bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Single-cell Spatial Proteomic Revelations on the Multiparametric MRI Heterogeneity of Clinically Significant Prostate Cancer
Authors: Pachynski Russell K. , Kim Eric H. , Miheecheva Natalia , Kotlov Nikita , Ramachandran Akshaya , Postovalova Ekaterina , Galkin Ilia , Svekolkin Viktor , Lyu Yang , Zou Qiong , Cao Dengfeng , Gaut Joseph , Ippolito Joseph E. , Bagaev Alexander , Bruttan Maria , Gancharova Olga , Nomie Krystle , Tsiper Maria , Andriole Gerald L. , Ataullakhanov Ravshan , Hsieh James J.
Published: April 2023

AbstractPurpose:
Multiparametric MRI (mpMRI) has become an indispensable radiographic tool in diagnosing prostate cancer. However, mpMRI fails to visualize approximately 15% of clinically significant prostate cancer (csPCa). The molecular, cellular, and spatial underpinnings of such radiographic heterogeneity in csPCa are unclear.
Experimental Design:
We examined tumor tissues from clinically matched patients with mpMRI-invisible and mpMRI-visible csPCa who underwent radical prostatectomy. Multiplex immunofluorescence single-cell spatial imaging and gene expression profiling were performed. Artificial intelligence–based analytic algorithms were developed to examine the tumor ecosystem and integrate with corresponding transcriptomics.
Results:
More complex and compact epithelial tumor architectures were found in mpMRI-visible than in mpMRI-invisible prostate cancer tumors. In contrast, similar stromal patterns were detected between mpMRI-invisible prostate cancer and normal prostate tissues. Furthermore, quantification of immune cell composition and tumor-immune interactions demonstrated a lack of immune cell infiltration in the malignant but not in the adjacent nonmalignant tissue compartments, irrespective of mpMRI visibility. No significant difference in immune profiles was detected between mpMRI-visible and mpMRI-invisible prostate cancer within our patient cohort, whereas expression profiling identified a 24-gene stromal signature enriched in mpMRI-invisible prostate cancer. Prostate cancer with strong stromal signature exhibited a favorable survival outcome within The Cancer Genome Atlas prostate cancer cohort. Notably, five recurrences in the 8 mpMRI-visible patients with csPCa and no recurrence in the 8 clinically matched patients with mpMRI-invisible csPCa occurred during the 5-year follow-up post-prostatectomy.
Conclusions:
Our study identified distinct molecular, cellular, and structural characteristics associated with mpMRI-visible csPCa, whereas mpMRI-invisible tumors were similar to normal prostate tissue, likely contributing to mpMRI invisibility.
Data from Final Results of the Prospective Biomarker Trial PETra: [11C]-MET-Accumulation in Postoperative PET/MRI Predicts Outcome after Radiochemotherapy in Glioblastoma
Authors: Seidlitz Annekatrin , Beuthien-Baumann Bettina , Löck Steffen , Jentsch Christina , Platzek Ivan , Zöphel Klaus , Linge Annett , Kotzerke Jörg , Petr Jan , van den Hoff Jörg , Steinbach Jörg , Krex Dietmar , Schmitz-Schackert Gabriele , Falk Monique , Baumann Michael , Krause Mechthild
Published: April 2023

AbstractPurpose:
This prospective trial investigates the association of time to recurrence (TTR) in glioblastoma with [11C]methionine (MET) tracer uptake before postoperative radiochemotherapy (RCT) aiming to guide radiotherapy boost regions.
Experimental Design:
Between 2013 and 2016, 102 patients with glioblastoma were recruited. RCT was performed with concurrent and adjuvant temozolomide to a total dose of 60 Gy. Tumor residues in postresection PET and MRI were together defined as gross tumor volumes for radiotherapy treatment planning. [11C]methionine (MET)-PET/MRI was performed before RCT and at each follow-up.
Results:
The primary hypothesis of a longer TTR for patients without increased tracer accumulation in postoperative MET-PET was confirmed in 89 patients. With 18.9 months (95% confidence interval, 9.3–28.5 months), median TTR was significantly (P < 0.001) longer for patients without (n = 29, 32.6%) as compared with 6.3 months (3.6–8.9) for patients with MET accumulation (n = 60, 67.4%) in pre-RCT PET. Although MRI often did not detect all PET-positive regions, an unfavorable impact of residual tumor in postsurgical MRI (n = 38, 42.7%) on TTR was observed [4.6 (4.2–5.1) vs. 15.5 months (6.0–24.9), P < 0.001]. Significant multivariable predictors for TTR were MRI positivity, PET-positive volume, and O6-methylguanine DNA methyltransferase (MGMT) hypermethylation.
Conclusions:
Postsurgical amino acid PET has prognostic value for TTR after RCT in glioblastoma. Because of the added value of the metabolic beyond the pure structural information, it should complement MRI in radiotherapy planning if available with reasonable effort, at least in the context of maximal therapy. Furthermore, the spatial correlation of regions of recurrence with PET-positive volumes could provide a bioimaging basis for further trials, for example, testing local radiation dose escalation.
Data from B7-H3: An Attractive Target for Antibody-based Immunotherapy
Authors: Kontos Filippos , Michelakos Theodoros , Kurokawa Tomohiro , Sadagopan Ananthan , Schwab Joseph H. , Ferrone Cristina R. , Ferrone Soldano
Published: April 2023

Abstract
The recent impressive clinical responses to antibody-based immunotherapy have prompted the identification of clinically relevant tumor antigens that can serve as targets in solid tumors. Among them, B7-H3, a member of the B7 ligand family, represents an attractive target for antibody-based immunotherapy, it is overexpressed on differentiated malignant cells and cancer-initiating cells, with limited heterogeneity, and high frequency (60% of 25,000 tumor samples) in many different cancer types, but has a limited expression at low level in normal tissues. In nonmalignant tissues, B7-H3 has a predominantly inhibitory role in adaptive immunity, suppressing T-cell activation and proliferation. In malignant tissues, B7-H3 inhibits tumor antigen–specific immune responses, leading to a protumorigenic effect. B7-H3 also has nonimmunologic protumorigenic functions, such as promoting migration and invasion, angiogenesis, chemoresistance, and endothelial-to-mesenchymal transition, as well as affecting tumor cell metabolism. As a result, B7-H3 expression in tumors is associated with poor prognosis. Although experimental B7-H3 silencing reduces cancer cell malignant potential, there has been limited emphasis on the development of B7-H3–blocking antibodies, most likely because the B7-H3 receptor remains unknown. Instead, many antibody-based strategies utilizing distinct effector mechanisms to target B7-H3–expressing cancer cells have been developed. These strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Ongoing clinical trials are assessing their safety and efficacy in patients. Identification of the B7-H3 receptor will improve our understanding of its role in tumor immunity, and will suggest rational strategies to develop blocking antibodies, which may enhance the therapeutic efficacy of tumor immunity.
Data from Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity
Authors: Gandhi Shipra , Pandey Manu R. , Attwood Kristopher , Ji Wenyan , Witkiewicz Agnieszka K. , Knudsen Erik S. , Allen Cheryl , Tario Joseph D. , Wallace Paul K. , Cedeno Carlos D. , Levis Maria , Stack Suzanne , Funchain Pauline , Drabick Joseph J. , Bucsek Mark J. , Puzanov Igor , Mohammadpour Hemn , Repasky Elizabeth A. , Ernstoff Marc S.
Published: April 2023

AbstractPurpose:
Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti–PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma.
Patients and Methods:
A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months.
Results:
Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders.
Conclusions:
Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.
Data from Dynamic Changes of Post-Radiotherapy Plasma Epstein–Barr Virus DNA in a Randomized Trial of Adjuvant Chemotherapy Versus Observation in Nasopharyngeal Cancer
Authors: Hui Edwin Pun , Ma Brigette B.Y. , Lam W.K. Jacky , Chan K.C. Allen , Mo Frankie , Ai Qi-yong Hemis , King Ann D. , Wong Chi Hang , Wong Kenneth C.W. , Lam Daisy C.M. , Tong Macy , Poon Darren M.C. , Li Leung , Lau Thomas K.H. , Wong Kwan Hung , Lo Y.M. Dennis , Chan Anthony T.C.
Published: April 2023

AbstractPurpose:
To study the dynamic changes in plasma Epstein–Barr virus (pEBV) DNA after radiotherapy in nasopharyngeal cancer (NPC).
Experimental Design:
We conducted a randomized controlled trial of adjuvant chemotherapy versus observation in patients with NPC who had detectable pEBV DNA at 6 weeks post-radiotherapy. Randomized patients had a second pEBV DNA checked at 6 months post-randomization. The primary endpoint was progression-free survival (PFS).
Results:
We prospectively enrolled 789 patients. Baseline post-radiotherapy pEBV DNA was undetectable in 573 (72.6%) patients, and detectable in 216 (27.4%) patients, of whom 104 (13.2%) patients were eligible for randomization to adjuvant chemotherapy (n = 52) versus observation (n = 52). The first post-radiotherapy pEBV DNA had a sensitivity of 0.48, specificity of 0.81, area under receiver-operator characteristics curve (AUC) of 0.65, false positive (FP) rate of 13.8%, and false negative (FN) rate of 14.4% for disease progression. The second post-radiotherapy pEBV DNA had improved sensitivity of 0.81, specificity of 0.75, AUC of 0.78, FP rate of 14.3%, and FN rate of 8.1%. Patients with complete clearance of post-radiotherapy pEBV DNA (51%) had survival superior to that of patients without post-radiotherapy pEBV DNA clearance (5-year PFS, 85.5% vs. 23.3%; HR, 9.6; P < 0.0001), comparable with patients with initially undetectable post-radiotherapy pEBV DNA (5-year PFS, 77.1%), irrespective of adjuvant chemotherapy or observation.
Conclusions:
Patients with NPC with detectable post-radiotherapy pEBV DNA who experienced subsequent pEBV DNA clearance had superior survival comparable with patients with initially undetectable post-radiotherapy pEBV DNA. Post-radiotherapy pEBV DNA clearance may serve as an early surrogate endpoint for long-term survival in NPC.
Data from Combined Inhibition of Gαq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma
Authors: Hitchman Tyler D. , Bayshtok Gabriella , Ceraudo Emilie , Moore Amanda R. , Lee Cindy , Jia Ruobing , Wang Naitao , Pachai Mohini R. , Shoushtari Alexander N. , Francis Jasmine H. , Guan Youxin , Chen Juliet , Chang Matthew T. , Taylor Barry S. , Sakmar Thomas P. , Huber Thomas , Chi Ping , Chen Yu
Published: April 2023

AbstractPurpose:
All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the G-protein alpha-q (Gαq) pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of Gαq have shown promising preclinical results, but their therapeutic activity in distinct Gαq mutational contexts and in vivo have remained elusive.
Experimental Design:
We used an isogenic melanocytic cellular system to systematically examine hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (L129Q) found in human uveal melanoma. This cellular system and human uveal melanoma cell lines were used in vitro and in in vivo xenograft studies to assess the efficacy of Gαq inhibition as a single agent and in combination with MEK inhibition.
Results:
We demonstrate that the Gαq inhibitor YM-254890 inhibited downstream signaling and in vitro growth in all mutants. In vivo, YM-254890 slowed tumor growth but did not cause regression in human uveal melanoma xenografts. Through comprehensive transcriptome analysis, we observed that YM-254890 caused inhibition of the MAPK signaling with evidence of rebound by 24 hours and combination treatment of YM-254890 and a MEK inhibitor led to sustained MAPK inhibition. We further demonstrated that the combination caused synergistic growth inhibition in vitro and tumor shrinkage in vivo.
Conclusions:
These data suggest that the combination of Gαq and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gαq in uveal melanoma.

See related commentary by Neelature Sriramareddy and Smalley, p. 1217
Data from A Phase I Dose-Escalation Study to Evaluate the Safety and Tolerability of Evofosfamide in Combination with Ipilimumab in Advanced Solid Malignancies
Authors: Hegde Aparna , Jayaprakash Priyamvada , Couillault Coline A. , Piha-Paul Sarina , Karp Daniel , Rodon Jordi , Pant Shubham , Fu Siqing , Dumbrava Ecaterina E. , Yap Timothy A. , Subbiah Vivek , Bhosale Priya , Coarfa Cristian , Higgins Jack P. , Williams Eric T. , Wilson Thomas F. , Lim JoAnn , Meric-Bernstam Funda , Sumner Elizabeth , Zain Hira , Nguyen Di , Nguyen Ly M. , Rajapakshe Kimal , Curran Michael A. , Hong David S.
Published: April 2023

AbstractPurpose:
As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically “cold” cancers, which are intrinsically insensitive to immunotherapy, as well as in “hot/warm” metastatic cancers that are, atypical of such cancers, resistant to immunotherapy.
Patients and Methods:
In a phase I, 3+3 dose-escalation trial (NCT03098160), evofosfamide (400–640 mg/m2) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1–2, while the latter was administered on day 8 of cycles 1–4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression.
Results:
Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer (n = 11), pancreatic cancer (n = 7), immunotherapy-resistant melanoma (n = 2), and human papillomavirus–negative head and neck cancer (n = 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m2 evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia.
Conclusions:
No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.
Data from Adaptive Natural Killer Cells Facilitate Effector Functions of Daratumumab in Multiple Myeloma
Authors: Cho Hyunsoo , Kim Kyung Hwan , Lee Hoyoung , Kim Chang Gon , Chung Haerim , Choi Yoon Seok , Park Su-Hyung , Cheong June-Won , Min Yoo Hong , Shin Eui-Cheol , Kim Jin Seok
Published: April 2023

AbstractPurpose:
To investigate the different roles of heterogeneous natural killer (NK)-cell subpopulations in multiple myeloma and to identify NK-cell subsets that support the robust anti-myeloma activity of daratumumab via antibody-dependent cellular cytotoxicity (ADCC).
Experimental Design:
We performed single-cell RNA sequencing of NK cells from patients with newly diagnosed multiple myeloma (NDMM) and delineated adaptive NK cells in their bone marrow (BM). We further characterized the distinct immunophenotypic features and functions of adaptive NK cells by multicolor flow cytometry in 157 patients with NDMM.
Results:
Adaptive NK cells exhibit a significantly lower level of CD38 expression compared with conventional NK cells, suggesting that they may evade daratumumab-induced fratricide. Moreover, adaptive NK cells exert robust daratumumab-mediated effector functions ex vivo, including cytokine production and degranulation, compared with conventional NK cells. The composition of adaptive NK cells in BM determines the daratumumab-mediated ex vivo functional activity of BM NK cells in patients with NDMM. Unlike conventional NK cells, sorted adaptive NK cells from the BM of patients with NDMM exert substantial cytotoxic activity against myeloma cells in the presence of daratumumab.
Conclusions:
Our findings indicate that adaptive NK cells are an important mediator of ADCC in multiple myeloma and support direct future efforts to better predict and improve the treatment outcome of daratumumab by selectively employing adaptive NK cells.
Data from Integrative Analysis of miRNAs Identifies Clinically Relevant Epithelial and Stromal Subtypes of Head and Neck Squamous Cell Carcinoma
Authors: Holt Jeremiah , Walter Vonn , Yin Xiaoying , Marron David , Wilkerson Matthew D. , Choi Hyo Young , Zhao Xiaobei , Jo Heejoon , Hayes David Neil , Ko Yoon Ho
Published: April 2023

AbstractPurpose:
The objective of this study is to characterize the role of miRNAs in the classification of head and neck squamous cell carcinoma (HNSCC).
Experimental Design:
Here, we analyzed 562 HNSCC samples, 88 from a novel cohort and 474 from The Cancer Genome Atlas, using miRNA microarray and miRNA sequencing, respectively. Using an integrative correlations method followed by miRNA expression–based hierarchical clustering, we validated miRNA clusters across cohorts. Evaluation of clusters by logistic regression and gene ontology approaches revealed subtype-based clinical and biological characteristics.
Results:
We identified two independently validated and statistically significant (P < 0.01) tumor subtypes and named them “epithelial” and “stromal” based on associations with functional target gene ontology relating to differing stages of epithelial cell differentiation. miRNA-based subtypes were correlated with individual gene expression targets based on miRNA seed sequences, as well as with miRNA families and clusters including the miR-17 and miR-200 families. These correlated genes defined pathways relevant to normal squamous cell function and pathophysiology. miRNA clusters statistically associated with differential mutation patterns including higher proportions of TP53 mutations in the stromal class and higher NSD1 and HRAS mutation frequencies in the epithelial class. miRNA classes correlated with previously reported gene expression subtypes, clinical characteristics, and clinical outcomes in a multivariate Cox proportional hazards model with stromal patients demonstrating worse prognoses (HR, 1.5646; P = 0.006).
Conclusions:
We report a reproducible classification of HNSCC based on miRNA that associates with known pathologically altered pathways and mutations of squamous tumors and is clinically relevant.
Data from Oncolytic Reovirus (pelareorep) Induces Autophagy in KRAS-mutated Colorectal Cancer
Authors: Jiffry Jeeshan , Thavornwatanayong Thongthai , Rao Devika , Fogel Elisha J. , Saytoo Durvanand , Nahata Rishika , Guzik Hillary , Chaudhary Imran , Augustine Titto , Goel Sanjay , Maitra Radhashree
Published: April 2023

AbstractPurpose:
To explore the effects of pelareorep on autophagy in multiple models of colorectal cancer, including patient-derived peripheral blood mononuclear cells (PBMCs).
Experimental Design:
HCT116 [KRAS mutant (mut)] and Hke3 [KRAS wild-type (WT)] cells were treated with pelareorep (multiplicity of infection, 5) and harvested at 6 and 9 hours. LC3 A/B expression was determined by immunofluorescence and flow cytometry; five autophagic proteins were analyzed by Western blotting. The expression of 88 autophagy genes was determined by qRT-PCR. Syngeneic mouse models, CT26/Balb-C (KRAS mut) and MC38/C57B6 (KRAS WT), were developed and treated with pelareorep (10 × 106 plaque-forming unit/day) intraperitoneally. Protein and RNA were extracted from harvested tumor tissues. PBMCs from five experimental and three control patients were sampled at 0 (pre) and 48 hours, and on days 8 and 15. The gene expression normalized to “pre” was determined using 2−ΔΔCt method.
Results:
Pelareorep induced significant upregulation of LC3 A/B in HCT116 as compared with Hke3 cells by immunofluorescence (3.24 × and 8.67 ×), flow cytometry (2.37 × and 2.58 ×), and autophagosome formation (2.02 × and 1.57 ×), at 6 and 9 hours, respectively; all P < 0.05. Western blot analysis showed an increase in LC3 A/B (2.38 × and 6.82 ×) and Beclin1 (1.17 × and 1.24 ×) at 6 and 9 hours, ATG5 (2.4 ×) and P-62 (1.52 ×) at 6 hours, and VPS-34 (1.39 ×) at 9 hours (all P < 0.05). Induction of 13 transcripts in cell lines (>4 ×; 6 and 9 hours; P < 0.05), 12 transcripts in CT26 (qRT-PCR), and 14 transcripts in human PBMCs (P < 0.05) was observed. LC3 A/B, RICTOR, and RASD1 expression was upregulated in all three model systems.
Conclusions:
Pelareorep hijacks host autophagic machinery in KRAS-mut conditions to augment its propagation and preferential oncolysis of the cancer cells.
Data from Exploiting B-cell Receptor Stereotypy to Design Tailored Immunotherapy in Chronic Lymphocytic Leukemia
Authors: Rovida Alessandra , Maccalli Cristina , Scarfò Lydia , Dellabona Paolo , Stamatopoulos Kostas , Ghia Paolo
Published: April 2023

AbstractPurpose:
Approximately 30% of patients with chronic lymphocytic leukemia (CLL) can be grouped into subsets with stereotyped B-cell receptor immunoglobulin (BcR IG) displaying remarkable similarity in the heavy complementarity-determining region 3 (VH CDR3). Here, we investigated whether the consensus VH CDR3 sequences from CLL stereotyped subsets can be exploited for immunotherapy approaches.
Experimental Design:
Immunogenic epitopes from the consensus VH CDR3 sequence of the clinically aggressive subsets #1 and #2 and from Eμ-TCL1 mice, which spontaneously develop CLL with BcR IG stereotypy, were identified and used to generate specific HLA class I– and II–restricted T cells in vitro. T-cell reactivity was assayed in vitro as IFNγ production. Bone marrow–derived dendritic cells loaded with the peptides were used as vaccination strategy to restrain leukemia development in the Eμ-TCL1 mouse model.
Results:
These stereotyped epitopes were naturally processed and presented by CLL cells to the VH CDR3–specific T cells. Furthermore, we validated the efficacy of VH CDR3 peptide–based immunotherapy in the Eμ-TCL1 transplantable mouse model. Immunization of mice against defined VH CDR3 peptide epitopes, prior to the challenge with the corresponding leukemia cells, resulted in the control of CLL development in a significant fraction of mice, and increased overall survival.
Conclusions:
Our data highlight the immunogenicity of stereotyped VH CDR3 sequences and support the feasibility and efficacy of their use for novel cancer vaccine in CLL. Such approach has the advantage to generate “off-the-shelf” therapeutic vaccines for relevant groups of patients belonging to stereotyped subsets.

See related commentary by Seiffert, p. 659
Data from Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations
Authors: Sztupinszki Zsofia , Diossy Miklos , Krzystanek Marcin , Borcsok Judit , Pomerantz Mark M. , Tisza Viktoria , Spisak Sandor , Rusz Orsolya , Csabai István , Freedman Matthew L. , Szallasi Zoltan
Published: April 2023

AbstractPurpose:
Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. We investigated whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, likely rendering those sensitive to HR-directed therapies.
Experimental Design:
Homologous recombination deficiency (HRD) levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach on whole-genome sequencing (WGS; n = 311) and whole-exome sequencing (WES) data (n = 498) of both primary and metastatic prostate adenocarcinomas to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies.
Results:
Known BRCA-deficient samples showed all previously described HRD-associated mutational signatures in the WGS data. HRD-associated mutational signatures were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. Similar results, albeit with lower sensitivity and accuracy, were also obtained from WES data.
Conclusions:
These findings may expand the number of cases likely to respond to PARP inhibitor treatment. On the basis of the HR-associated mutational signatures, 5% to 8% of localized prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).
Data from VLA4-Targeted Nanoparticles Hijack Cell Adhesion–Mediated Drug Resistance to Target Refractory Myeloma Cells and Prolong Survival
Authors: Fontana Francesca , Scott Michael J. , Allen John S. , Yang Xiaoxia , Cui Grace , Pan Dipanjan , Yanaba Noriko , Fiala Mark A. , O'Neal Julie , Schmieder-Atteberry Anne H. , Ritchey Julie , Rettig Michael , Simons Kathleen , Fletcher Steven , Vij Ravi , DiPersio John F. , Lanza Gregory M.
Published: April 2023

AbstractPurpose:
In multiple myeloma, drug-resistant cells underlie relapse or progression following chemotherapy. Cell adhesion–mediated drug resistance (CAM-DR) is an established mechanism used by myeloma cells (MMC) to survive chemotherapy and its markers are upregulated in residual disease. The integrin very late antigen 4 (VLA4; α4β1) is a key mediator of CAM-DR and its expression affects drug sensitivity of MMCs. Rather than trying to inhibit its function, here, we hypothesized that upregulation of VLA4 by resistant MMCs could be exploited for targeted delivery of drugs, which would improve safety and efficacy of treatments.
Experimental Design:
We synthetized 20 nm VLA4-targeted micellar nanoparticles (V-NP) carrying DiI for tracing or a novel camptothecin prodrug (V-CP). Human or murine MMCs, alone or with stroma, and immunocompetent mice with orthotopic multiple myeloma were used to track delivery of NPs and response to treatments.
Results:
V-NPs selectively delivered their payload to MMCs in vitro and in vivo, and chemotherapy increased their uptake by surviving MMCs. V-CP, alone or in combination with melphalan, was well tolerated and prolonged survival in myeloma-bearing mice. V-CP also reduced the dose requirement for melphalan, reducing tumor burden in association with suboptimal dosing without increasing overall toxicity.
Conclusions:
V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer.
Data from Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
Authors: Kim Seok-Young , Kim Sang-Min , Lim Sumin , Lee Ji Yeon , Choi Su-Jin , Yang San-Duk , Yun Mi Ran , Kim Chang Gon , Gu Seo Rin , Park Chaewon , Park A-Young , Lim Sun Min , Heo Seong Gu , Kim HyunKi , Cho Byoung Chul
Published: April 2023

AbstractPurpose:
Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets.
Experimental Design:
Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (n = 12). Organoids were analyzed by whole-exome sequencing (n = 61) and RNA sequencing (n = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts.
Results:
PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non–small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an EGFR exon 19 deletion and a BRAF G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an EGFR L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against ERBB2 exon 20 insertions and pralsetinib against RET fusions.
Conclusions:
We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.
Data from Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)
Authors: Foster Jennifer H. , Voss Stephan D. , Hall David C. , Minard Charles G. , Balis Frank M. , Wilner Keith , Berg Stacey L. , Fox Elizabeth , Adamson Peter C. , Blaney Susan M. , Weigel Brenda J. , Mossé Yael P.
Published: April 2023

AbstractPurpose:
Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration.
Patients and Methods:
Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the antitumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study.
Results:
The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count.
Conclusions:
Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity.

See related commentary by Schulte and Eggert, p. 3507
Data from The FDA Oncology Center of Excellence Scientific Collaborative: Charting a Course for Applied Regulatory Science Research in Oncology
Authors: Schneider Julie A. , Gong Yutao , Goldberg Kirsten B. , Kluetz Paul G. , Theoret Marc R. , Amiri-Kordestani Laleh , Beaver Julia A. , Fashoyin-Aje Lola , Gormley Nicole J. , Jaigirdar Adnan A. , Lemery Steven J. , Mishra-Kalyani Pallavi S. , Reaman Gregory H. , Rivera Donna R. , Rubinstein Wendy S. , Singh Harpreet , Sridhara Rajeshwari , Pazdur Richard
Published: April 2023

Abstract
The FDA Oncology Center of Excellence (OCE) is a leader within the agency in scientific outreach activities and regulatory science research. On the basis of analysis of scientific workshops, internal meetings, and publications, the OCE identified nine scientific priority areas and one cross-cutting area of high interest for collaboration with external researchers. This article describes the process for identifying these scientific interest areas and highlights funded and unfunded opportunities for external researchers to work with FDA staff on critical regulatory science challenges.
Data from Organoid Platform in Preclinical Investigation of Personalized Immunotherapy Efficacy in Appendiceal Cancer: Feasibility Study
Authors: Forsythe Steven D. , Erali Richard A. , Sasikumar Shyama , Laney Preston , Shelkey Ethan , D'Agostino Ralph , Miller Lance D. , Shen Perry , Levine Edward A. , Soker Shay , Votanopoulos Konstantinos I.
Published: April 2023

AbstractPurpose:
Immunotherapy efficacy data on appendiceal cancer from clinical trials does not exist, due to appendiceal cancer incidence of 0.97 per 100,000. The goal of this study was to preclinically explore the application of immunotherapy in treating appendiceal cancer in a personalized organoid model.
Experimental Design:
Patient tumor organoids (PTO) were fabricated using unsorted tumor cells with and without enrichment with patient-matched immune components derived from peripheral blood leukocytes, spleen, or lymph nodes [immune-enhanced PTOs (iPTO)]. Organoids were cultured for 7 days, followed by treatment with immunotherapy (pembrolizumab, ipilimumab, nivolumab), and assessed for treatment efficacy.
Results:
Between September 2019 and May 2021, 26 patients were enrolled in the study. Successful testing was conducted in 19 of 26 (73.1%) patients, with 13 of 19 (68.4%) and 6 of 19 (31.6%) patients having low-grade appendiceal (LGA) and high-grade appendiceal (HGA) primaries, respectively. Immunotherapy response, with increased expression of granzyme B and cleaved caspase 3 and decreased expression of CK20 and ATP activity, was exhibited in 4 of 19 (21.1%) pembrolizumab-treated and 2 of 19 (10.5%) nivolumab-treated iPTOs. Post-immunotherapy cellular viability, in responding HGA organoids to pembrolizumab, decreased to less than 15% (P < 0.05). LGA iPTO treatment responses were observed in pembrolizumab and nivolumab, with an 8%–47.4% (P < 0.05) viability compared with controls. Ipilimumab showed no efficacy in the examined cohort.
Conclusions:
Immunotherapy shows measurable efficacy in appendiceal cancer organoids. Information derived from immunocompetent organoids may be applied in selecting patients for clinical trial enrollment in rare diseases where preclinical models of disease are lacking.
Data from Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas
Authors: Shoushtari Alexander N. , Chatila Walid K. , Arora Arshi , Sanchez-Vega Francisco , Kantheti Havish S. , Rojas Zamalloa Jorge A. , Krieger Penina , Callahan Margaret K. , Betof Warner Allison , Postow Michael A. , Momtaz Parisa , Nair Suresh , Ariyan Charlotte E. , Barker Christopher A. , Brady Mary Susan , Coit Daniel G. , Rosen Neal , Chapman Paul B. , Busam Klaus J. , Solit David B. , Panageas Katherine S. , Wolchok Jedd D. , Schultz Nikolaus
Published: April 2023

AbstractPurpose:
Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown.
Experimental Design:
Patients with melanoma were prospectively offered tumor sequencing of 341–468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables.
Results:
A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P < 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months.
Conclusions:
Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor–refractory melanoma.
Data from Delta-24-RGD, an Oncolytic Adenovirus, Increases Survival and Promotes Proinflammatory Immune Landscape Remodeling in Models of AT/RT and CNS-PNET
Authors: Garcia-Moure Marc , Gonzalez-Huarriz Marisol , Labiano Sara , Guruceaga Elizabeth , Bandres Eva , Zalacain Marta , Marrodan Lucia , de Andrea Carlos , Villalba Maria , Martinez-Velez Naiara , Laspidea Virginia , Puigdelloses Montse , Gallego Perez-Larraya Jaime , Iñigo-Marco Ignacio , Stripecke Renata , Chan Jennifer A. , Raabe Eric H. , Kool Marcel , Gomez-Manzano Candelaria , Fueyo Juan , Patiño-García Ana , Alonso Marta M.
Published: April 2023

AbstractPurpose:
Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells.
Experimental Design:
Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in vitro in a battery of CNS-PNET and AT/RT cell lines. In vivo, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34+-NSG-SGM3).
Results:
Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC50 value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. In vivo, a single intratumoral Delta-24-RGD injection (107 or 108 PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD–treated tumors revealed increased CD8+ T-cell infiltration.
Conclusions:
Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.
Data from Detection of Molecular Signatures of Homologous Recombination Deficiency in Bladder Cancer
Authors: Börcsök Judit , Diossy Miklos , Sztupinszki Zsofia , Prosz Aurel , Tisza Viktoria , Spisak Sandor , Rusz Orsolya , Stormoen Dag R. , Pappot Helle , Csabai Istvan , Brunak Søren , Mouw Kent W. , Szallasi Zoltan
Published: April 2023

AbstractPurpose:
Poly (ADP ribose)-polymerase (PARP) inhibitors are approved for use in breast, ovarian, prostate, and pancreatic cancers, which are the solid tumor types that most frequently have alterations in key homologous recombination (HR) genes, such as BRCA1/2. However, the frequency of HR deficiency (HRD) in other solid tumor types, including bladder cancer, is less well characterized.
Experimental Design:
Specific DNA aberration profiles (mutational signatures) are induced by HRD, and the presence of these “genomic scars” can be used to assess the presence or absence of HRD in a given tumor biopsy even in the absence of an observed alteration of an HR gene. Using whole-exome and whole-genome data, we measured various HRD-associated mutational signatures in bladder cancer.
Results:
We found that a subset of bladder tumors have evidence of HRD. In addition to a small number of tumors with biallelic BRCA1/2 events, approximately 10% of bladder tumors had significant evidence of HRD-associated mutational signatures. Increased levels of HRD signatures were associated with promoter methylation of RBBP8, which encodes CtIP, a key protein involved in HR.
Conclusions:
A subset of bladder tumors have genomic features suggestive of HRD and therefore may be more likely to benefit from therapies such as platinum agents and PARP inhibitors that target tumor HRD.
Data from HAND1 and BARX1 Act as Transcriptional and Anatomic Determinants of Malignancy in Gastrointestinal Stromal Tumor
Authors: Hemming Matthew L. , Coy Shannon , Lin Jia-Ren , Andersen Jessica L. , Przybyl Joanna , Mazzola Emanuele , Abdelhamid Ahmed Amr H. , van de Rijn Matt , Sorger Peter K. , Armstrong Scott A. , Demetri George D. , Santagata Sandro
Published: April 2023

AbstractPurpose:
Gastrointestinal stromal tumor (GIST) arises from interstitial cells of Cajal (ICC) or their precursors, which are present throughout the gastrointestinal tract. Although gastric GIST is commonly indolent and small intestine GIST more aggressive, a molecular understanding of disease behavior would inform therapy decisions in GIST. Although a core transcription factor (TF) network is conserved across GIST, accessory TFs HAND1 and BARX1 are expressed in a disease state-specific pattern. Here, we characterize two divergent transcriptional programs maintained by HAND1 and BARX1, and evaluate their association with clinical outcomes.
Experimental Design:
We evaluated RNA sequencing and TF chromatin immunoprecipitation with sequencing in GIST samples and cultured cells for transcriptional programs associated with HAND1 and BARX1. Multiplexed tissue-based cyclic immunofluorescence and IHC evaluated tissue- and cell-level expression of TFs and their association with clinical factors.
Results:
We show that HAND1 is expressed in aggressive GIST, modulating KIT and core TF expression and supporting proliferative cellular programs. In contrast, BARX1 is expressed in indolent and micro-GISTs. HAND1 and BARX1 expression were superior predictors of relapse-free survival, as compared with standard risk stratification, and they predict progression-free survival on imatinib. Reflecting the developmental origins of accessory TF programs, HAND1 was expressed solely in small intestine ICCs, whereas BARX1 expression was restricted to gastric ICCs.
Conclusions:
Our results define anatomic and transcriptional determinants of GIST and molecular origins of clinical phenotypes. Assessment of HAND1 and BARX1 expression in GIST may provide prognostic information and improve clinical decisions on the administration of adjuvant therapy.
Data from KRAS Inhibitor Resistance in MET-Amplified KRASG12C Non–Small Cell Lung Cancer Induced By RAS- and Non–RAS-Mediated Cell Signaling Mechanisms
Authors: Suzuki Shinichiro , Yonesaka Kimio , Teramura Takeshi , Takehara Toshiyuki , Kato Ryoji , Sakai Hitomi , Haratani Koji , Tanizaki Junko , Kawakami Hisato , Hayashi Hidetoshi , Sakai Kazuko , Nishio Kazuto , Nakagawa Kazuhiko
Published: April 2023

AbstractPurpose:
Treatment with KRASG12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non–small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRASG12C NSCLC cells.
Experimental Design:
Clones of sotorasib-sensitive KRASG12C NSCLC H23 cells exposed to different concentrations of sotorasib were examined using whole-genomic transcriptome analysis, multiple receptor kinase phosphorylation analysis, and gene copy-number evaluation. The underlying mechanisms of resistance were investigated using immunologic examination, and a treatment aimed at overcoming resistance was tested in vitro and in vivo.
Results:
Unbiased screening detected subclonal evolution of MET amplification in KRASG12C NSCLC cells that had developed resistance to sotorasib in vitro. MET knockdown using small interfering RNA (siRNA) restored susceptibility to sotorasib in these resistant cells. MET activation by its amplification reinforced RAS cycling from its inactive form to its active form. In addition to RAS-mediated MEK–ERK induction, MET induced AKT activation independently of RAS. Crizotinib, a MET inhibitor, restored sensitivity to sotorasib by eliminating RAS–MEK–ERK as well as AKT signaling. MET/KRASG12C dual inhibition led to tumor shrinkage in sotorasib-resistant xenograft mice.
Conclusions:
MET amplification leads to the development of resistance to KRASG12C inhibitors in NSCLC. Dual blockade of MET and KRASG12C could be a treatment option for MET-amplified, KRASG12C-mutated NSCLC.