Featured
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Article |
A spatial architecture-embedding HLA signature to predict clinical response to immunotherapy in renal cell carcinoma
Multiomics and spatial mapping of tumor samples derived from a real-world cohort of patients with advanced renal cell carcinoma, as well as integration of transcriptomics and human leukocyte antigen genotyping data, provides a machine learning-derived signature of response to immune checkpoint blockade.
- Lisa Kinget
- , Stefan Naulaerts
- & Abhishek D. Garg
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Article
| Open Access
Pemigatinib in previously treated solid tumors with activating FGFR1–FGFR3 alterations: phase 2 FIGHT-207 basket trial
In a tumor-agnostic phase 2 basket trial, the oral FGFR1–FGFR3 inhibitor pemigatinib elicits responses in tumor types beyond cholangiocarcinoma and bladder cancer and in tumor types with rarer FGFR alterations, with insights provided into resistance mechanisms.
- Jordi Rodón
- , Silvia Damian
- & Lipika Goyal
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Article
| Open Access
First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial
In the homologous recombination repair-deficient population of TALAPRO-2, a placebo-controlled phase 3 trial, treatment of patients with metastatic castration-resistant prostate cancer with the poly(ADP-ribose) polymerase inhibitor talazoparib plus enzalutamide led to prolonged progression-free survival compared with placebo plus enzalutamide.
- Karim Fizazi
- , Arun A. Azad
- & Neeraj Agarwal
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News & Views |
Organ-sparing precision treatment for muscle-invasive bladder cancer
The response to neoadjuvant treatment can be used to stratify individuals with muscle-invasive bladder cancer according to their risk of progression, enabling bladder-sparing approaches for some — and heralding a shift from the existing one-size-fits-all approach.
- Roger Li
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Article
| Open Access
Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial
In a phase 2 trial, the combination of gemcitabine, cisplatin and anti-PD-1 led to a clinical complete response in 43% of patients with muscle-invasive bladder cancer, which facilitated bladder sparing and was associated with long-term bladder-intact metastasis-free survival.
- Matthew D. Galsky
- , Siamak Daneshmand
- & Sumanta K. Pal
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Article
| Open Access
Genetically adjusted PSA levels for prostate cancer screening
Analyses of large population-based cohorts and clinical trials show that using polygenic scores to account for variability in PSA levels improves detection of prostate cancer, suggesting an approach for enhancing screening accuracy.
- Linda Kachuri
- , Thomas J. Hoffmann
- & John S. Witte
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Article |
Neoadjuvant enoblituzumab in localized prostate cancer: a single-arm, phase 2 trial
In a single-arm phase 2 study, enoblituzumab (a humanized, Fc-engineered, B7-H3-targeting antibody) was found to be safe and showed preliminary evidence of potential clinical activity in men with high-risk localized prostate cancer.
- Eugene Shenderov
- , Angelo M. De Marzo
- & Emmanuel S. Antonarakis
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Brief Communication |
High- or low-dose preoperative ipilimumab plus nivolumab in stage III urothelial cancer: the phase 1B NABUCCO trial
High-dose ipilimumab plus nivolumab in locoregionally advanced urothelial cancer led to a higher pathological complete response rate than low-dose ipilimumab in cohort 2. Presurgical absence of plasma (but not urinary) circulating tumor DNA correlated with clinical outcome.
- Jeroen van Dorp
- , Christodoulos Pipinikas
- & Michiel S. van der Heijden
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Article |
PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial
CAR T cells targeting PSMA and engineered to be resistant to immunosuppressive TGFβ signaling exhibit dose-dependent toxicity and expansion following infusion, with some transient antitumor activity, in patients with metastatic castration-resistant prostate cancer
- Vivek Narayan
- , Julie S. Barber-Rotenberg
- & Naomi B. Haas
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News & Views |
A probiotic supplement boosts response to cancer immunotherapy
Patients with kidney cancer who took probiotic supplements of Clostridium butyricum had improved response to immunotherapy, according to a randomized phase 1 study.
- Lisa Derosa
- & Laurence Zitvogel
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Article
| Open Access
Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial
A randomized trial in treatment-naive patients with metastatic renal cell carcinoma shows that the addition of a live bacterial product to an immunotherapy combination elicits promising clinical benefit in association with an enrichment of bacterial species, circulating cytokines and immune cell populations in responders.
- Nazli Dizman
- , Luis Meza
- & Sumanta K. Pal
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Article
| Open Access
Artificial intelligence for diagnosis and Gleason grading of prostate cancer: the PANDA challenge
Through a community-driven competition, the PANDA challenge provides a curated diverse dataset and a catalog of models for prostate cancer pathology, and represents a blueprint for evaluating AI algorithms in digital pathology.
- Wouter Bulten
- , Kimmo Kartasalo
- & Jeonghyuk Park
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Article |
Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial
In the phase 3 IMbassador250 clinical trial, a checkpoint immunotherapy combination with enzalutamide did not improve survival over enzalutamide alone in patients with metastatic castration-resistant prostate cancer whose disease progressed on abiraterone. The study uncovered genomic and immune biomarkers that may identify patients deriving benefit.
- Thomas Powles
- , Kobe C. Yuen
- & Christopher J. Sweeney
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Article |
Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial
Biomarker analysis of the phase 3 JAVELIN Bladder 100 trial leads to the development of a multi-parameter model comprising tumor and immune features that might identify patients with advanced urothelial cancer who will benefit from avelumab maintenance therapy.
- Thomas Powles
- , Srikala S. Sridhar
- & Craig B. Davis
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Research Highlight |
Hormone-producing bacteria drive prostate cancer
During androgen-deprivation therapy, certain bacteria in the gut can synthesize androgens, thereby promoting tumor progression and therapy resistance.
- Karen O’Leary
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Letter |
An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer
The adaptive, biomarker-driven BISCAY trial evaluating durvalumab with targeted agents in patients with metastatic urothelial carcinoma based on tumor genomic alterations finds no added clinical benefit over durvalumab monotherapy.
- Thomas Powles
- , Danielle Carroll
- & Dónal Landers
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Letter |
Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis
A first-in-human trial of hypoxia-inducible factor (HIF)-2α inhibitor belzutifan (MK-6482) has a favorable safety profile and shows promising clinical activity for the treatment of patients with renal cell carcinoma who have been heavily pre-treated.
- Toni K. Choueiri
- , Todd M. Bauer
- & Eric Jonasch
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Letter
| Open Access
Transcriptional mediators of treatment resistance in lethal prostate cancer
Single-cell transcriptomic analysis of metastatic castration-resistant prostate cancer uncovers pervasive coexpression of androgen receptor isoforms and cancer cell–intrinsic and microenvironmental programs of treatment resistance
- Meng Xiao He
- , Michael S. Cuoco
- & Eliezer M. Van Allen
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Letter |
Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial
Neoadjuvant immunotherapy combination in the NABUCCO trial elicits high pathological complete response rates in patients with locoregionally advanced (stage III) urothelial cancer and provides molecular biomarkers of treatment efficacy.
- Nick van Dijk
- , Alberto Gil-Jimenez
- & Michiel S. van der Heijden
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Letter |
Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma
Neoadjuvant combination of immune checkpoint therapy in patients with cisplatin-ineligible bladder cancer achieves clinical efficacy and uncovers immune features as potential predictive biomarkers of treatment response.
- Jianjun Gao
- , Neema Navai
- & Padmanee Sharma
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Perspective |
Targeting the HIF2–VEGF axis in renal cell carcinoma
Anticancer therapies that target the HIF oxygen-sensing pathways are moving into the clinic, in particular in kidney cancer.
- Toni K. Choueiri
- & William G. Kaelin Jr
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Article |
Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial
Biomarker analysis of the phase 3 JAVELIN Renal 101 trial uncovers molecular determinants of therapy-specific outcomes, which may inform personalized treatment strategies for patients with advanced renal cell carcinoma.
- Robert J. Motzer
- , Paul B. Robbins
- & Toni K. Choueiri
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Brief Communication |
Detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes
A cell-free DNA-methylation sequencing assay accurately identifies renal cell carcinoma using plasma and urine samples.
- Pier Vitale Nuzzo
- , Jacob E. Berchuck
- & Matthew L. Freedman
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Article |
Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma
A pooled genetic, transcriptomic and immunopathologic analysis of over 500 tumors from patients with advanced renal cell cancer suggests that response to PD-1 blockade depends on both CD8+ T cell infiltration and enrichment of tumor-intrinsic somatic alterations.
- David A. Braun
- , Yue Hou
- & Toni K. Choueiri
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Letter |
High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade
In a retrospective analysis of data from three clinical trials, increased baseline peripheral and tumor IL-8 levels were associated with worse clinical outcomes in patients with metastatic urothelial carcinoma and metastatic renal cell carcinoma treated with anti-PD-L1 therapy.
- Kobe C. Yuen
- , Li-Fen Liu
- & Sanjeev Mariathasan
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Brief Communication |
Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors
In a retrospective analysis of data from four phase 3 clinical trials, elevated baseline serum IL-8 levels were associated with worse clinical outcomes in patients with multiple tumor types treated with anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combinatorial therapy.
- Kurt A. Schalper
- , Michael Carleton
- & Ignacio Melero
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Letter |
Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers
In a large and prospective cohort, higher polygenic risk is associated with higher risk and earlier age of onset for cardiometabolic disorders and cancer, and has added value to clinical risk scores in clinical disease prediction.
- Nina Mars
- , Jukka T. Koskela
- & Samuli Ripatti
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News & Views |
Biomarkers for neoadjuvant checkpoint blockade response in urothelial cancer
Activated CD8+ T cells in the tumor and cytotoxic T cell signature correlate with immune response in patients receiving neoadjuvant immunotherapy for treatment of muscle invasive bladder cancer.
- Pooja Ghatalia
- & Elizabeth Plimack
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Letter |
Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial
A single-arm multicenter phase 2 trial demonstrates clinical efficacy of neoadjuvant PD-L1 blockade in patients with resectable muscle-invasive bladder cancer ineligible for cisplatin and examines biomarkers associated with patient outcome.
- Thomas Powles
- , Mark Kockx
- & Daniel Castellano
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Resource |
Genome-wide germline correlates of the epigenetic landscape of prostate cancer
Genetic variants in the germ line modulate DNA methylation in tumors and contribute to the aggressiveness of prostate cancer.
- Kathleen E. Houlahan
- , Yu-Jia Shiah
- & Paul C. Boutros
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Letter |
Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression
Inhibition of histone and DNA methyltransferase activity enhances sensitivity to platinum-based and immunotherapy in a novel transgenic mouse model of metastatic bladder cancer.
- Cristina Segovia
- , Edurne San José-Enériz
- & Jesús M. Paramio
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Article |
ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis
ONECUT2 is a targetable transcription factor that antagonizes androgen receptor signaling and drives androgen independence and neuroendocrine differentiation in castration-resistant prostate cancer.
- Mirja Rotinen
- , Sungyong You
- & Michael R. Freeman
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Article |
Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma
An exploratory randomized controlled clinical trial of renal cell carcinoma identifies molecular patterns distinguishing responders to immune checkpoint blockade alone or combined with angiogenesis inhibitor versus angiogenesis inhibitor alone.
- David F. McDermott
- , Mahrukh A. Huseni
- & Thomas Powles
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Article |
Diverse genetic-driven immune landscapes dictate tumor progression through distinct mechanisms
Pier Paolo Pandolfi and colleagues report that the genetic background of tumors in mice recruits specific immune-cell subsets, suggesting that precision medicine should account for both the tumor drivers and the distinct immune-cell microenvironments that they elicit.
- Marco Bezzi
- , Nina Seitzer
- & Pier Paolo Pandolfi
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News & Views |
SPOP tips the balance of BETs in cancer
Cancer-associated mutations in speckle-type POZ (pox virus and zinc-finger) protein confer neomorphic activity, altering its substrate affinities and its response to bromodomain and extraterminal inhibitors in prostate and endometrial cancer.
- Katie A Fennell
- & Mark A Dawson
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News & Views |
A mouse model of renal cell carcinoma
A mouse model with combined renal epithelium-specific deletion of Vhl, Trp53 and Rb1 that develops clear-cell renal cell carcinoma provides a research tool for investigating the mechanisms that drive this cancer, and for evaluating the efficacy of novel therapeutic agents.
- Laura S Schmidt
- & W Marston Linehan
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Perspective |
Biology and evolution of poorly differentiated neuroendocrine tumors
Rubin and colleagues discuss the origin and evolution of poorly differentiated neuroendocrine tumors, and highlight potential new therapeutic strategies.
- David S Rickman
- , Himisha Beltran
- & Mark A Rubin
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Article |
Combined mutation in Vhl, Trp53 and Rb1 causes clear cell renal cell carcinoma in mice
Through combined deletion of Vhl, Trp53 and Rb1 in renal epithelial cells, the authors develop a new mouse model of renal cell carcinoma that recapitulates the cellular and molecular features of a large proportion of human tumors. This model uncovers a role for primary-cilium-related genes in the development of the disease and provides a reliable platform for preclinical therapeutic studies.
- Sabine Harlander
- , Désirée Schönenberger
- & Ian J Frew
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News Feature |
Shapeshifters in cancer: How some tumor cells change phenotype to evade therapy
- Amanda B Keener
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Article |
ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer
ROR-γ antagonists suppress androgen receptor expression and growth of prostate tumors, but not of androgen-responsive healthy tissue, in preclinical models.
- Junjian Wang
- , June X Zou
- & Hong-Wu Chen
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Article |
Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer
Genomic analysis of a single metastasis informs about the oncogenic—and potentially druggable—genomic alterations present in other tumors within the same man with metastatic prostate cancer.
- Akash Kumar
- , Ilsa Coleman
- & Peter S Nelson
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Letter |
Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer
Genome-wide DNA methylation analysis of metastatic biopsies from patients with castration-resistant prostate cancer reveals marked epigenetic differences between samples with adenocarcinoma and neuroendocrine histologies.
- Himisha Beltran
- , Davide Prandi
- & Francesca Demichelis
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Technical Report |
CAUSEL: an epigenome- and genome-editing pipeline for establishing function of noncoding GWAS variants
A pipeline incorporating genetic fine mapping, epigenome editing, and genome editing enables functional analysis of disease-associated SNPs located in non-protein-coding regions of the genome.
- Sándor Spisák
- , Kate Lawrenson
- & Matthew L Freedman
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Letter |
A new tumor suppressor role for the Notch pathway in bladder cancer
Rampias et al. report that inactivating mutations in Notch pathway components are frequent in human bladder cancer and drive bladder tumorigenesis in mice.
- Theodoros Rampias
- , Paraskevi Vgenopoulou
- & Apostolos Klinakis
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Article |
Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer
Whether the molecular drivers of tumor initiation are the same factors that promote metastasis during tumor progression is addressed in this report. In renal carcinoma, common primary driving alterations such as VHL loss do not necessarily correlate with outcome, and the authors show that additional epigenetic adaptations are required to unleash prometastatic behavior. Two important metastastic drivers, CXCR4 and CYTIP, are activated downstream of VHL loss through epigenetic reprogramming involving differential chromatin modification or DNA methylation, exemplifying the complex evolution of tumorigenic traits downstream of driving alterations.
- Sakari Vanharanta
- , Weiping Shu
- & Joan Massagué
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Technical Report |
Annotating MYC status with 89Zr-transferrin imaging
By exploiting the relationship between the transcription factor MYC and the transferrin receptor, where the level of transferrin receptor 1 expression may indicate activation of the MYC oncogenic pathway, Jason Holland and his colleagues have developed a novel PET radiotracer to quantitatively and noninvasively measure MYC activity. The 89Zr-desferrioxamine transferrin PET radiotracer was tested in several murine models of inflammation and MYC-driven prostate cancer.
- Jason P Holland
- , Michael J Evans
- & Jason S Lewis
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Article |
Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B
Responses to anticancer therapy are hampered by several factors, and Peter S. Nelson and colleagues here identify a protective effect of the tumor microenvironment. After cytotoxic chemotherapy, inflammatory NF-κB signaling activates the secretion of WNT16B, which acts on epithelial cells, promoting their survival and fostering tumor growth in vivo. This pathway is also active in human tumors treated with chemotherapy and illustrates the potential caveats of cyclical therapy and the need to overcome environmental protection to successfully eliminate tumors.
- Yu Sun
- , Judith Campisi
- & Peter S Nelson
Arrests reveal debate about costs and benefits of proton therapy
Early-stage therapies target surgery-induced erectile dysfunction