Welcome to Dana-Farber's Research News
May 15, 2023
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: Michael_buller@dfci.harvard.edu.
Blood
Biology and Therapeutic Targeting of Molecular Mechanisms in MPNs
How J, Garcia JS, Mullally A
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription signaling. As a result, JAK inhibitors have been the standard therapy for treatment of patients with myelofibrosis (MF). Although currently approved JAK inhibitors successfully ameliorate MPN-related symptoms, they are not known to substantially alter the MF disease course. Similarly, in essential thrombocythemia and polycythemia vera, treatments are primarily aimed at reducing the risk of cardiovascular and thromboembolic complications, with a watchful waiting approach often used in patients who are considered to be at a lower risk for thrombosis. However, better understanding of MPN biology has led to the development of rationally designed therapies, with the goal of not only addressing disease complications but also potentially modifying disease course. We review the most recent data elucidating mechanisms of disease pathogenesis and highlight emerging therapies that target MPN on several biologic levels, including JAK2-mutant MPN stem cells, JAK and non-JAK signaling pathways, mutant calreticulin, and the inflammatory bone marrow microenvironment.
Journal of Clinical Oncology
At a Loss: Patient Deaths and Clinical Research Coordinators
Deary EC, Daskalakis E, Abrahm JL, Morris SE, Amonoo HL
As clinical research coordinators (CRCs) working on health outcomes research in patients with hematologic malignancies, we frequently navigate a patient's chart to coordinate study appointments and collect clinical information. When opening a patient's electronic health record, a snapshot immediately appears on the screen with the patient's medical information: demographics, problem list, medical history, allergies, medications, and so on. However, there are times when the chart does not open immediately, and our stomachs drop. A small gray pop-up box that we know all too well reads: “You are opening the chart of [patient's name], who is deceased. Date of death: [date].”
Journal of Clinical Oncology
Haddad RI
PURPOSE: CheckMate 651 (ClinicalTrials.gov identifier: NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab plus cisplatin/carboplatin plus fluorouracil ? six cycles, then cetuximab maintenance) in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).
METHODS: Patients without prior systemic therapy for R/M SCCHN were randomly assigned 1:1 to nivolumab plus ipilimumab or EXTREME. Primary end points were overall survival (OS) in the all randomly assigned and programmed death-ligand 1 combined positive score (CPS) ? 20 populations. Secondary end points included OS in the programmed death-ligand 1 CPS ? 1 population, and progression-free survival, objective response rate, and duration of response in the all randomly assigned and CPS ? 20 populations.
RESULTS: Among 947 patients randomly assigned, 38.3% had CPS ? 20. There were no statistically significant differences in OS with nivolumab plus ipilimumab versus EXTREME in the all randomly assigned (median: 13.9 v 13.5 months; hazard ratio [HR], 0.95; 97.9% CI, 0.80 to 1.13; P = .4951) and CPS ? 20 (median: 17.6 v 14.6 months; HR, 0.78; 97.51% CI, 0.59 to 1.03; P = .0469) populations. In patients with CPS ? 1, the median OS was 15.7 versus 13.2 months (HR, 0.82; 95% CI, 0.69 to 0.97). Among patients with CPS ? 20, the median progression-free survival was 5.4 months (nivolumab plus ipilimumab) versus 7.0 months (EXTREME), objective response rate was 34.1% versus 36.0%, and median duration of response was 32.6 versus 7.0 months. Grade 3/4 treatment-related adverse events occurred in 28.2% of patients treated with nivolumab plus ipilimumab versus 70.7% treated with EXTREME.
CONCLUSION: CheckMate 651 did not meet its primary end points of OS in the all randomly assigned or CPS ? 20 populations. Nivolumab plus ipilimumab showed a favorable safety profile compared with EXTREME. There continues to be a need for new therapies in patients with R/M SCCHN.
JAMA Oncology
Waks AG, Ogayo ER, Tarantino P, Desai N, Guerriero J, Metzger O, Tung NM, Krop IE, Winer EP, Tolaney SM, Mittendorf EA
IMPORTANCE: Patients with early-stage ERBB2 (formerly HER2)-positive breast cancer (ERBB2+ BC) who experience a pathologic complete response (pCR) after receiving neoadjuvant therapy have favorable survival outcomes. Predicting the likelihood of pCR may help optimize neoadjuvant therapy.
OBJECTIVE: To test the ability of the HER2DX assay to predict the likelihood of pCR in patients with early-stage ERBB2+ BC who are receiving deescalated neoadjuvant therapy.
DESIGN, SETTING, AND PARTICIPANTS: In this diagnostic/prognostic study, the HER2DX assay was administered on pretreatment tumor biopsy samples from patients enrolled in the single-arm, multicenter, prospective phase 2 DAPHNe clinical trial who had newly diagnosed stage II to III ERBB2+ BC that was treated with neoadjuvant paclitaxel weekly for 12 weeks plus trastuzumab and pertuzumab every 3 weeks for 4 cycles.
INTERVENTIONS AND EXPOSURES: The HER2DX assay is a classifier derived from gene expression and limited clinical features that provides 2 independent scores to predict prognosis and likelihood of pCR in patients with early-stage ERBB2+ BC. The assay was administered on baseline tumor samples from 80 of 97 patients (82.5%) in the DAPHNe trial.
MAIN OUTCOMES AND MEASURES: The primary aim was to test the ability of the HER2DX pCR likelihood score (as a continuous variable from 0-100) to predict pCR (ypT0/isN0).
RESULTS: Of 80 participants, 79 (98.8%) were women and there were 4 African American (5.0%), 6 Asian (7.5%), 4 Hispanic (5.0%), and 66 White individuals (82.5%); the mean (range) age was 50.3 (26.0-78.0) years. The HER2DX pCR score was significantly associated with pCR (odds ratio, 1.05; 95% CI, 1.03-1.08; P?
CONCLUSIONS AND RELEVANCE: The results of this diagnostic/prognostic study suggest that the HER2DX pCR score assay could predict pCR following treatment with deescalated neoadjuvant paclitaxel with trastuzumab and pertuzumab in patients with early-stage ERBB2+ BC. The HER2DX pCR score might guide therapeutic decisions by identifying patients who are candidates for deescalated or escalated approaches.
JAMA Oncology
Is Appendiceal Cancer a Lynch Syndrome-Associated Cancer?
Yurgelun MB, Papke DJ Jr, Redston MS
To the Editor We read with interest the cohort study by Holowatyj et al examining the prevalence and spectrum of cancer susceptibility gene pathogenic germline variants (PGVs) among individuals with appendiceal cancer referred for germline testing. We want to congratulate the authors on their study, especially since appendiceal cancers have historically been understudied. As has now become common in the genetic testing literature, probands were ascertained from a genetic testing laboratory, suggesting elevated pretest suspicion for inherited cancer risk, so the findings are not generalizable to all patients with appendiceal cancer.
Blood
Two to Tango! IL-13 and TGF-b Drive Myelofibrosis
Jutzi JS, Mullally A
In this issue of Blood, Melo-Cardenas et al explore the role of interleukin-13 (IL-13)/IL-4 signaling in myelofibrosis as an important pathway driving fibrotic progression through megakaryocyte expansion and increased transforming growth factor-? (TGF-?) production.
Molecular Cell
Hixon KA, Comstock DE, Collings CK, Cervantes KS, Hinkley MM, Haining WN, Qi J, Kadoch C
Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.
Molecular Cell
Otto JE, Ursu O, Wu AP, Winter EB, Cuoco MS, Ma S, Qian K, Michel BC, Buenrostro JD, Berger B, Regev A, Kadoch C
The mammalian SWI/SNF (mSWI/SNF or BAF) family of chromatin remodeling complexes play critical roles in regulating DNA accessibility and gene expression. The three final-form subcomplexes-cBAF, PBAF, and ncBAF-are distinct in biochemical componentry, chromatin targeting, and roles in disease; however, the contributions of their constituent subunits to gene expression remain incompletely defined. Here, we performed Perturb-seq-based CRISPR-Cas9 knockout screens targeting mSWI/SNF subunits individually and in select combinations, followed by single-cell RNA-seq and SHARE-seq. We uncovered complex-, module-, and subunit-specific contributions to distinct regulatory networks and defined paralog subunit relationships and shifted subcomplex functions upon perturbations. Synergistic, intra-complex genetic interactions between subunits reveal functional redundancy and modularity. Importantly, single-cell subunit perturbation signatures mapped across bulk primary human tumor expression profiles both mirror and predict cBAF loss-of-function status in cancer. Our findings highlight the utility of Perturb-seq to dissect disease-relevant gene regulatory impacts of heterogeneous, multi-component master regulatory complexes
Nature
PI3K? Controls Immune Evasion in PTEN-Deficient Breast Tumours
Bergholz JS, Wang Q, Wang Q, Ramseier M, Prakadan S, Wang W, Fang R, Kabraji S, Gray GK,
Abell-Hart K, Xie S, Guo X, Gu H, Von T, Jiang T, Tang S, Freeman GJ, Kim HJ, Shalek AK,
Roberts TM, Zhao JJ
Loss of the PTEN tumour suppressor is one of the most common oncogenic drivers across all cancer types1. PTEN is the major negative regulator of PI3K signalling. The PI3K? isoform has been shown to play an important role in PTEN-deficient tumours, but the mechanisms underlying the importance of PI3K? activity remain elusive. Here, using a syngeneic genetically engineered mouse model of invasive breast cancer driven by ablation of both Pten and Trp53 (which encodes p53), we show that genetic inactivation of PI3K? led to a robust anti-tumour immune response that abrogated tumour growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3K? inactivation in the PTEN-null setting led to reduced STAT3 signalling and increased the expression of immune stimulatory molecules, thereby promoting anti-tumour immune responses. Pharmacological PI3K? inhibition also elicited anti-tumour immunity and synergized with immunotherapy to inhibit tumour growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumours upon re-challenge. Our findings demonstrate a molecular mechanism linking PTEN loss and STAT3 activation in cancer and suggest that PI3K? controls immune escape in PTEN-null tumours, providing a rationale for combining PI3K? inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.
Nature Communications
Pancreatic Cancer is Associated with Medication Changes Prior to Clinical Diagnosis
Zhang Y, Wang QL, Yuan C, Lee AA, Babic A, Ng K, Perez K, Nowak JA, Stampfer MJ,
Giovannucci EL, Sander C, Rosenthal MH, Kraft P, Wolpin BM
Patients with pancreatic ductal adenocarcinoma (PDAC) commonly develop symptoms and signs in the 1-2 years before diagnosis that can result in changes to medications. We investigate recent medication changes and PDAC diagnosis in Nurses' Health Study (NHS; females) and Health Professionals Follow-up Study (HPFS; males), including up to 148,973 U.S. participants followed for 2,994,057 person-years and 991 incident PDAC cases. Here we show recent initiation of antidiabetic (NHS) or anticoagulant (NHS, HFS) medications and cessation of antihypertensive medications (NHS, HPFS) are associated with pancreatic cancer diagnosis in the next 2?years. Two-year PDAC risk increases as number of relevant medication changes increases (P-trend?<1?×?10-5), with participants who recently start antidiabetic and stop antihypertensive medications having multivariable-adjusted hazard ratio of 4.86 (95%CI, 1.74-13.6). These changes are not associated with diagnosis of other digestive system cancers. Recent medication changes should be considered as candidate features in multi-factor risk models for PDAC, though they are not causally implicated in development of PDAC.
Science
Oncogenic CDK13 Mutations Impede Nuclear RNA Surveillance
Insco ML, Wu C, Chen KY, Liu D, Cox AM, Martin BJE, Ludwig CG, Fabo T, Modhurima R,
Henriques T, Adelman K, Zon LI
RNA surveillance pathways detect and degrade defective transcripts to ensure RNA fidelity. We found that disrupted nuclear RNA surveillance is oncogenic. Cyclin-dependent kinase 13 (CDK13) is mutated in melanoma, and patient-mutated CDK13 accelerates zebrafish melanoma. CDK13 mutation causes aberrant RNA stabilization. CDK13 is required for ZC3H14 phosphorylation, which is necessary and sufficient to promote nuclear RNA degradation. Mutant CDK13 fails to activate nuclear RNA surveillance, causing aberrant protein-coding transcripts to be stabilized and translated. Forced aberrant RNA expression accelerates melanoma in zebrafish. We found recurrent mutations in genes encoding nuclear RNA surveillance components in many malignancies, establishing nuclear RNA surveillance as a tumor-suppressive pathway. Activating nuclear RNA surveillance is crucial to avoid accumulation of aberrant RNAs and their ensuing consequences in development and disease.
Angewandte Chemie International Edition
Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader
Teng M, Jiang J, Donovan KA, Mageed N, Yue H, Nowak RP, Wang J, Manz TD, Fischer ES,
Cantley LC
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
Proteomic Approaches to Study Ubiquitinomics
Sahu I, Zhu H, Buhrlage SJ, Marto JA
ChemBioChem
Development and Characterization of Selective FAK Inhibitors and PROTACs with in Vivo Activity
Koide E, Mohardt ML, Doctor ZM, Yang A, Hao M, Donovan KA, Che J, Aguirre AJ, Fischer ES,
Jiang B
Clinical Cancer Research
Ricciuti B, Alessi J, Wang X, Li Y, Gupta H, Bertram AA, Pecci F, Lamberti G, Barrichello A, Vaz VR, Gandhi M, Lee E, Shapiro GI, Park H, Nishino M, Lindsay J, Felt KD, Sharma B, Cherniack AD,
Rodig S, Rakaee M, Janne PA, Sholl LM, Awad MM
Clinical Cancer Research
Clonal Hematopoiesis in Young Women Treated for Breast Cancer
Gibson CJ, Fell GG, Sperling AS, Snow C, Kirkner G, Patel A, Dillon D, Neuberg D, Partridge AH, Miller PG
Clinical and Experimental Dermatology
Said JT, Iriarte C, Talia J, Leung B, Virgen CA, Robertson M, Rabin MS, Larocca C, LeBoeuf NR
Current Treatment Options in Oncology
Available Systemic Treatments and Emerging Therapies for Breast Cancer Brain Metastases
Lin NU, Sammons SL
Developmental Cell
A Tubule-Sheet Continuum Model for the Mechanism of Nuclear Envelope Assembly
Zhao G, Liu S, Arun S, Pellman D
European Radiology
Nishino M, Wang X, Ricciuti B, Tseng SC, Park H, Alessi JV, Vaz VR, Hatabu H, Lin X, Christiani DC, Awad MM
iScience
Yan Q, Ding J, Khan SJ, Lawton LN, Shipp MA
Journal of Correctional Health Care
Cancer Screening Rates and Outcomes for Justice-Involved Individuals: A Scoping Review
Manz CR, Odayar VS
Journal of Gastrointestinal Cancer
Surana R
Journal of Palliative Medicine
Block SD
Radiology
Nishino M
STAR Protocols
Liu SY, Mulugeta N, Dougan SK, Qiang L
Supportive Care in Cancer
Yang E, Lu W, Tanasijevic AM, Ligibel JA
Trends in Cancer
Immune Mechanisms of Toxicity from Checkpoint Inhibitors
Wang SJ, Dougan SK, Dougan M
Trends in Microbiology
Viral Sponges Sequester Nucleotide Signals to Inactivate Immunity
Richmond-Buccola D, Kranzusch PJ
Viruses
Gabuzda D, Yin J, Misra V, Chettimada S