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Dana-Farber Research Publication 6.1.2022

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June 1, 2022

This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at:

Annals of Oncology

Deciphering Radiological Stable Disease to Immune Checkpoint Inhibitors

Luo J, Osorio JC

BACKGROUND: "Stable disease (SD)" per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research.
PATIENTS AND METHODS: A systematic review was performed to characterize SD in ICI trials. SD and objective response was compared to proliferation index using TCGA gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of NSCLC. Serial cutpoints of two variables, % best overall response (BOR) and PFS, were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts.
RESULTS: Among trials of ICIs (59 studies, 14,280 patients), SD ranged from 16-42% in different tumor types and was associated with disease-specific proliferation index (œÅ=-0.75, p=0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC (1220 patients, 313 [26%] with SD to ICIs), PFS ranged widely in SD (0.2 to 49 months, median 4.9 months). The subset with PFS>6 months and no tumor growth mirrored PR-minor (OS HR 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated.
CONCLUSION: RECIST-defined SD to immunotherapy is common, heterogenous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS>6 months and no tumor growth may be considered "SD responders." This definition may improve the efficiency of and insight derivable from clinical and translational research.


Lenalidomide Promotes the Development of TP53-Mutated Therapy-Related Myeloid Neoplasms

Sperling AS, Kennedy JA, Nguyen AT, Miller PG, McConkey ME, Quevedo Barrios VA, Ebert BL

There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies (CRT). Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiololgy of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Due to differences in CK1a degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.

Cancer Discovery

Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics

Haq R

A hallmark of cancer is cell death evasion, underlying suboptimal responses to chemotherapy, targeted agents, and immunotherapies. The approval of the antiapoptotic BCL2 antagonist venetoclax has finally validated the potential of targeting apoptotic pathways in patients with cancer. Nevertheless, pharmacologic modulators of cell death have shown markedly varied responses in preclinical and clinical studies. Here, we review emerging concepts in the use of this class of therapies. Building on these observations, we propose that treatment-induced changes in apoptotic dependency, rather than pretreatment dependencies, will need to be recognized and targeted to realize the precise deployment of these new pharmacologic agents.
SIGNIFICANCE: Targeting antiapoptotic family members has proven efficacious and tolerable in some cancers, but responses are infrequent, particularly for patients with solid tumors. Biomarkers to aid patient selection have been lacking. Precision functional approaches that overcome adaptive resistance to these compounds could drive durable responses to chemotherapy, targeted therapy, and immunotherapies.

Cancer Discovery

MOZ and Menin-MLL Complexes are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor

Hemming ML, Benson MR, Loycano MA, Anderson JA, Taddei ML, Krivtsov AV, Aubrey BJ, Cutler JA, Hatton C, Sicinska E, Armstrong SA

Gastrointestinal stromal tumor (GIST) is commonly characterized by activating mutations in the receptor tyrosine kinase KIT. Tyrosine kinase inhibitors are the only approved therapy for GIST, and complementary treatment strategies are urgently needed. As GIST lacks oncogene amplification and relies upon an established network of transcription factors, we hypothesized that unique chromatin modifying enzymes are essential in orchestrating the GIST epigenome. We identified through genome-scale CRISPR screening that MOZ and Menin-MLL chromatin regulatory complexes are cooperative and unique dependencies in GIST. These complexes were enriched at GIST-relevant genes and regulated their transcription. Inhibition of MOZ and Menin-MLL complexes decreased GIST cell proliferation by disrupting interactions with transcriptional/chromatin regulators, such as DOT1L. MOZ and Menin inhibition caused significant reductions in tumor burden in vivo, with superior effects observed with combined Menin and KIT inhibition. These results define unique chromatin regulatory dependencies in GIST and identify potential therapeutic strategies for clinical application.


Quiescent Cancer Cells Resist T-Cell Attack by Forming an Immunosuppressive Niche

Baldominos P, Barbera-Mourelle A, Barreiro O, Huang Y, Wight A, Cho JW, Zhao X, Estivill G, Adam I, Sanchez X, McCarthy S, Schaller J, Khan Z, Ruzo A, Pastorello R, Richardson ET, Dillon D, Montero-Llopis P, Forman J, Shukla SA, Tolaney SM, Mittendorf EA, von Andrian UH, Wucherpfennig KW, Hemberg M, Agudo J

Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T-cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T-cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T-cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.


CREB5 Reprograms FOXA1 Nuclear Interactions to Promote Resistance to Androgen Receptor Targeting Therapies

Arafeh R, Seo JH, Baca SC, Sawyer L, Richter C, Rennhack JP, Kwon J, So J, Van Allen EM, Freedman ML, Hahn WC

Metastatic castration resistant prostate cancers (mCRPC) are treated with therapies that antagonize the androgen receptor (AR). Nearly all patients develop resistance to AR-targeted therapies (ART). Our previous work identified CREB5 as an upregulated target gene in human mCRPC that promoted resistance to all clinically-approved ART. The mechanisms by which CREB5 promotes progression of mCRPC or other cancers remains elusive. Integrating ChIP-seq and rapid immunoprecipitation and mass spectroscopy of endogenous proteins (RIME), we report that cells overexpressing CREB5 demonstrate extensive reprogramming of nuclear protein-protein interactions in response to the ART agent enzalutamide. Specifically, CREB5 physically interacts with AR, the pioneering actor FOXA1, and other known co-factors of AR and FOXA1 at transcription regulatory elements recently found to be active in mCRPC patients. We identified a subset of CREB5/FOXA1 co-interacting nuclear factors that have critical functions for AR transcription (GRHL2, HOXB13) while others (TBX3, NFIC) regulated cell viability and ART resistance and were amplified or overexpressed in mCRPC. Upon examining the nuclear protein interactions and the impact of CREB5 expression on the mCRPC patient transcriptome, we found CREB5 was associated with Wnt signaling and epithelial to mesenchymal transitions, implicating these pathways in CREB5/FOXA1-mediated ART resistance. Overall, these observations define the molecular interactions among CREB5, FOXA1, and pathways that promote ART resistance.

Journal of Clinical Oncology

Phase II Study of Copanlisib in Patients with Tumors with PIK3CA Mutations: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1F

Zhao F, Gray RJ, Wang V, Flaherty KT

PURPOSE: Activating mutations in PIK3CA are observed across multiple tumor types. The NCI-MATCH (EAY131) is a tumor-agnostic platform trial that enrolls patients to targeted therapies on the basis of matching genomic alterations. Arm Z1F evaluated copanlisib, an  and  isoform-specific phosphoinositide 3-kinase (PI3K) inhibitor, in patients with PIK3CA mutations (with or without PTEN loss).
PATIENTS AND METHODS: Patients received copanlisib (60 mg intravenous) once weekly on days 1, 8, and 15 in 28-day cycles until progression or toxicity. Patients with KRAS mutations, human epidermal growth factor receptor 2-positive breast cancers, and lymphomas were excluded. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival, 6-month progression-free survival, and overall survival.
RESULTS: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the Protocol. Multiple histologies were enrolled, with gynecologic (n = 6) and gastrointestinal (n = 6) being the most common. Sixty-eight percent of patients had 3 lines of prior therapy. The ORR was 16% (4 of 25, 90% CI, 6 to 33) with P = .0341 against a null rate of 5%. The most common reason for protocol discontinuation was disease progression (n = 17, 68%). Grade 3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition. Sixteen patients (53%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycemia (n = 19), fatigue (n = 12), diarrhea (n = 11), hypertension (n = 10), and nausea (n = 10).
CONCLUSION: The study met its primary end point with an ORR of 16% (P = .0341) with copanlisib showing clinical activity in select tumors with PIK3CA mutation in the refractory setting.

Journal of Clinical Oncology

Reply to T. Olivier et al

Hodi FS

We appreciate the thoughtful comments from Drs Olivier and Prasad regarding the primary manuscript and editorial describing the CheckMate 067 6.5-year follow-up data. In general, we agree that there is no single standard of care for all patients with metastatic melanoma. The choice of primary therapy is one that requires careful balancing of antitumor activity with toxicities and is best decided through transparent discussions between patients and oncology clinicians. We also concur that such decisions are best informed by randomized trials and that only data from such trials would address the important point made regarding combination checkpoint blockade or monotherapy. However, the choice of a control arm for such a trial is challenging given the dynamic nature of available therapies for metastatic melanoma. As noted in the editorial, given the recently published RELATIVITY-047 results, which demonstrated superior progression-free survival with nivolumab plus relatlimab (a LAG-3–blocking antibody) versus nivolumab monotherapy, an ethical question would emerge when comparing nivolumab plus ipilimumab with nivolumab monotherapy.

Lancet Oncology

Cancer in Sub-Saharan Africa: A Lancet Oncology Commission

Ngwa W, Bih N, Rebbeck TR, Swanson W

In sub-Saharan Africa (SSA), urgent action is needed to curb a growing crisis in cancer incidence and mortality. Without rapid interventions, data estimates show a major increase in cancer mortality from 520‚Äâ348 in 2020 to about 1 million deaths per year by 2030. Here, we detail the state of cancer in SSA, recommend key actions on the basis of analysis, and highlight case studies and successful models that can be emulated, adapted, or improved across the region to reduce the growing cancer crises. Recommended actions begin with the need to develop or update national cancer control plans in each country. Plans must include childhood cancer plans, managing comorbidities such as HIV and malnutrition, a reliable and predictable supply of medication, and the provision of psychosocial, supportive, and palliative care. Plans should also engage traditional, complementary, and alternative medical practices employed by more than 80% of SSA populations and pathways to reduce missed diagnoses and late referrals. More substantial investment is needed in developing cancer registries and cancer diagnostics for core cancer tests. We show that investments in, and increased adoption of, some approaches used during the COVID-19 pandemic, such as hypofractionated radiotherapy and telehealth, can substantially increase access to cancer care in Africa, accelerate cancer prevention and control efforts, increase survival, and save billions of US dollars over the next decade. The involvement of African First Ladies in cancer prevention efforts represents one practical approach that should be amplified across SSA. Moreover, investments in workforce training are crucial to prevent millions of avoidable deaths by 2030. We present a framework that can be used to strategically plan cancer research enhancement in SSA, with investments in research that can produce a return on investment and help drive policy and effective collaborations. Expansion of universal health coverage to incorporate cancer into essential benefits packages is also vital. Implementation of the recommended actions in this Commission will be crucial for reducing the growing cancer crises in SSA and achieving political commitments to the UN Sustainable Development Goals to reduce premature mortality from non-communicable diseases by a third by 2030.

Lancet Oncology

G-CSF-Induced Carotid Inflammation

Singh H, Rosenthal MH, Wolpin BM

A 58-year-old woman with newly diagnosed metastatic duodenal adenocarcinoma presented at the emergency department of Brigham and Women's Hospital (Boston, MA, USA) in June, 2021, with worsening right-sided neck and jaw pain and difficulty swallowing. 9 days beforehand, the patient had started chemotherapy with FOLFOXIRI (fluorouracil continuous infusion 1600 mg/m2/day for 46 h, folinic acid 200 mg/m2, irinotecan 165 mg/m2, and oxaliplatin 85 mg/m2) and bevacizumab (5 mg/kg). 7 days prior to presentation, the patient was given pegfilgrastim (pegylated granulocyte colony-stimulating factor [G-CSF], 6 mg) for primary prevention of chemotherapy-induced neutropenia. The patient was febrile to 101° F with a decreased absolute neutrophil count and was started on broad-spectrum antibiotics (vancomycin 15 mg/kg intravenously every 12 h and cefepime 2000 mg intravenously every 8 h) because of concerns about infection. CT imaging revealed soft tissue thickening and enhancement around the right carotid artery bifurcation with adjacent fat stranding (figure A, yellow arrow). Inflammation was confirmed by diffuse fluorodeoxyglucose avidity surrounding the distal right common carotid artery on PET-CT scan. Common causes of large vessel vasculitis such as giant cell arteritis, Takayasu's arteritis, and Beçhet's syndrome were believed to be unlikely given that the patient did not have any additional characteristic clinical features such as diplopia or vision changes, and the absence of any other large vessel involvement on PET-CT. A superficial temporal artery ultrasound showed no vascular abnormality. Antineutrophil cytoplasmic antibody serologies were negative. Rare infectious causes of large vessel vasculitis such as herpes simplex virus types 1 or 2, HIV, and syphilis were excluded by molecular testing.

Molecular Cell

The FUS::DDIT3 Fusion Oncoprotein Inhibits BAF Complex Targeting and Activity in Myxoid Liposarcoma

Zullow HJ, Sankar A, Same Guerra DD, D'Avino AR, Collings CK, Liang Y, Qi J, Kadoch C

Mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes play critical roles in governing genomic architecture and gene expression and are frequently perturbed in human cancers. Transcription factors (TFs), including fusion oncoproteins, can bind to BAF complex surfaces to direct chromatin targeting and accessibility, often activating oncogenic gene loci. Here, we demonstrate that the FUS::DDIT3 fusion oncoprotein hallmark to myxoid liposarcoma (MLPS) inhibits BAF complex-mediated remodeling of adipogenic enhancer sites via sequestration of the adipogenic TF, CEBPB, from the genome. In mesenchymal stem cells, small-molecule inhibition of BAF complex ATPase activity attenuates adipogenesis via failure of BAF-mediated DNA accessibility and gene activation at CEBPB target sites. BAF chromatin occupancy and gene expression profiles of FUS::DDIT3-expressing cell lines and primary tumors exhibit similarity to SMARCB1-deficient tumor types. These data present a mechanism by which a fusion oncoprotein generates a BAF complex loss-of-function phenotype, independent of deleterious subunit mutations.

New England Journal of Medicine

Trastuzumab Deruxtecan in Non-Small-Cell Lung Cancer. Reply

Jänne PA

Both intravenous antibody–drug conjugates and oral tyrosine kinase inhibitors targeting receptor tyrosine-protein kinase erbB-2 (ERBB2 or HER2) are under late-stage development for lung cancers with ERBB2 mutations. Li et al. (Jan. 20 issue)1 report the initial data from the DESTINY-Lung01 trial of trastuzumab deruxtecan, including for 9 patients with a response who had previously received an ERBB2 tyrosine kinase inhibitor. However, the specific tyrosine kinase inhibitor was not provided. The majority of clinically available ERBB2 tyrosine kinase inhibitors (afatinib, dacomitinib, lapatinib, and neratinib) do not have an effective therapeutic window against either common ERBB2 exon 20 insertion mutations or rare ERBB2 point mutations that drive lung-cancer tumorigenesis.2 New ERBB2 tyrosine kinase inhibitors, such as poziotinib and mobocertinib, have shown both preclinical therapeutic windows and clinical activity (albeit limited) in ERBB2-mutated lung cancers.2-5 We report (in a case series supported by the National Cancer Institute [R37CA218707]) consecutive cases of patients receiving poziotinib before trastuzumab deruxtecan (Figure 1). These cases suggest that cross-resistance to ERBB2 tyrosine kinase inhibitors and antibody–drug conjugates may be uncommon owing to their disparate mechanisms of action. Additional studies characterizing mechanisms of resistance to tyrosine kinase inhibitors, antibody–drug conjugates, and appropriate sequencing or combinations of therapies in ERBB2-mutated cancers are warranted.


CDC7-Independent G1/S Transition Revealed by Targeted Protein Degradation

Suski JM, Braun M, Zhang T, Strmiska V, Michowski W, Can G, Simoneau A, Snioch K, Cup M, Sullivan CM, Wu X, Nowacka J, Branigan TB, DeCaprio JA, Geng Y, Zou L, Gygi SP, Walter JC, Sicinski P

The entry of mammalian cells into the DNA synthesis phase (S phase) represents a key event in cell division1. According to current models of the cell cycle, the kinase CDC7 constitutes an essential and rate-limiting trigger of DNA replication, acting together with the cyclin-dependent kinase CDK2. Here we show that CDC7 is dispensable for cell division of many different cell types, as determined using chemical genetic systems that enable acute shutdown of CDC7 in cultured cells and in live mice. We demonstrate that another cell cycle kinase, CDK1, is also active during G1/S transition both in cycling cells and in cells exiting quiescence. We show that CDC7 and CDK1 perform functionally redundant roles during G1/S transition, and at least one of these kinases must be present to allow S-phase entry. These observations revise our understanding of cell cycle progression by demonstrating that CDK1 physiologically regulates two distinct transitions during cell division cycle, whereas CDC7 has a redundant function in DNA replication.


Landscape of Helper and Regulatory Antitumour CD4(+) T Cells in Melanoma

Oliveira G, Stromhaug K, Cieri N, Iorgulescu JB, Klaeger S, Wolff JO, Rachimi S, Chea V, Krause K, Freeman SS, Zhang W, Li S, Braun DA, Neuberg D, Carr SA, Livak KJ, Frederick DT, Fritsch EF, Hacohen N, Sade-Feldman M, Yoon CH, Keskin DB, Ott PA, Rodig SJ, Boland GM, Wu CJ

Within the tumour microenvironment, CD4+ T cells can promote or suppress antitumour responses through the recognition of antigens presented by human leukocyte antigen (HLA) class II molecules1,2, but how cancers co-opt these physiologic processes to achieve immune evasion remains incompletely understood. Here we performed in-depth analysis of the phenotype and tumour specificity of CD4+ T cells infiltrating human melanoma specimens, finding that exhausted cytotoxic CD4+ T cells could be directly induced by melanoma cells through recognition of HLA class II-restricted neoantigens, and also HLA class I-restricted tumour-associated antigens. CD4+ T regulatory (TReg) cells could be indirectly elicited through presentation of tumour antigens via antigen-presenting cells. Notably, numerous tumour-reactive CD4+ TReg clones were stimulated directly by HLA class II-positive melanoma and demonstrated specificity for melanoma neoantigens. This phenomenon was observed in the presence of an extremely high tumour neoantigen load, which we confirmed to be associated with HLA class II positivity through the analysis of 116 melanoma specimens. Our data reveal the landscape of infiltrating CD4+ T cells in melanoma and point to the presentation of HLA class II-restricted neoantigens and direct engagement of immunosuppressive CD4+ TReg cells as a mechanism of immune evasion that is favoured in HLA class II-positive melanoma.

Nature Communications

Comparative Optimization of Combinatorial CRISPR Screens

Li R, Monducci D, Young MJ, Rodriguez DJ, Bayyat Z, Dempster JM, Kesar D, Yang X, Zamanighomi M, Ito T, Sellers WR

Combinatorial CRISPR technologies have emerged as a transformative approach to systematically probe genetic interactions and dependencies of redundant gene pairs. However, the performance of different functional genomic tools for multiplexing sgRNAs vary widely. Here, we generate and benchmark ten distinct pooled combinatorial CRISPR libraries targeting paralog pairs to optimize digenic knockout screens. Libraries composed of dual Streptococcus pyogenes Cas9 (spCas9), orthogonal spCas9 and Staphylococcus aureus (saCas9), and enhanced Cas12a from Acidaminococcus were evaluated. We demonstrate a combination of alternative tracrRNA sequences from spCas9 consistently show superior effect size and positional balance between the sgRNAs as a robust combinatorial approach to profile genetic interactions of multiple genes.

Nature Communication

Molecular Basis for Cooperative Binding and Synergy of ATP-Site and Allosteric EGFR Inhibitors

Beyett TS, To C, Heppner DE, Rana JK, Schmoker AM, Jang J, De Clercq DJH, Gomez G, Scott DA, Gray NS, Jänne PA, Eck MJ

Lung cancer is frequently caused by activating mutations in the epidermal growth factor receptor (EGFR). Allosteric EGFR inhibitors offer promise as the next generation of therapeutics, as they are unaffected by common ATP-site resistance mutations and synergize with the drug osimertinib. Here, we examine combinations of ATP-competitive and allosteric inhibitors to better understand the molecular basis for synergy. We identify a subset of irreversible EGFR inhibitors that display positive binding cooperativity and synergy with the allosteric inhibitor JBJ-04-125-02 in several EGFR variants. Structural analysis of these complexes reveals conformational changes occur mainly in the phosphate-binding loop (P-loop). Mutation of F723 in the P-loop reduces cooperative binding and synergy, supporting a mechanism in which F723-mediated contacts between the P-loop and the allosteric inhibitor are critical for synergy. These structural and mechanistic insights will aid in the identification and development of additional inhibitor combinations with potential clinical value.

Nature Communications

MYC Drives Aggressive Prostate Cancer by Disrupting Transcriptional Pause Release at Androgen Receptor Targets

Qiu X, Feit A, Luoma AM, Zadra G, Xie Y, Gu S, Tang Q, Zhang Y, Syamala S, Seo JH, Bell C, O'Connor E, Cejas P, Wucherpfennig KW, Pomerantz MM, Freedman ML, Shirley Liu X, Brown M, Long HW

c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

Nature Methods

Metagenome Assembly of High-Fidelity Long Reads with Hifiasm-Meta

Feng X, Cheng H, Li H

De novo assembly of metagenome samples is a common approach to the study of microbial communities. Current metagenome assemblers developed for short sequence reads or noisy long reads were not optimized for accurate long reads. We thus developed hifiasm-meta, a metagenome assembler that exploits the high accuracy of recent data. Evaluated on seven empirical datasets, hifiasm-meta reconstructed tens to hundreds of complete circular bacterial genomes per dataset, consistently outperforming other metagenome assemblers.

Proceedings of the National Academy of Sciences

Antibody-Mediated Blockade of the IL23 Receptor Destabilizes Intratumoral Regulatory T Cells and Enhances Immunotherapy

Wight AE, Sido JM, Degryse S, Ao L, Nakagawa H, Qiu Vivian Y, Shen X, Oseghali O, Kim HJ, Cantor H

SignificanceRegulatory T cells rely on active processes to maintain a suppressive phenotype inside a tumor, leading to increased tumor burden and worse cancer outcomes. Here, we report a pathway to interfere with regulatory T cell (Treg) stability by disrupting the expression of the interleukin 23 receptor. This approach increases Treg responsiveness to interleukin 12, leading to increased production of gamma-interferon and more efficient antitumor immune responses. The combined engagement of independent pathways to destabilize Treg through the interleukin 23 receptor and the glucocorticoid-induced TNFR-related protein receptor has a synergistic impact on the Treg phenotype and promotes antitumor immune responses. These findings expand our understanding of regulatory T-cell biology and offer tools for cancer immunotherapy.

Academic Radiology

MRI Changes in Breast Skin Following Preoperative Therapy for Patients with Inflammatory Breast Cancer

Yeh E, Nakhlis F, Bay C, Harrison BT, Bellon JR, Remolano MC, Jacene H, Giess C, Overmoyer B

American Journal of Hematology

Phase 2 Studies of Lenalidomide, Subcutaneous Bortezomib, and Dexamethasone as Induction Therapy in Patients with Newly Diagnosed Multiple Myeloma

Laubach JP, Yee AJ, Rosenblatt J, DiPietro H, Cummings K, Savell A, Masone K, Guerrero Garcia T, Bianchi G, Richardson PG

Blood Advances

Prediction of Life-Threatening and Disabling Bleeding in Patients with AML Receiving Intensive Induction Chemotherapy

Versluis J, Flamand Y, Haydu JE, Belizaire R, Vedula RS, Charles A, Copson KM, Bendapudi PK, Stone RM, DeAngelo DJ, Neuberg D, Luskin MR, Lindsley RC

Blood Advances

Rapid Next-Generation Sequencing Aids in Diagnosis of Transient Abnormal Myelopoiesis in a Phenotypically Normal Newborn

Aziz-Bose R, Wachter F, Chiarle R, Lindeman NI, Kim AS, Degar BA, Davies K, Pikman Y

BMJ Open

Patient and Clinician Nudges to Improve Symptom Management in Advanced Cancer Using Patient-Generated Health Data: Study Protocol for the PROStep Randomised Controlled Trial

Manz CR

British Journal of Haematology

Daratumumab with Ifosfamide, Carboplatin and Etoposide for the Treatment of Relapsed Plasmablastic Lymphoma

Castillo JJ


CD123 and More: How to Target the Cell Surface of Blastic Plasmacytoid Dendritic Cell Neoplasm

Lane AA

Cannabis and Cannabinoid Research

Letter to the Editor: The Role of Cannabidiol in Cancer Care: Oncologist and Cancer Patient Perspectives

Nayak MM, Chai PR, Tung S, Sannes TS, Yusufov M, Braun IM

Clinical Cancer Research

Praluzatamab Ravtansine, a CD166-Targeting Antibody-Drug Conjugate, in Patients with Advanced Solid Tumors: An Open-Label Phase I/II Trial

Liu JF

Clinical Epigenetics

Androgen Receptor Reprogramming Demarcates Prognostic, Context-Dependent Gene Sets in Primary and Metastatic Prostate Cancer

Qiu X, Long H, Pomerantz MM

Critical Care Medicine

A Retrospective Observational Study Exploring 30- and 90-Day Outcomes for Patients With COVID-19 After Percutaneous Tracheostomy and Gastrostomy Placement

Kiser SB, Sciacca K, Jain N, Leiter R, Mazzola E, Gelfand S, Jehle J, Bernacki R, Lamas D, Cooper Z, Lakin JR

Critical Reviews in Oncology/Hematology

Exercise Oncology During and Beyond the COVID-19 Pandemic: Are Virtually Supervised Exercise Interventions a Sustainable Alternative?

Gonzalo-Encabo P, Wilson RL, Kang DW, Normann AJ, Dieli-Conwright CM

Critical Reviews in Oncology/Hematology

Quantifying Absolute Benefit for Adjuvant Treatment Options in Renal Cell Carcinoma: A Living Interactive Systematic Review and Network Meta-Analysis

Bin Riaz I, Xu W

Current Opinion in Urology

Editorial: Metastatic Prostate Cancer: A Wealth of Data to Put into Practice

Beltran H

Current Opinion in Urology

The Role of Chemotherapy in Metastatic Prostate Cancer

Riaz IB, Sweeney CJ


Analysis of a SARS-CoV-2 Convalescent Cohort Identified a Common Strategy for Escape of Vaccine-Induced Anti-RBD Antibodies by Beta and Omicron Variants

Chang MR, Ke H, Coherd CD, Wang Y, Mashima K, Kastrunes GM, Marasco WA


A Flexible Statistical Framework for Estimating Excess Mortality

Acosta RJ, Irizarry RA

European Journal of Cancer

Six-Year Absolute Invasive Disease-Free Survival Benefit of Adding Adjuvant Pertuzumab to Trastuzumab and Chemotherapy for Patients with Early HER2-Positive Breast Cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) Analysis of the APHINITY (BIG 4-11) Trial

Gelber RD, Wang XV, Krop I, Frank E

European Urology

Genomic Features of Muscle-invasive Bladder Cancer Arising After Prostate Radiotherapy

Mossanen M, Carvalho FLF, Muralidhar V, Preston MA, Reardon B, Conway JR, Curran C, Freeman D, Sonpavde G, Hirsch M, Kibel AS, Van Allen EM, Mouw KW

FASEB Journal

Mass Spectrometry Based Identification of Novel HLA Class I Restricted Peptides in Merkel Cell Carcinoma

Rachimi S, Klaeger S, Lee PC, Le PM, Chea VA, Carulli IP, Ananthapadmanabhan V, Tarren A, Sarkizova S, Apffel A, Clauser KR, DeCaprio JA, Carr SA, Wu CJ, Keskin DB

FASEB Journal

Role of Mitochondrial TNAP in Thermogenesis and Obesity

Sun Y, Spiegelman BM


Natural History of Waldenström Macroglobulinemia Following Acquired Resistance to Ibrutinib Monotherapy

Gustine JN, Sarosiek S, Flynn CA, Meid K, Leventoff C, White T, Guerrera ML, Xu L, Kofides A, Tsakmaklis N, Munshi M, Demos M, Patterson CJ, Liu X, Yang G, Hunter ZR, Branagan AR, Treon SP, Castillo JJ


Randomized Controlled Trial of Geriatric Consultation Versus Standard Care in Older Adults with Hematologic Malignancies

DuMontier C, Uno H, Hshieh T, Zhou G, Chen R, Magnavita ES, Javedan H, Stone RM, Soiffer RJ, Driver JA, Abel GA

International Journal of Radiation Oncology, Biology, Physics

Local Therapy Outcomes and Toxicity from the ATEMPT Trial (TBCRC 033): A Phase II Randomized Trial of Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination with Trastuzumab in Women with Stage I HER2-Positive Breast Cancer

Bellon JR, Tayob N, Yang DD, Isakoff SJ, DeMeo M, Burstein HJ, Partridge AH, Winer EP, Krop IE, Tolaney SM

Journal of the American Society of Nephrology

Clonal Hematopoiesis and CKD Progression

Belizaire R

Journal of Geriatric Oncology

Age and Comorbidity Association with Survival Outcomes in Metastatic Colorectal Cancer: CALGB 80405 Analysis

McCleary NJ, Zhang S, Ma C, Ng K, Mayer RJ, Meyerhardt JA

Journal of Integrative and Complementary Medicine

Auricular Acupuncture During Chemotherapy Infusion in Breast Cancer Patients: A Feasibility Study

Yang E, Lu W, Giobbie-Hurder A, Chen WY, Block CC, Partridge A, Jeselsohn RM, Tolaney SM, Freedman RA, Ligibel JA

Journal of Neuro-Oncology

DICER1 Mutations in Primary Central Nervous System Tumors: New Insights into Histologies, Mutations, and Prognosis

Liu KX, Cacciotti C, Aizer AA, Rahman R, Malinowski S, Meredith DM, Kamihara J, Wen PY, Ligon KL, Chi SN, Marcus KJ, Yeo KK, Alexandrescu S, Haas-Kogan DA

Journal of Pain and Symptom Management

International Standards for Pediatric Palliative Care: From IMPaCCT to GO-PPaCS

Wolfe J

Journal of Pain and Symptom Management

Naming the Problem: A Structural Racism Framework to Examine Disparities in Palliative Care

Umaretiya PJ, Wolfe J, Bona K

Journal of Palliative Medicine

Barriers and Facilitators to Advance Care Planning among Chinese Patients with Advanced Cancer and Their Caregivers

Jia Z, Yeh IM, Lee CH, Yeung AS, Tulsky JA, Leiter RE

Journal of Thoracic Oncology

Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial

Jänne PA

JAMA Network Open

Empirical Evaluations of Clinical Trial Designs

Trippa L

JCO Oncology Practice

Disparities in Cardio-Oncology Care in the Hispanic/Latinx Population

Suero-Abreu GA, Duma N

JCO Oncology Practice

Dónde Están? Latinx/Hispanic Representation in the Oncology Workforce: Present and Future

Duma N, Franco I, Kiel L

JCO Oncology Practice

Proyecto ELEVAR: Evaluating the Latinx Experience with the Health Care System Through Variables on Access and Resources

Franco I, Duma N

Lancet Haematology

Prevalence of Monoclonal Gammopathies and Clinical Outcomes in a High-Risk US Population Screened by Mass Spectrometry: A Multicentre Cohort Study

El-Khoury H, Lee DJ, Alberge JB, Redd R, Cea-Curry CJ, Perry J, Barr H, Murphy C, Leblebjian H, Davis MI, Amstutz J, Boehner CJ, Lightbody ED, Sklavenitis-Pistofidis R, Mo CC, Weiss ST, Karlson E, Trippa L, Rebbeck TR, Getz G, Marinac CR, Ghobrial IM

Lancet Regional Health - Americas

Effectiveness Estimates of Three COVID-19 Vaccines Based on Observational Data from Puerto Rico

Irizarry RA


Author Correction: Combination Therapy Targeting Erk1/2 and CDK4/6i in Relapsed Refractory Multiple Myeloma

Adamia S, Bhatt S, Wen K, Chyra Z, Fell GG, Tai YT, Pioso MS, Letai A, Dorfman DM, Hideshima T, Anderson KC

Molecular Cancer Research

Blocking PI3K p110b Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer

Gao X, Wang Y, Ribeiro CF, Manokaran C, Chang H, Von T, Rodrigues S, Cizmecioglu O, Jia S, Wang Z, Schmit F, Jiang L, Sethi I, Signoretti S, Yuan GC, Loda M, Zhao JJ, Roberts TM

Molecular Therapy

Development of a Double ShmiR Lentivirus Effectively Targeting Both BCL11A and ZNF410 for Enhanced Induction of Fetal Hemoglobin to Treat b-Hemoglobinopathies

Liu B, Brendel C, Vinjamur DS, Zhou Y, Harris C, McGuinness M, Manis JP, Bauer DE, Xu H, Williams DA

Nature Cancer

IKAROS and MENIN Coordinate Therapeutically Actionable Leukemogenic Gene Expression in MLL-r Acute Myeloid Leukemia

Aubrey BJ, Cutler JA, Bourgeois W, Donovan KA, Gu S, Hatton C, Perlee S, Perner F, Rahnamoun H, Theall ACP, Henrich JA, Zhu Q, Nowak RP, Kim YJ, Parvin S, Cremer A, Olsen SN, Eleuteri NA, Pikman Y, Stegmaier K, Letai A, Fischer ES, Liu XS, Armstrong SA


A Molecularly Integrated Grade for Meningioma

Driver J, Hoffman SE, Tavakol S, Woodward E, Maury EA, Bhave V, Aizer AA, Alexander BM, Ligon KL, Reardon DA, Wen PY, Al-Mefty O, Ligon AH, Dubuc AM, Beroukhim R, Claus EB, Santagata S, Linda Bi W

NPJ Breast Cancer

A Prospective Trial of Treatment De-Escalation Following Neoadjuvant Paclitaxel/Trastuzumab/Pertuzumab in HER2-Positive Breast Cancer

Waks AG, Desai NV, Li T, Poorvu PD, Partridge AH, Sinclair N, Spring LM, Faggen M, Constantine M, Metzger O, Alberti J, Deane J, Rosenberg SM, Frank E, Tolaney SM, Krop IE, Tung NM, Tayob N, King TA, Mittendorf EA, Winer EP

Nucleic Acids Research

The Metaphorical Swiss Army Knife: The Multitude and Diverse Roles of HEAT Domains in Eukaryotic Translation Initiation

Friedrich D, Arthanari H

Oncology Nursing Forum

Exploring Daily Salivary Cortisol Patterns as Biomarkers of Chronic Chemotherapy-Induced Peripheral Neuropathy Pain

Giobbie-Hurder A, Berfield J, Meyerhardt J, Wright A, Ligibel J


Computed Tomography Texture Analysis for Predicting Clinical Outcomes in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

Qin L, Bakouny Z, Krajewski KM, Van Allen EM, Choueiri TK, Shinagare AB


Longitudinal Evaluation of Circulating Tumor DNA Using Sensitive Amplicon-Based Next-Generation Sequencing to Identify Resistance Mechanisms to Immune Checkpoint Inhibitors for Advanced Urothelial Carcinoma

Ravi P, Ravi A, Riaz IB, Freeman D, Curran C, Mantia C, McGregor BA, Kilbridge KL, Pan CX, Sonpavde GP

Open Forum Infectious Diseases

Ibrutinib for Hospitalized Adults with Severe Coronavirus Disease 2019 Infection: Results of the Randomized, Double-Blind, Placebo-Controlled iNSPIRE Study

Treon SP


Association Between Baseline Body Mass Index and Survival in Men with Metastatic Hormone-Sensitive Prostate Cancer: ECOG-ACRIN CHAARTED E3805

Chen YH, Sweeney CJ

Seminars in Immunopathology

A Conceptual Framework for Inducing T Cell-Mediated Immunity Against Glioblastoma

Marx S, Godicelj A, Wucherpfennig KW

Seminars in Nuclear Medicine

Imaging for Radiation Planning in Breast Cancer

Sakellis CG, Jacene HA

Supportive Care in Cancer

Psychosocial Issues and Quality of Life of Parenting Partners of Young Women with Breast Cancer

Borstelmann NA, Gray TF, Gelber S, Rosenberg S, Zheng Y, Meyer M, Come S, Maramaldi P, Partridge AH

Transplantation and Cellular Therapy

Invasive Yeast Infection After Haploidentical Donor Hematopoietic Cell Transplantation Associated with Cytokine Release Syndrome

Little JS, Shapiro RM, Aleissa MM, Kim A, Chang JBP, Kubiak DW, Zhou G, Antin JH, Koreth J, Nikiforow S, Cutler CS, Romee R, Issa NC, Ho VT, Gooptu M, Soiffer RJ, Baden LR

Trends in Cancer

Interplay Between K-RAS and miRNAs

Shui B, Haigis KM