bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Safety and Clinical Activity of a New Anti-PD-L1 Antibody as Monotherapy or Combined with Targeted Therapy in Advanced Solid Tumors: The PACT Phase Ia/Ib Trial
Authors: Patnaik Amita , Yap Timothy A. , Chung Hyun Cheol , de Miguel Maria J. , Bang Yung-Jue , Lin Chia-Chi , Su Wu-Chou , Italiano Antoine , Chow Kay Hoong , Szpurka Anna M. , Yu Danni , Zhao Yumin , Carlsen Michelle , Schmidt Shelly , Vangerow Burkhard , Gandhi Leena , Xu Xiaojian , Bendell Johanna
Published: April 2023

AbstractPurpose:
This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334).
Patients and Methods:
Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy (N = 15) or combined with ramucirumab (N = 10), abemaciclib (N = 24), or merestinib (N = 12). The phase Ib dose expansion enrolled 8 patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety.
Results:
Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months.
Conclusions:
LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens.
Data from Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non–Small Cell Lung Cancer
Authors: Zhang Jiajia , Ji Zhicheng , Caushi Justina X. , El Asmar Margueritta , Anagnostou Valsamo , Cottrell Tricia R. , Chan Hok Yee , Suri Prerna , Guo Haidan , Merghoub Taha , Chaft Jamie E. , Reuss Joshua E. , Tam Ada J. , Blosser Richard L. , Abu-Akeel Mohsen , Sidhom John-William , Zhao Ni , Ha Jinny S. , Jones David R. , Marrone Kristen A. , Naidoo Jarushka , Gabrielson Edward , Taube Janis M. , Velculescu Victor E. , Brahmer Julie R. , Housseau Franck , Hellmann Matthew D. , Forde Patrick M. , Pardoll Drew M. , Ji Hongkai , Smith Kellie N.
Published: April 2023

AbstractPurpose:
Neoadjuvant PD-1 blockade is a promising treatment for resectable non–small cell lung cancer (NSCLC), yet immunologic mechanisms contributing to tumor regression and biomarkers of response are unknown. Using paired tumor/blood samples from a phase II clinical trial (NCT02259621), we explored whether the peripheral T-cell clonotypic dynamics can serve as a biomarker for response to neoadjuvant PD-1 blockade.
Experimental Design:
T-cell receptor (TCR) sequencing was performed on serial peripheral blood, tumor, and normal lung samples from resectable NSCLC patients treated with neoadjuvant PD-1 blockade. We explored the temporal dynamics of the T-cell repertoire in the peripheral and tumoral compartments in response to neoadjuvant PD-1 blockade by using the TCR as a molecular barcode.
Results:
Higher intratumoral TCR clonality was associated with reduced percent residual tumor at the time of surgery, and the TCR repertoire of tumors with major pathologic response (MPR; <10% residual tumor after neoadjuvant therapy) had a higher clonality and greater sharing of tumor-infiltrating clonotypes with the peripheral blood relative to tumors without MPR. Additionally, the posttreatment tumor bed of patients with MPR was enriched with T-cell clones that had peripherally expanded between weeks 2 and 4 after anti–PD-1 initiation and the intratumoral space occupied by these clonotypes was inversely correlated with percent residual tumor.
Conclusions:
Our study suggests that exchange of T-cell clones between tumor and blood represents a key correlate of pathologic response to neoadjuvant immunotherapy and shows that the periphery may be a previously underappreciated originating compartment for effective antitumor immunity.

See related commentary by Henick, p. 1205
Data from FGFR Inhibition Overcomes Resistance to EGFR-targeted Therapy in Epithelial-like Cutaneous Carcinoma
Authors: Bernat-Peguera Adrià , Navarro-Ventura Juan , Lorenzo-Sanz Laura , da Silva-Diz Victoria , Bosio Mattia , Palomero Luis , Penin Rosa M. , Pérez Sidelnikova Diana , Bermejo Josep Oriol , Taberna Miren , Vilariño Noelia , Piulats Josep M. , Mesia Ricard , Viñals Joan Maria , González-Suárez Eva , Capella-Gutierrez Salvador , Villanueva Alberto , Viñals Francesc , Muñoz Purificación
Published: April 2023

AbstractPurpose:
Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy, but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with patients with advanced and metastatic cSCC. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy.
Experimental Design:
We generated primary cell cultures and patient cSCC–derived xenografts (cSCC-PDXs) that recapitulate the histopathologic and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance.
Results:
cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal-like cSCCs. Gefitinib treatment strongly blocked epithelial-like cSCC-PDX growth in the absence of EGFR and RAS mutations, whereas tumors carrying the E545K PIK3CA-activating mutation were resistant to treatment. A subset of initially responding tumors acquired resistance after long-term treatment, which was induced by the bypass from EGFR to FGFR signaling to allow tumor cell proliferation and survival upon gefitinib treatment. Pharmacologic inhibition of FGFR signaling overcame resistance to EGFR inhibitor, even in PIK3CA-mutated tumors.
Conclusions:
EGFR-targeted therapy may be appropriate for treating many epithelial-like cSCCs without PIK3CA-activating mutations. Combined EGFR- and FGFR-targeted therapy may be used to treat cSCCs that show intrinsic or acquired resistance to EGFR inhibitors.
Data from BRAF-Mutant Transcriptional Subtypes Predict Outcome of Combined BRAF, MEK, and EGFR Blockade with Dabrafenib, Trametinib, and Panitumumab in Patients with Colorectal Cancer
Authors: Middleton Gary , Yang Yiqun , Campbell Catarina D. , André Thierry , Atreya Chloe E. , Schellens Jan H.M. , Yoshino Takayuki , Bendell Johanna C. , Hollebecque Antoine , McRee Autumn J. , Siena Salvatore , Gordon Michael S. , Tabernero Josep , Yaeger Rona , O'Dwyer Peter J. , De Vos Filip , Van Cutsem Eric , Millholland John M. , Brase Jan C. , Rangwala Fatima , Gasal Eduard , Corcoran Ryan B.
Published: April 2023

AbstractPurpose:
The influence of the transcriptional and immunologic context of mutations on therapeutic outcomes with targeted therapy in cancer has not been well defined. BRAF V600E–mutant (BM) colorectal cancer comprises two main transcriptional subtypes, BM1 and BM2. We sought to determine the impact of BM subtype, as well as distinct biological features of those subtypes, on response to BRAF/MEK/EGFR inhibition in patients with colorectal cancer.
Patients and Methods:
Paired fresh tumor biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM colorectal cancer enrolled in a phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS).
Results:
Confirmed response rates, median PFS, and median overall survival (OS) were higher in BM1 subtype patients compared with BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, whereas cell-cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell-cycle signatures revealed that BM subtype encompasses the majority of the effect.
Conclusions:
BM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context.
Data from Sequential Prostate Magnetic Resonance Imaging in Newly Diagnosed High-risk Prostate Cancer Treated with Neoadjuvant Enzalutamide is Predictive of Therapeutic Response
Authors: Karzai Fatima , Walker Stephanie M. , Wilkinson Scott , Madan Ravi A. , Shih Joanna H. , Merino Maria J. , Harmon Stephanie A. , VanderWeele David J. , Cordes Lisa M. , Carrabba Nicole V. , Bright John R. , Terrigino Nicolas T. , Chun Guinevere , Bilusic Marijo , Couvillon Anna , Hankin Amy , Williams Monique N. , Lis Rosina T. , Ye Huihui , Choyke Peter L. , Gulley James L. , Sowalsky Adam G. , Turkbey Baris , Pinto Peter A. , Dahut William L.
Published: April 2023

AbstractPurpose:
For high-risk prostate cancer, standard treatment options include radical prostatectomy (RP) or radiotherapy plus androgen deprivation therapy (ADT). Despite definitive therapy, many patients will have disease recurrence. Imaging has the potential to better define characteristics of response and resistance. In this study, we evaluated prostate multiparametric MRI (mpMRI) before and after neoadjuvant enzalutamide plus ADT.
Patients and Methods:
Men with localized intermediate- or high-risk prostate cancer underwent a baseline mpMRI and mpMRI-targeted biopsy followed by a second mpMRI after 6 months of enzalutamide and ADT prior to RP. Specimens were sectioned in the same plane as mpMRI using patient-specific 3D-printed molds to permit mpMRI-targeted biopsies to be compared with the same lesion from the RP. Specimens were analyzed for imaging and histologic correlates of response.
Results:
Of 39 patients enrolled, 36 completed imaging and RP. Most patients (92%) had high-risk disease. Fifty-eight lesions were detected on baseline mpMRI, of which 40 (69%) remained measurable at 6-month follow-up imaging. Fifty-five of 59 lesions (93%) demonstrated >50% volume reduction on posttreatment mpMRI. Three of 59 lesions (5%) demonstrated growth in size at follow-up imaging, with two lesions increasing more than 3-fold in volume. On whole-mount pathology, 15 patients demonstrated minimal residual disease (MRD) of <0.05 cc or pathologic complete response. Low initial mpMRI relative tumor burden was most predictive of MRD on final pathology.
Conclusions:
Low relative lesion volume at baseline mpMRI was predictive of pathologic response. A subset of patients had limited response. Selection of patients based on these metrics may improve outcomes in high-risk disease.
Data from Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion–Positive Lung Cancer
Authors: Lin Jessica J. , Choudhury Noura J. , Yoda Satoshi , Zhu Viola W. , Johnson Ted W. , Sakhtemani Ramin , Dagogo-Jack Ibiayi , Digumarthy Subba R. , Lee Charlotte , Do Andrew , Peterson Jennifer , Prutisto-Chang Kylie , Malik Wafa , Hubbeling Harper G. , Langenbucher Adam , Schoenfeld Adam J. , Falcon Christina J. , Temel Jennifer S. , Sequist Lecia V. , Yeap Beow Y. , Lennerz Jochen K. , Shaw Alice T. , Lawrence Michael S. , Ou Sai-Hong Ignatius , Hata Aaron N. , Drilon Alexander , Gainor Justin F.
Published: April 2023

AbstractPurpose:
Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion (ROS1)-positive (ROS1+) non–small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1+ NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1+ disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib.
Experimental Design:
Biopsies from patients with ROS1+ NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing.
Results:
From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, ROS1 mutations were identified in 38% and 46%, respectively. ROS1 G2032R was the most commonly occurring mutation in approximately one third of cases. Additional ROS1 mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1L2086F causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1L2086F, ROS1G2032R/L2086F, and ROS1S1986F/G2032R/L2086F were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and ROS1 L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified MET amplification (4%), KRAS G12C (4%), KRAS amplification (4%), NRAS mutation (4%), and MAP2K1 mutation (4%).
Conclusions:
ROS1 mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms.
Data from A Biparatopic Antibody That Modulates MET Trafficking Exhibits Enhanced Efficacy Compared with Parental Antibodies in MET-Driven Tumor Models
Authors: DaSilva John O. , Yang Katie , Perez Bay Andres E. , Andreev Julian , Ngoi Peter , Pyles Erica , Franklin Matthew C. , Dudgeon Drew , Rafique Ashique , Dore Anthony , Delfino Frank J. , Potocky Terra B. , Babb Robert , Chen Gang , MacDonald Douglas , Olson William C. , Thurston Gavin , Daly Christopher
Published: April 2023

AbstractPurpose:
Recent clinical data demonstrate that tumors harboring MET genetic alterations (exon 14 skip mutations and/or gene amplification) respond to small-molecule tyrosine kinase inhibitors, validating MET as a therapeutic target. Although antibody-mediated blockade of the MET pathway has not been successful in the clinic, the failures are likely the result of inadequate patient selection strategies as well as suboptimal antibody design. Thus, our goal was to generate a novel MET blocking antibody with enhanced efficacy.
Experimental Design:
Here, we describe the activity of a biparatopic MET×MET antibody that recognizes two distinct epitopes in the MET Sema domain. We use a combination of in vitro assays and tumor models to characterize the effect of our antibody on MET signaling, MET intracellular trafficking, and the growth of MET-dependent cells/tumors.
Results:
In MET-driven tumor models, our biparatopic antibody exhibits significantly better activity than either of the parental antibodies or the mixture of the two parental antibodies and outperforms several clinical-stage MET antibodies. Mechanistically, the biparatopic antibody inhibits MET recycling, thereby promoting lysosomal trafficking and degradation of MET. In contrast to the parental antibodies, the biparatopic antibody fails to activate MET-dependent biological responses, consistent with the observation that it recycles inefficiently and induces very transient downstream signaling.
Conclusions:
Our results provide strong support for the notion that biparatopic antibodies are a promising therapeutic modality, potentially having greater efficacy than that predicted from the properties of the parental antibodies.
Data from Efficacy of Decitabine plus Anti-PD-1 Camrelizumab in Patients with Hodgkin Lymphoma Who Progressed or Relapsed after PD-1 Blockade Monotherapy
Authors: Wang Chunmeng , Liu Yang , Dong Liang , Li Xiang , Yang Qingming , Brock Malcolm V. , Mei Qian , Liu Jiejie , Chen Meixia , Shi Fengxia , Liu Miao , Nie Jing , Han Weidong
Published: April 2023

AbstractPurpose:
Programmed death-1 (PD-1) blockade monotherapy is effective in relapsed/refractory classical Hodgkin lymphoma (cHL), but a subset of patients is recalcitrant to PD-1 inhibitors and only a minority of patients achieves durable remission. Effective treatment regimens for those with relapsed/progressive cHL after single-agent anti-PD-1 are urgently needed. Anti-PD-1 combination with the DNA-demethylating agent decitabine showed positive preliminary results in our test cohort patients who were resistant to anti-PD-1. Here, we assess the efficacy of decitabine plus anti-PD-1 therapy in an expansion cohort and after longer follow-up.
Patients and Methods:
We present the response and progression-free survival rates from patients with relapsed/refractory cHL who relapsed/progressed after prior anti-PD-1 monotherapy, and who received decitabine (10 mg/day, days 1–5) plus the anti-PD-1 camrelizumab (200 mg, day 8), every 3 weeks in a phase II trial (ClinicalTrials.gov: NCT02961101 and NCT03250962).
Results:
Overall, 51 patients (test cohort: 25, expansion cohort: 26) were treated and 50 evaluated for efficacy. The objective response rate was 52% [nine complete responses (CR); 36%] in the test cohort, and 68% (six CRs; 24%) in the expansion cohort. Median progression-free survival with decitabine plus camrelizumab was 20.0 and 21.6 months, respectively, which was significantly longer than that achieved with prior anti-PD-1 monotherapy. Durable response was observed in an estimated 78% of patients who achieved CR at 24 months. After decitabine plus camrelizumab, the ratio increase of circulating peripheral central memory T cells directly correlated with both clinical response and progression-free survival.
Conclusions:
Decitabine plus camrelizumab is associated with high response rates and long-term benefits in patients with relapsed/refractory cHL who failed PD-1 inhibitors.
Data from Therapeutic Efficacy of Combined JAK1/2, Pan-PIM, and CDK4/6 Inhibition in Myeloproliferative Neoplasms
Authors: Rampal Raajit K. , Pinzon-Ortiz Maria , Somasundara Amritha Varshini Hanasoge , Durham Benjamin , Koche Richard , Spitzer Barbara , Mowla Shoron , Krishnan Aishwarya , Li Bing , An Wenbin , Derkach Andriy , Devlin Sean , Rong Xianhui , Longmire Tyler , Eisman Shira Esther , Cordner Keith , Whitfield Justin T. , Vanasse Gary , Cao Zhu A. , Levine Ross L.
Published: April 2023

AbstractPurpose:
The JAK1/2 inhibitor ruxolitinib has demonstrated significant benefits for patients with myeloproliferative neoplasms (MPN). However, patients often lose response to ruxolitinib or suffer disease progression despite therapy with ruxolitinib. These observations have prompted efforts to devise treatment strategies to improve therapeutic efficacy in combination with ruxolitinib therapy. Activation of JAK–STAT signaling results in dysregulation of key downstream pathways, notably increased expression of cell-cycle mediators including CDC25A and the PIM kinases.
Experimental Design:
Given the involvement of cell-cycle mediators in MPNs, we sought to examine the efficacy of therapy combining ruxolitinib with a CDK4/6 inhibitor (LEE011) and a PIM kinase inhibitor (PIM447). We utilized JAK2-mutant cell lines, murine models, and primary MPN patient samples for these studies.
Results:
Exposure of JAK2-mutant cell lines to the triple combination of ruxolitinib, LEE011, and PIM447 resulted in expected on-target pharmacodynamic effects, as well as increased apoptosis and a decrease in the proportion of cells in S-phase, compared with ruxolitinib. As compared with ruxolitinib monotherapy, combination therapy led to reductions in spleen and liver size, reduction of bone marrow reticulin fibrosis, improved overall survival, and elimination of disease-initiating capacity of treated bone marrow, in murine models of MPN. Finally, the triple combination reduced colony formation capacity of primary MPN patient samples to a greater extent than ruxolitinib.
Conclusions:
The triple combination of ruxolitinib, LEE011, and PIM447 represents a promising therapeutic strategy with the potential to increase therapeutic responses in patients with MPN.
Data from Agrin in the Muscularis Mucosa Serves as a Biomarker Distinguishing Hyperplastic Polyps from Sessile Serrated Lesions
Authors: Rickelt Steffen , Condon Charlene , Mana Miyeko , Whittaker Charlie , Pfirschke Christina , Roper Jatin , Patil Deepa T. , Brown Ian , Mattia Anthony R. , Zukerberg Lawrence , Zhao Qing , Chetty Runjan , Lauwers Gregory Y. , Neyaz Azfar , Leijssen Lieve G.J. , Boylan Katherine , Yilmaz Omer H. , Deshpande Vikram , Hynes Richard O.
Published: April 2023

AbstractPurpose:
Sessile serrated lesions (SSL) are precursors to colon carcinoma, and their distinction from other polyps, in particular hyperplastic polyps (HP), presents significant diagnostic challenges. We evaluated expression patterns in colonic polyps of previously identified colon carcinoma–associated extracellular matrix (ECM) proteins to identify markers distinguishing SSLs from other polyps.
Experimental Design:
Gene-expression analyses of ECM proteins were performed using publicly available data on preneoplastic colonic polyps. In parallel, we evaluated by IHC the expression of agrin (AGRN) in over 400 colonic polyps, including HP, SSL with and without dysplasia, traditional serrated adenomas (TSA), and tubular adenomas (TA), and compared the consistency of standard histologic diagnosis of SSLs by experienced gastrointestinal pathologists with that of AGRN IHC.
Results:
Differential gene expression analysis and IHC identified AGRN, serine peptidase inhibitor (SERPINE2), and TIMP metallopeptidase inhibitor 1 (TIMP1) elevated in SSLs and HPs but decreased in TAs and absent in normal colon. AGRN-positive basal laminae were noted in all TA, TSA, HP, and SSL in distinguishable patterns, whereas other polyps and normal mucosa were negative. SSL with or without dysplasia consistently showed IHC staining for AGRN in the muscularis mucosae, which was absent in HP, TSA, TA, and other polyps. In contrast, histologic evaluation showed only weak interobserver agreement (kappa value = 0.493) in distinguishing SSLs.
Conclusions:
Muscularis mucosae–based AGRN immunostaining is a novel biomarker to distinguish SSL from HP, TSA, and TA, with a specificity of 97.1% and sensitivity of 98.9% and can assist in diagnosis of morphologically challenging colonic polyps.
Data from Single-Cell Analyses Reveal Mechanisms of Cancer Stem Cell Maintenance and Epithelial–Mesenchymal Transition in Recurrent Bladder Cancer
Authors: Wang Huanjun , Mei Yan , Luo Cheng , Huang Qun , Wang Zifeng , Lu Guan-Ming , Qin Lili , Sun Zhun , Huang Chao-Wen , Yang Zhi-Wen , Chen Junxing , Yin Weiguo , Qian Chao-Nan , Zeng Jianming , Chen Lingwu , Leng Qibin , Guo Yan , Jia Guangshuai
Published: April 2023

AbstractPurpose:
Bladder cancer treatment remains a major clinical challenge due to therapy resistance and a high recurrence rate. Profiling intratumor heterogeneity can reveal the molecular mechanism of bladder cancer recurrence.
Experimental Design:
Here, we performed single-cell RNA sequencing and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on tumors from 13 patients with low recurrence risk, high recurrence risk, and recurrent bladder cancer.
Results:
Our study generated a comprehensive cancer-cell atlas consisting of 54,971 single cells and identified distinct cell subpopulations. We found that the cancer stem-cell subpopulation is enriched during bladder cancer recurrence with elevated expression of EZH2. We further defined a subpopulation-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the NCAM1 gene, thereby inactivating the cell invasive and stemness transcriptional program. Furthermore, taking advantage of this large single-cell dataset, we elucidated the spectrum of epithelial–mesenchymal transition (EMT) in clinical samples and revealed distinct EMT features associated with bladder cancer subtypes. We identified that TCF7 promotes EMT in corroboration with single-cell ATAC with high-throughput sequencing (scATAC-seq) analysis. Additionally, we constructed regulatory networks specific to recurrent bladder cancer.
Conclusions:
Our study and analytic approaches herein provide a rich resource for the further study of cancer stem cells and EMT in the bladder cancer research field.
Data from Clinical Outcomes in Patients with Multi-Hit TP53 Chronic Lymphocytic Leukemia Treated with Ibrutinib
Authors: Brieghel Christian , Aarup Kathrine , Torp Mathias H. , Andersen Michael A. , Yde Christina W. , Tian Xin , Wiestner Adrian , Ahn Inhye E. , Niemann Carsten U.
Published: April 2023

AbstractPurpose:
TP53 aberration (TP53 mutation and/or 17p deletion) is the most important predictive marker in chronic lymphocytic leukemia (CLL). Although each TP53 aberration is considered an equal prognosticator, the prognostic value of carrying isolated (single-hit) or multiple (multi-hit) TP53 aberrations remains unclear, particularly in the context of targeted agents.
Patients and Methods:
We performed deep sequencing of TP53 using baseline samples collected from 51 TP53 aberrant patients treated with ibrutinib in a phase II study (NCT01500733).
Results:
We identified TP53 mutations in 43 patients (84%) and del(17p) in 47 (92%); 9 and 42 patients carried single-hit and multi-hit TP53, respectively. The multi-hit TP53 subgroup was enriched with younger patients who had prior treatments and unmutated immunoglobulin heavy-chain variable region gene status. We observed significantly shorter overall survival, progression-free survival (PFS), and time-to-progression (TTP) in patients with multi-hit TP53 compared with those with single-hit TP53. Clinical outcomes were similar in patient subgroups stratified by 2 or >2 TP53 aberrations. In multivariable analyses, multi-hit TP53 CLL was independently associated with inferior PFS and TTP. In sensitivity analyses, excluding mutations below 1% VAF demonstrated similar outcome. Results were validated in an independent population-based cohort of 112 patients with CLL treated with ibrutinib.
Conclusions:
In this study, single-hit TP53 defines a distinct subgroup of patients with an excellent long-term response to single-agent ibrutinib, whereas multi-hit TP53 is independently associated with shorter PFS. These results warrant further investigations on prognostication and management of multi-hit TP53 CLL.

See related commentary by Bomben et al., p. 4462
Data from Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer
Authors: Kazi Aslamuzzaman , Chen Liwei , Xiang Shengyan , Vangipurapu Rajanikanth , Yang Hua , Beato Francisca , Fang Bin , Williams Terence M. , Husain Kazim , Underwood Patrick , Fleming Jason B. , Malafa Mokenge , Welsh Eric A. , Koomen John , Trevino José , Sebti Saïd M.
Published: April 2023

AbstractPurpose:
Among human cancers that harbor mutant (mt) KRas, some, but not all, are dependent on mt KRas. However, little is known about what drives KRas dependency.
Experimental Design:
Global phosphoproteomics, screening of a chemical library of FDA drugs, and genome-wide CRISPR/Cas9 viability database analysis were used to identify vulnerabilities of KRas dependency.
Results:
Global phosphoproteomics revealed that KRas dependency is driven by a cyclin-dependent kinase (CDK) network. CRISPR/Cas9 viability database analysis revealed that, in mt KRas-driven pancreatic cancer cells, knocking out the cell-cycle regulators CDK1 or CDK2 or the transcriptional regulators CDK7 or CDK9 was as effective as knocking out KRas. Furthermore, screening of a library of FDA drugs identified AT7519, a CDK1, 2, 7, and 9 inhibitor, as a potent inducer of apoptosis in mt KRas-dependent, but not in mt KRas-independent, human cancer cells. In vivo AT7519 inhibited the phosphorylation of CDK1, 2, 7, and 9 substrates and suppressed growth of xenografts from 5 patients with pancreatic cancer. AT7519 also abrogated mt KRas and mt p53 primary and metastatic pancreatic cancer in three-dimensional (3D) organoids from 2 patients, 3D cocultures from 8 patients, and mouse 3D organoids from pancreatic intraepithelial neoplasia, primary, and metastatic tumors.
Conclusions:
A link between CDK hyperactivation and mt KRas dependency was uncovered and pharmacologically exploited to abrogate mt KRas-driven pancreatic cancer in highly relevant models, warranting clinical investigations of AT7519 in patients with pancreatic cancer.
Data from Genomic Landscape and Tumor Mutational Burden Determination of Circulating Tumor DNA in Over 5,000 Chinese Patients with Lung Cancer
Authors: Shi Jie , Wang Zhiyu , Zhang Junping , Xu Yaping , Xiao Xiao , Quan Xiangming , Bai Ying , Yang Xia , Ming Zongjuan , Guo Xiaojin , Feng Huijing , Yang Xiaoling , Zhuang Xiaofei , Han Fei , Wang Kai , Shi Yonglei , Lei Yu , Bai Jun , Yang Shuanying
Published: April 2023

AbstractPurpose:
Having emerged as a noninvasive and clinically applicable approach for molecular determination of lung cancer, a genomic overview of circulating tumor DNA (ctDNA) of large-scale cohort may be helpful in novel biomarker development and therapeutic innovation.
Experimental Design:
Primary cohort encompasses 5,671 blood samples from 4,892 patients with lung cancer. Pair-wise tissue samples from 579 patients and additional 358 sample pairs were collected to evaluate the correlation between blood and tissue tumor mutational burden (TMB). Parallel sequencing with plasma/tissue and white blood cells was performed using a 1,021-gene panel.
Results:
Histologic subtyping was the most relevant to ctDNA detectability independent of other demographic characteristics, with small cell lung cancer showing the highest detectability, ctDNA abundance, and blood TMB (bTMB). Mutational landscape demonstrated significant differences, and integrated clonality analysis highlighted distinct driver-pattern and functional pathway interaction among various subtypes. The clonality and concurrent genes of EGFR mutations could predict the therapeutic efficacy of tyrosine kinase inhibitors (TKI), and RB1 mutations in non–small cell lung cancer characterized a subset with high bTMB, elevated ctDNA level, and potential small cell transformation. Most importantly, we developed an adjusted algorithm for bTMB in samples with extremely low ctDNA level and validated its correlation with tissue TMB in an independent cohort.
Conclusions:
ctDNA could serve as a promising alternative in genomic profiling for lung cancer. The novel identification of ctDNA clonality and adjusted bTMB might improve therapeutic and prognostic evaluation. This dataset was also a valuable resource for the development of new therapeutic targets and new genomically guided clinical trials.
Data from Randomized Phase II Trial of Sipuleucel-T with or without Radium-223 in Men with Bone-metastatic Castration-resistant Prostate Cancer
Authors: Marshall Catherine H. , Fu Wei , Wang Hao , Park Jong Chul , DeWeese Theodore L. , Tran Phuoc T. , Song Daniel Y. , King Serina , Afful Michaella , Hurrelbrink Julia , Manogue Charlotte , Cotogno Patrick , Moldawer Nancy P. , Barata Pedro C. , Drake Charles G. , Posadas Edwin M. , Armstrong Andrew J. , Sartor Oliver , Antonarakis Emmanuel S.
Published: April 2023

AbstractPurpose:
To investigate whether radium-223 increases peripheral immune responses to sipuleucel-T in men with bone-predominant, minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods:
A total of 32 patients were randomized 1:1 in this open-label, phase II multicenter trial. Patients in the control arm received three sipuleucel-T treatments, 2 weeks apart. Those in the combination arm received six doses of radium-223 monthly, with sipuleucel-T intercalated between the second and fourth doses of radium-223. The primary endpoint was a comparison of peripheral antigen PA2024-specific T-cell responses (measured by proliferation index). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and PSA responses.
Results:
We enrolled 32 patients, followed for a median of 1.6 years. Six weeks after the first sipuleucel-T dose, participants in the control arm had a 3.2-fold greater change in PA2024-specific T-cell responses compared with those who received combination treatment (P = 0.036). Patients in the combination arm were more likely to have a >50% PSA decline [5 (31%) vs. 0 patients; P = 0.04], and also demonstrated longer PFS [39 vs. 12 weeks; HR, 0.32; 95% confidence interval (CI), 0.14–0.76] and OS (not reached vs. 2.6 years; HR, 0.32; 95% CI, 0.08–1.23).
Conclusions:
Our data raise the possibility of greater clinical activity with the combination of sipuleucel-T and radium-223 in men with asymptomatic bone mCRPC, despite the paradoxically lower immune responses observed. Additional study to confirm these findings in a larger trial is warranted.
Data from Neratinib-Plus-Cetuximab in Quadruple-WT (KRAS, NRAS, BRAF, PIK3CA) Metastatic Colorectal Cancer Resistant to Cetuximab or Panitumumab: NSABP FC-7, A Phase Ib Study
Authors: Jacobs Samuel A. , Lee James J. , George Thomas J. , Wade James L. , Stella Philip J. , Wang Ding , Sama Ashwin R. , Piette Fanny , Pogue-Geile Katherine L. , Kim Rim S. , Gavin Patrick G. , Lipchik Corey , Feng Huichen , Wang Ying , Finnigan Melanie , Kiesel Brian F. , Beumer Jan H. , Wolmark Norman , Lucas Peter C. , Allegra Carmen J. , Srinivasan Ashok
Published: April 2023

AbstractPurpose:
In metastatic colorectal cancer (mCRC), HER2 (ERBB2) gene amplification is implicated in anti-EGFR therapy resistance. We sought to determine the recommended phase II dose (RP2D) and efficacy of neratinib, a pan-ERBB kinase inhibitor, combined with cetuximab, in patients with progressive disease (PD) on anti-EGFR treatment.
Patients and Methods:
Twenty-one patients with quadruple-wild-type, refractory mCRC enrolled in this 3+3 phase Ib study. Standard dosage cetuximab was administered with neratinib at 120 mg, 160 mg, 200 mg, and 240 mg/day orally in 28-day cycles. Samples were collected for molecular and pharmacokinetic studies.
Results:
Sixteen patients were evaluable for dose-limiting toxicity (DLT). 240 mg was determined to be the RP2D wherein a single DLT occurred (1/7 patients). Treatment-related DLTs were not seen at lower doses. Best response was stable disease (SD) in 7 of 16 (44%) patients. HER2 amplification (chromogenic in situ IHC) was detected in 2 of 21 (9.5%) treatment-naïve tumors and 4 of 16 (25%) biopsies upon trial enrollment (post-anti-EGFR treatment and progression). Compared with matched enrollment biopsies, 6 of 8 (75%) blood samples showed concordance for HER2 CNV in circulating cell-free DNA. Five SD patients had HER2 amplification in either treatment-naïve or enrollment biopsies. Examination of gene-expression, total protein, and protein phosphorylation levels showed relative upregulation of ≥2 members of the HER-family receptors or ligands upon enrollment versus matched treatment-naïve samples.
Conclusions:
The RP2D of neratinib in this combination was 240 mg/day, which was well tolerated with low incidence of G3 AEs. There were no objective responses; SD was seen at all neratinib doses. HER2 amplification, detectable in both tissue and blood, was more frequent post-anti-EGFR therapy.
Data from Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non–Small Cell Lung Cancers on the LIBRETTO-001 Trial
Authors: Subbiah Vivek , Gainor Justin F. , Oxnard Geoffrey R. , Tan Daniel S.W. , Owen Dwight H. , Cho Byoung Chul , Loong Herbert H. , McCoach Caroline E. , Weiss Jared , Kim Yu Jung , Bazhenova Lyudmila , Park Keunchil , Daga Haruko , Besse Benjamin , Gautschi Oliver , Rolfo Christian , Zhu Edward Y. , Kherani Jennifer F. , Huang Xin , Kang Suhyun , Drilon Alexander
Published: April 2023

AbstractPurpose:
We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for RET fusion-positive non–small cell lung cancers (NSCLC).
Patients and Methods:
In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced RET-altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with RET fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed.
Results:
Eighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0–10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60–95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, n = 38), median duration of intracranial response was not reached (95% CI, 9.3–NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9–NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population.
Conclusions:
Selpercatinib has robust and durable intracranial efficacy in patients with RET fusion-positive NSCLC.
Data from Pilot Phase II Trial of Neoadjuvant Immunotherapy in Locoregionally Advanced, Resectable Cutaneous Squamous Cell Carcinoma of the Head and Neck
Authors: Ferrarotto Renata , Amit Moran , Nagarajan Priyadharsini , Rubin M. Laura , Yuan Ying , Bell Diana , El-Naggar Adel K. , Johnson Jason M. , Morrison William H. , Rosenthal David I. , Glisson Bonnie S. , Johnson Faye M. , Lu Charles , Mott Frank E. , Esmaeli Bita , Diaz Eduardo M. , Gidley Paul W. , Goepfert Ryan P. , Lewis Carol M. , Weber Randal S. , Wargo Jennifer A. , Basu Sreyashi , Duan Fei , Yadav Shalini S. , Sharma Padmanee , Allison James P. , Myers Jeffrey N. , Gross Neil D.
Published: April 2023

AbstractPurpose:
In locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN), surgery followed by radiotherapy is standard but can be cosmetically and functionally devastating, and many patients will have recurrence.
Patients and Methods:
Newly diagnosed or recurrent stage III–IVA CSCC-HN patients amenable to curative-intent surgery received two cycles of neoadjuvant PD-1 inhibition. The primary endpoint was ORR per RECIST 1.1. Secondary endpoints included pathologic response [pathologic complete response (pCR) or major pathologic response (MPR; ≤10% viable tumor)], safety, DSS, DFS, and OS. Exploratory endpoints included immune biomarkers of response.
Results:
Of 20 patients enrolled, 7 had recurrent disease. While only 6 patients [30%; 95% confidence interval (CI), 11.9–54.3] had partial responses by RECIST, 14 patients (70%; 95% CI, 45.7–88.1) had a pCR (n = 11) or MPR (n = 3). No SAEs ocurred during or after the neoadjuvant treatment. At a median follow-up of 22.6 months (95% CI, 21.7–26.1), one patient progressed and died, one died without disease, and two developed recurrence. The 12-month DSS, DFS, and OS rates were 95% (95% CI, 85.9–100), 89.5% (95% CI, 76.7–100), and 95% (95% CI, 85.9–100), respectively. Gene expression studies revealed an inflamed tumor microenvironment in patients with pCR or MPR, and CyTOF analyses demonstrated a memory CD8+ T-cell cluster enriched in patients with pCR.
Conclusions:
Neoadjuvant immunotherapy in locoregionally advanced, resectable CSCC-HN is safe and induces a high pathologic response rate. Pathologic responses were associated with an inflamed tumor microenvironment.
Data from Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a Post Hoc Analysis of the PRODIGE-GERCOR IDEA-France Trial
Authors: Taieb Julien , Taly Valérie , Henriques Julie , Bourreau Camille , Mineur Laurent , Bennouna Jaafar , Desrame Jérôme , Louvet Christophe , Lepere Céline , Mabro May , Egreteau Joëlle , Bouche Olivier , Mulot Claire , Hormigos Katia , Chaba Kariman , Mazard Thibault , de Gramont Aimery , Vernerey Dewi , André Thierry , Laurent-Puig Pierre
Published: April 2023

AbstractPurpose:
Circulating tumor DNA (ctDNA) has been suggested as a major prognostic factor in resected stage-III colon cancer. We analyzed ctDNA of patients randomized in the phase III IDEA-France trial.
Experimental Design:
ctDNA was tested for WIF1 and NPY by droplet digital PCR with method developed and validated for colorectal cancer. Disease-free survival (DFS) and overall survival (OS) were analyzed via multivariable analysis in patients with ctDNA samples and in sub-groups according to treatment duration (3/6 months) and disease stage (high/low-risk stage III).
Results:
Of 2,010 randomized patients, 1,345 had available ctDNA samples (1,017 collected both post-surgery and pre-chemotherapy). More Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (78% versus 69%) and T4 and/or N2 (40% versus 36%) were observed in patients studied (n = 1017) versus not analyzed (n = 993). There were 877 ctDNA-negative (86.2%) and 140 ctDNA-positive (13.8%) patients; their baseline characteristics were similar. With a median follow-up of 6.6 years, the 3-year DFS rate was 66.39% for ctDNA-positive patients and 76.71% for ctDNA-negative patients (P = 0.015). ctDNA was confirmed as an independent prognostic marker for DFS (adjusted HR = 1.55, 95% CI 1.13–2.12, P = 0.006) and OS (HR = 1.65, 95% CI 1.12–2.43, P = 0.011). ctDNA was prognostic in patients treated for 3 months and with T4 and/or N2 tumors, but not in those treated for 6 months and with T1–3/N1 tumors.
Conclusions:
In this first ctDNA assessment of a large series of patients with stage III colon cancer enrolled in phase III trial, post-surgery ctDNA was found in 13.8% of them and was confirmed as an independent prognostic marker.

See related commentary by Bent and Kopetz, p. 5449
Data from Camrelizumab plus Famitinib in Patients with Advanced or Metastatic Renal Cell Carcinoma: Data from an Open-label, Multicenter Phase II Basket Study
Authors: Qu Yuan-Yuan , Zhang Hai-Liang , Guo Hongqian , Luo Hong , Zou Qing , Xing Nianzeng , Xia Shujie , Sun Zhongquan , Zhang Xuepei , He Chaohong , Cai Jinling , Zhang Xiao , Wang Quanren , Ye Ding-Wei
Published: April 2023

AbstractPurpose:
Blockade of immune checkpoint and angiogenesis is an effective treatment strategy for advanced or metastatic renal cell carcinoma (RCC). We report the results of camrelizumab plus famitinib in the RCC cohort of an open-label, multicenter, phase II basket study.
Patients and Methods:
Eligible patients were enrolled to receive camrelizumab (200 mg i.v. every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1.
Results:
Totally, 38 patients were recruited, including 13 (34.2%) treatment-naïve and 25 (65.8%) previously treated patients. With a median duration from enrollment to data cutoff of 16.5 months (range, 6.1–20.4), 23 patients achieved a confirmed objective response, and ORR was 60.5% [95% confidence interval (CI), 43.4–76.0]. Responses in 18 (78.3%) responders were still ongoing, and Kaplan–Meier estimated median duration of response had not been reached yet (range, 1.0+–14.8+ months). Median progression-free survival (PFS) was 14.6 months (95% CI, 6.2–not reached). ORR was 84.6% (95% CI, 54.6–98.1) in treatment-naïve patients and 48.0% (95% CI, 27.8–68.7) in pretreated patients; median PFS had not been reached and was 13.4 months (95% CI, 4.1–not reached), respectively. Most common grade 3 or 4 treatment-related adverse events included proteinuria (18.4%), hypertension (18.4%), decreased neutrophil count (13.2%), palmar-plantar erythrodysesthesia syndrome (10.5%), and hypertriglyceridemia (10.5%). No treatment-related deaths occurred, and no new safety signals were observed.
Conclusions:
Camrelizumab plus famitinib showed potent and enduring antitumor activity in patients with advanced or metastatic RCC, both in treatment-naïve and previously treated population.
Data from BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program
Authors: Kim Dae-Hwan , Sun Duanchen , Storck William K. , Welker Leng Katherine , Jenkins Chelsea , Coleman Daniel J. , Sampson David , Guan Xiangnan , Kumaraswamy Anbarasu , Rodansky Eva S. , Urrutia Joshua A. , Schwartzman Jacob A. , Zhang Chao , Beltran Himisha , Labrecque Mark P. , Morrissey Colm , Lucas Jared M. , Coleman Ilsa M. , Nelson Peter S. , Corey Eva , Handelman Samuel K. , Sexton Jonathan Z. , Aggarwal Rahul , Abida Wassim , Feng Felix Y. , Small Eric J. , Spratt Daniel E. , Bankhead Armand , Rao Arvind , Gesner Emily M. , Attwell Sarah , Lakhotia Sanjay , Campeau Eric , Yates Joel A. , Xia Zheng , Alumkal Joshi J.
Published: April 2023

AbstractPurpose:
Lineage plasticity in prostate cancer—most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program—is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t-NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to de novo NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown. Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear.
Experimental Design:
Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity.
Results:
AR inhibition accentuates lineage plasticity in t-NEPC cells—an effect not observed in parental, enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4-regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial.
Conclusions:
E2F1 and BRD4 are critical for activating an AR-repressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program.