical response in the R-ID group, with a similar trend detected in the IB group. Notably, in constrast to FCR that induced T-cell repertoire reconstitution, B-cell receptor signaling inhibitors (BcRi) preserved pretreatment clones. Extensive comparisons both within CLL as well as against T-cell receptor sequence databases showed little similarity with other entities, but instead revealed major clonotypes shared exclusively by patients with CLL, alluding to selection by conserved CLL-associated antigens. We then evaluated the functional effect of treatments on T cells and found that (i) R-ID upregulated the expression of activation markers in effector memory T cells, and (ii) both BcRi improved antitumor T-cell immune synapse formation, in marked contrast to FCR.
Conclusions:
Taken together, our NGS immunoprofiling data suggest that BcRi retain T-cell clones that may have developed against CLL-associated antigens. Phenotypic and immune synapse bioassays support a concurrent restoration of functionality, mostly evident for R-ID, arguably contributing to clinical response.
Data from Targeting Endoglin-Expressing Regulatory T Cells in the Tumor Microenvironment Enhances the Effect of PD1 Checkpoint Inhibitor Immunotherapy
Authors: Schoonderwoerd Mark J.A. , Koops Maaike F.M. , Angela Ricardo A. , Koolmoes Bryan , Toitou Melpomeni , Paauwe Madelon , Barnhoorn Marieke C. , Liu Yingmiao , Sier Cornelis F.M. , Hardwick James C.H. , Nixon Andrew B. , Theuer Charles P. , Fransen Marieke F. , Hawinkels Lukas J.A.C.
Published: April 2023

AbstractPurpose:
Endoglin is a coreceptor for TGFβ ligands that is highly expressed on proliferating endothelial cells and other cells in the tumor microenvironment. Clinical studies have noted increased programmed cell death (PD)-1 expression on cytotoxic T cells in the peripheral blood of patients with cancer treated with TRC105, an endoglin-targeting antibody. In this study, we investigated the combination of endoglin antibodies (TRC105 and M1043) with an anti-PD1 antibody.
Experimental Design:
The combination anti-endoglin/anti-PD1 antibodies was tested in four preclinical mouse models representing different stages of cancer development. To investigate the underlying mechanism, Fc-receptor–knockout mice were used complemented with depletion of multiple immune subsets in mice. Tumor growth and the composition of immune infiltrate were analyzed by flow cytometry. Finally, human colorectal cancer specimens were analyzed for presence of endoglin-expressing regulatory T cells (Treg).
Results:
In all models, the combination of endoglin antibody and PD1 inhibition produced durable tumor responses, leading to complete regressions in 30% to 40% of the mice. These effects were dependent on the presence of Fcγ receptors, indicating the involvement of antibody-dependent cytotoxic responses and the presence of CD8+ cytotoxic T cells and CD4+ Th cells. Interestingly, treatment with the endoglin antibody, TRC105, significantly decreased the number of intratumoral Tregs. Endoglin-expressing Tregs were also detected in human colorectal cancer specimens.
Conclusions:
Taken together, these data provide a rationale for combining TRC105 and anti-PD1 therapy and provide additional evidence of endoglin's immunomodulatory role.
Data from Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts
Authors: Gris-Oliver Albert , Palafox Marta , Monserrat Laia , Brasó-Maristany Fara , Òdena Andreu , Sánchez-Guixé Mònica , Ibrahim Yasir H. , Villacampa Guillermo , Grueso Judit , Parés Mireia , Guzmán Marta , Rodríguez Olga , Bruna Alejandra , Hirst Caroline S. , Barnicle Alan , de Bruin Elza C. , Reddy Avinash , Schiavon Gaia , Arribas Joaquín , Mills Gordon B. , Caldas Carlos , Dienstmann Rodrigo , Prat Aleix , Nuciforo Paolo , Razavi Pedram , Scaltriti Maurizio , Turner Nicholas C. , Saura Cristina , Davies Barry R. , Oliveira Mafalda , Serra Violeta
Published: April 2023

AbstractPurpose:
AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor–positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel.
Experimental Design:
Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel.
Results:
Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in PIK3CA/AKT1 and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in MTOR or TSC1, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding PTEN from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of AKT1 p.E17K.
Conclusions:
This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.
Data from Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front–Mutant ROS1-Rearranged Non–Small Cell Lung Cancer
Authors: Yun Mi Ran , Kim Dong Hwi , Kim Seok-Young , Joo Hyeong-Seok , Lee You Won , Choi Hun Mi , Park Chae Won , Heo Seong Gu , Kang Han Na , Lee Sung Sook , Schoenfeld Adam J. , Drilon Alexander , Kang Seok-Gu , Shim Hyo Sup , Hong Min Hee , Cui J. Jean , Kim Hye Ryun , Cho Byoung Chul
Published: April 2023

AbstractPurpose:
Although first-line crizotinib treatment leads to clinical benefit in ROS1+ lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1G2032R) mutation and progression in the central nervous system (CNS) represents a therapeutic challenge. Here, we investigated the antitumor activity of repotrectinib, a novel next-generation ROS1/TRK/ALK-tyrosine kinase inhibitor (TKI) in ROS1+ patient-derived preclinical models.
Experimental Design:
Antitumor activity of repotrectinib was evaluated in ROS1+ patient-derived preclinical models including treatment-naïve and ROS1G2032R models and was further demonstrated in patients enrolled in an on-going phase I/II clinical trial (NCT03093116). Intracranial antitumor activity of repotrectinib was evaluated in a brain-metastasis mouse model.
Results:
Repotrectinib potently inhibited in vitro and in vivo tumor growth and ROS1 downstream signal in treatment-naïve YU1078 compared with clinically available crizotinib, ceritinib, and entrectinib. Despite comparable tumor regression between repotrectinib and lorlatinib in YU1078-derived xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. Moreover, repotrectinib induced profound antitumor activity in the CNS with efficient blood–brain barrier penetrating properties. Notably, repotrectinib showed selective and potent in vitro and in vivo activity against ROS1G2032R. These findings were supported by systemic and intracranial activity of repotrectinib observed in patients enrolled in the on-going clinical trial.
Conclusions:
Repotrectinib is a novel next-generation ROS1-TKI with improved potency and selectivity against treatment-naïve and ROS1G2032R with efficient CNS penetration. Our findings suggest that repotrectinib can be effective both as first-line and after progression to prior ROS1-TKI.
Data from Drugs That Modify Cholesterol Metabolism Alter the p38/JNK-Mediated Targeted and Nontargeted Response to Alpha and Auger Radioimmunotherapy
Authors: Ladjohounlou Riad , Lozza Catherine , Pichard Alexandre , Constanzo Julie , Karam Jihad , Le Fur Pierre , Deshayes Emmanuel , Boudousq Vincent , Paillas Salomé , Busson Muriel , Le Blay Marion , Jarlier Marta , Marcatili Sara , Bardiès Manuel , Bruchertseifer Frank , Morgenstern Alfred , Torgue Julien , Navarro-Teulon Isabelle , Pouget Jean-Pierre
Published: April 2023

AbstractPurpose:
For the development of new anticancer therapeutic radiopharmaceuticals, including alpha particle emitters, it is important to determine the contribution of targeted effects in irradiated cells, and also of nontargeted effects in nonirradiated neighboring cells, because they may affect the therapeutic efficacy and contribute to side effects.
Experimental Design:
Here, we investigated the contribution of nontargeted cytotoxic and genotoxic effects in vitro and in vivo (in xenografted mice) during alpha (212Pb/212Bi, 213Bi) and Auger (125I) radioimmunotherapy (RIT).
Results:
Between 67% and 94% (alpha RIT) and 8% and 15% (Auger RIT) of cancer cells were killed by targeted effects, whereas 7% to 36% (alpha RIT) and 27% to 29% (Auger RIT) of cells were killed by nontargeted effects. We then demonstrated that the nontargeted cell response to alpha and Auger RIT was partly driven by lipid raft–mediated activation of p38 kinase and JNK. Reactive oxygen species also played a significant role in these nontargeted effects, as demonstrated by NF-κB activation and the inhibitory effects of antioxidant enzymes and radical scavengers. Compared with RIT alone, the use of RIT with ASMase inhibitor (imipramine) or with a lipid raft disruptor (e.g., methyl-beta-cyclodextrin or filipin) led to an increase in clonogenic cell survival in vitro and to larger tumors and less tissue DNA damage in vivo. These results were supported by an inhibitory effect of pravastatin on Auger RIT.
Conclusions:
Cell membrane–mediated nontargeted effects play a significant role during Auger and alpha RIT, and drugs that modulate cholesterol level, such as statins, could interfere with RIT efficacy.
Data from The Splicing Factor PTBP1 Promotes Expression of Oncogenic Splice Variants and Predicts Poor Prognosis in Patients with Non–muscle-Invasive Bladder Cancer
Authors: Bielli Pamela , Panzeri Valentina , Lattanzio Rossano , Mutascio Simona , Pieraccioli Marco , Volpe Elisabetta , Pagliarulo Vincenzo , Piantelli Mauro , Giannantoni Antonella , Di Stasi Savino M. , Sette Claudio
Published: April 2023

Abstract
Purpose: Non–muscle-invasive bladder cancer (NMIBC) is a malignant disease characterized by high heterogeneity, which corresponds to dysregulated gene expression and alternative splicing (AS) profiles. Bioinformatics analyses of splicing factors potentially linked to bladder cancer progression identified the heterogeneous nuclear ribonucleoprotein I (i.e., PTBP1) as candidate. This study aimed at investigating whether PTBP1 expression associates with clinical outcome in patients with NMIBC.

Experimental Design: A cohort of 152 patients presenting with primary NMIBC (pTa-pT1) was enrolled. Primary NMIBCs were assessed for PTBP1 expression by IHC, and the results were correlated with clinical data using Kaplan–Meier curves and Cox regression analyses. Cell proliferation and survival assays were performed to assess the function of PTBP1. Furthermore, the impact of PTBP1 on the AS pattern of specific bladder cancer–related genes was investigated in cancer cell lines and in patients' specimens.

Results: Public datasets querying highlighted a positive correlation between PTBP1 expression and NMIBC progression, which was then confirmed by IHC analysis. High PTBP1 expression was associated with worse clinical outcome in terms of incidence of tumor relapse and survival in patients with NMIBC. Interestingly, downregulation of PTBP1 in bladder cancer cell lines affected prosurvival features. Accordingly, PTBP1 modulated AS of bladder cancer–related genes in cell lines and patient's specimens.

Conclusions: PTBP1 expression correlates with disease progression, poor prognosis, and worse survival in patients with NMIBC. Downregulation of PTBP1 expression affects prosurvival features of bladder cancer cells and modulates AS of genes with relevance for bladder cancer, suggesting its role as an outcome-predictor in this disease. Clin Cancer Res; 24(21); 5422–32. ©2018 AACR.
Data from A Phase 1b Dose Escalation Trial of NC-6300 (Nanoparticle Epirubicin) in Patients with Advanced Solid Tumors or Advanced, Metastatic, or Unresectable Soft-tissue Sarcoma
Authors: Chawla Sant P. , Goel Sanjay , Chow Warren , Braiteh Fadi , Singh Arun S. , Olson Juneko E. Grilley , Osada Atsushi , Bobe Iulian , Riedel Richard F.
Published: April 2023

AbstractPurpose:
NC-6300 is a novel nanoparticle formulation of epirubicin that has a pH-sensitive linker conjugated to epirubicin. It exhibits selective tumor accumulation owing to enhanced permeability and retention effect. We conducted a phase 1b trial to determine MTD and recommended phase II dose (RP2D) of NC-6300 monotherapy in advanced, metastatic, or unresectable solid tumors, including soft-tissue sarcomas.
Patients and Methods:
This phase 1b dose-escalation trial of NC-6300 monotherapy employed a Bayesian continuous reassessment method design. NC-6300 was administered on day 1 of every 21-day cycle, with epirubicin-equivalent dose increments from 125 to 215 mg/m2. Safety, efficacy, quality of life, and pharmacokinetic profile of NC-6300 monotherapy were evaluated.
Results:
Twenty-nine subjects (16 male) were enrolled: 17 with soft-tissue sarcoma, one with osteosarcoma, and 11 with other solid tumors. Observed dose-limiting toxicities included thrombocytopenia, stomatitis, lung infection, and febrile neutropenia. The most common grade 3/4 adverse events were neutropenia (59%), anemia (24%), thrombocytopenia (24%), and febrile neutropenia (21%). MTD and RP2D were determined to be 185 mg/m2 and 150 mg/m2, respectively. The objective response rate in the evaluable population was 11%. Partial response was observed in angiosarcoma and endometrial stromal sarcoma. A dose-dependent increase was observed in both total and released epirubicin concentrations.
Conclusions:
NC-6300 was well tolerated with a manageable side effect profile, despite the MTD and RP2D being higher than conventional epirubicin doses. A signal of preliminary activity was observed in angiosarcoma. NC-6300 warrants further investigation in patients with advanced solid tumors, including sarcoma.
Data from A Frameshift Peptide Neoantigen-Based Vaccine for Mismatch Repair-Deficient Cancers: A Phase I/IIa Clinical Trial
Authors: Kloor Matthias , Reuschenbach Miriam , Pauligk Claudia , Karbach Julia , Rafiyan Mohammad-Reza , Al-Batran Salah-Eddin , Tariverdian Mirjam , Jäger Elke , von Knebel Doeberitz Magnus
Published: April 2023

AbstractPurpose:
DNA mismatch repair (MMR) deficiency is a hallmark of Lynch syndrome, the most common inherited cancer syndrome. MMR-deficient cancer cells accumulate numerous insertion/deletion mutations at microsatellites. Mutations of coding microsatellites (cMS) lead to the generation of immunogenic frameshift peptide (FSP) neoantigens. As the evolution of MMR-deficient cancers is triggered by mutations inactivating defined cMS-containing tumor suppressor genes, distinct FSP neoantigens are shared by most MMR-deficient cancers. To evaluate safety and immunogenicity of an FSP-based vaccine, we performed a clinical phase I/IIa trial (Micoryx).
Patients and Methods:
The trial comprised three cycles of four subcutaneous vaccinations (FSP neoantigens derived from mutant AIM2, HT001, TAF1B genes) mixed with Montanide ISA-51 VG over 6 months. Inclusion criteria were history of MMR-deficient colorectal cancer (UICC stage III or IV) and completion of chemotherapy. Phase I evaluated safety and toxicity as primary endpoint (six patients), phase IIa addressed cellular and humoral immune responses (16 patients).
Results:
Vaccine-induced humoral and cellular immune responses were observed in all patients vaccinated per protocol. Three patients developed grade 2 local injection site reactions. No vaccination-induced severe adverse events occurred. One heavily pretreated patient with bulky metastases showed stable disease and stable CEA levels over 7 months.
Conclusions:
FSP neoantigen vaccination is systemically well tolerated and consistently induces humoral and cellular immune responses, thus representing a promising novel approach for treatment and even prevention of MMR-deficient cancer.
Data from Facts and New Hopes on Selective FGFR Inhibitors in Solid Tumors
Authors: Facchinetti Francesco , Hollebecque Antoine , Bahleda Rastislav , Loriot Yohann , Olaussen Ken A. , Massard Christophe , Friboulet Luc
Published: April 2023

Abstract
Precision oncology relies on the identification of molecular alterations, responsible for tumor initiation and growth, which are suitable targets of specific inhibitors. The development of FGFR inhibitors represents an edifying example of the rapid evolution in the field of targeted oncology, with 10 different FGFR tyrosine kinase inhibitors actually under clinical investigation. In parallel, the discovery of FGFR activating molecular alterations (mainly FGFR3 mutations and FGFR2 fusions) across many tumor types, especially urothelial carcinomas and intrahepatic cholangiocarcinomas, widens the selection of patients that might benefit from selective FGFR inhibitors. The ongoing concomitant clinical evaluation of selective FGFR inhibitors in molecularly selected solid tumors brings new hopes for patients with metastatic cancer, for tumors so far excluded from molecularly guided treatments. Matching molecularly selected tumors with selective FGFR inhibitors has indeed led to promising results in phase I and II trials, justifying their registration to be expected in a near future, such as the recent accelerated approval of erdafitinib granted by the FDA for urothelial cancer. Widening our knowledge of the activity, efficacy, and toxicities relative to the selective FGFR tyrosine kinase inhibitors under clinical investigation, according to the exact FGFR molecular alteration, will be crucial to determine the optimal therapeutic strategy for patients suffering from FGFR-driven tumors. Similarly, identifying with appropriate molecular diagnostic, every single tumor harboring targetable FGFR alterations will be of utmost importance to attain the best outcomes for patients with FGFR-driven cancer.
Data from Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients with Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial)
Authors: Kawazoe Akihito , Kuboki Yasutoshi , Shinozaki Eiji , Hara Hiroki , Nishina Tomohiro , Komatsu Yoshito , Yuki Satoshi , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Kuwata Takeshi , Kawazu Masahito , Mano Hiroyuki , Togashi Yosuke , Nishikawa Hiroyoshi , Yoshino Takayuki
Published: April 2023

AbstractPurpose:
This is a phase I/II trial to assess the efficacy and safety of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC).
Patients and Methods:
Phase I was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240 to 480 mg twice daily) with 200 mg pembrolizumab every 3 weeks. Phase II included cohort A (n = 10, microsatellite instability high, MSI-H) and cohort B (n = 40, microsatellite stable, MSS). The primary endpoint was immune-related objective response rate (irORR). PD-L1 combined positive score (CPS), genomic profiles, and the consensus molecular subtypes (CMS) of colorectal cancer were assessed.
Results:
A total of 55 patients were enrolled in this study. In phase I, no patients experienced dose-limiting toxicities, and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS < 1, 1≤ CPS <10, and CPS ≥ 10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3%, and 33.3% in CMS1, CMS2, CMS3, and CMS4, respectively. The common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B.
Conclusions:
Napabucasin with pembrolizumab showed antitumor activity with acceptable toxicities for patients with MSS mCRC as well as MSI-H mCRC, although it did not meet the primary end point. The impact of related biomarkers on the efficacy warrants further investigations in the additional cohort.

See related commentary by Nusrat, p. 5775
Data from Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy
Authors: Marsavela Gabriela , Lee Jenny , Calapre Leslie , Wong Stephen Q. , Pereira Michelle R. , McEvoy Ashleigh C. , Reid Anna L. , Robinson Cleo , Warburton Lydia , Abed Afaf , Khattak Muhammad A. , Meniawy Tarek M. , Dawson Sarah-Jane , Sandhu Shahneen , Carlino Matteo S. , Menzies Alexander M. , Scolyer Richard A. , Long Georgina V. , Amanuel Benhur , Millward Michael , Ziman Melanie R. , Rizos Helen , Gray Elin S.
Published: April 2023

AbstractPurpose:
We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment.
Experimental Design:
Plasma circulating tumor DNA (ctDNA) was quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- (n = 32) or second-line (n = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (n = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- (N = 77) or second-line (N = 51) settings.
Results:
In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20; 95% confidence interval (CI) 0.07–0.53; P < 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42; 95% CI, 0.22–0.83; P = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti–PD-1 monotherapy, relative to those treated with combination anti–CTLA-4/anti–PD-1 inhibitors.
Conclusions:
Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs.
Data from Long-term Consequences of Pelvic Irradiation: Toxicities, Challenges, and Therapeutic Opportunities with Pharmacologic Mitigators
Authors: Huh Jung Wook , Tanksley Jarred , Chino Junzo , Willett Christopher G. , Dewhirst Mark W.
Published: April 2023

Abstract
A percentage of long-term cancer survivors who receive pelvic irradiation will develop treatment-related late effects, collectively termed pelvic radiation disease. Thus, there is a need to prevent or ameliorate treatment-related late effects in these patients. Modern radiotherapy methods can preferentially protect normal tissues from radiation toxicities to permit higher doses to targets. However, concerns about chronic small bowel toxicity, for example, still constrain the prescription dose. This provides strong rationale for considering adding pharmacologic mitigators. Implementation of modern targeted radiotherapy methods enables delivery of focused radiation to target volumes, while minimizing dose to normal tissues. In prostate cancer, these technical advances enabled safe radiation dose escalation and better local tumor control without increasing normal tissue complications. In other pelvic diseases, these new radiotherapy methods have not resulted in the low probability of normal tissue damage achieved with prostate radiotherapy. The persistence of toxicity provides rationale for pharmacologic mitigators. Several new agents could be readily tested in clinical trials because they are being or have been studied in human patients already. Although there are promising preclinical data supporting mitigators, no clinically proven options to treat or prevent pelvic radiation disease currently exist. This review highlights therapeutic options for prevention and/or treatment of pelvic radiation disease, using pharmacologic mitigators. Successful development of mitigators would reduce the number of survivors who suffer from these devastating consequences of pelvic radiotherapy. It is important to note that pharmacologic mitigators to ameliorate pelvic radiation disease may be applicable to other irradiated sites in which chronic toxicity impairs quality of life.