Welcome to Dana-Farber's Research News
December 15, 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: Michael_buller@dfci.harvard.edu.
Blood
Fathi AT, Stone RM, Lane AA
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN also can invade other extramedullary compartments including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and while hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Ra), and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN ages 2 and older. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and relapsed/refractory BPDCN patient outcomes remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. In order to begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts includes a multi-disciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, and was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein.
Cancer Cell
Immune Biomarkers of Response to Immunotherapy in Patients with High-Risk Smoldering Myeloma
Sklavenitis-Pistofidis R, Aranha MP, Redd RA, Baginska J, Haradhvala NJ, Hallisey M, Dutta AK, Savell A, Varmeh S, Heilpern-Mallory D, Ujwary S, Zavidij O, Aguet F, Su NK, Lightbody ED, Bustoros M, Tahri S, Mouhiedine TH, Wu T, Anand S, Rosenblatt JM, Yee AJ, Laubach J, Nadeem O, Richardson P, Trippa L, Getz G, Ghobrial IM
Patients with smoldering multiple myeloma (SMM) are observed until progression, but early treatment may improve outcomes. We conducted a phase II trial of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM and performed single-cell RNA and T cell receptor (TCR) sequencing on 149 bone marrow (BM) and peripheral blood (PB) samples from patients and healthy donors (HDs). We find that early treatment with EloLenDex is safe and effective and provide a comprehensive characterization of alterations in immune cell composition and TCR repertoire diversity in patients. We show that the similarity of a patient's immune cell composition to that of HDs may have prognostic relevance at diagnosis and after treatment and that the abundance of granzyme K (GZMK)+ CD8+ effector memory T (TEM) cells may be associated with treatment response. Last, we uncover similarities between immune alterations observed in the BM and PB, suggesting that PB-based immune profiling may have diagnostic and prognostic utility.
Cell
Architecture of the Outbred Brown Fat Proteome Defines Regulators of Metabolic Physiology
Xiao H, Bozi LHM, Sun Y, Riley CL, Li J, Zhang T, Mills EL, Emont MP, Reddy A, Garrity R, Vitas LP, Laznik-Bogoslavski D, Ordonez M, Liu X, Chen X, Wang Y, Liu W, Tran N, Liu Y, Zhang Y, White AP, He Y, Paulo JA, Jedrychowski MP, Banks AS, Tseng YH, Tsai LT, Rosen ED, Huttlin EL, Spiegelman BM, Gygi SP, Chouchani ET
Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.
JAMA Oncology
Rakaee M, Adib E, Ricciuti B, Sholl LM, Shi W, Alessi JV, Awad MM, Kwiatkowski DJ
IMPORTANCE: Currently, predictive biomarkers for response to immune checkpoint inhibitor (ICI) therapy in lung cancer are limited. Identifying such biomarkers would be useful to refine patient selection and guide precision therapy.
OBJECTIVE: To develop a machine-learning (ML)-based tumor-infiltrating lymphocytes (TILs) scoring approach, and to evaluate TIL association with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC).
DESIGN, SETTING, AND PARTICIPANTS: This multicenter retrospective discovery-validation cohort study included 685 ICI-treated patients with NSCLC with median follow-up of 38.1 and 43.3 months for the discovery (n = 446) and validation (n = 239) cohorts, respectively. Patients were treated between February 2014 and September 2021. We developed an ML automated method to count tumor, stroma, and TIL cells in whole-slide hematoxylin-eosin-stained images of NSCLC tumors. Tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) expression were assessed separately, and clinical response to ICI therapy was determined by medical record review. Data analysis was performed from June 2021 to April 2022.
EXPOSURES: All patients received anti-PD-(L)1 monotherapy.
MAIN OUTCOMES AND MEASURES: Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were determined by blinded medical record review. The area under curve (AUC) of TIL levels, TMB, and PD-L1 in predicting ICI response were calculated using ORR.
RESULTS: Overall, there were 248 (56%) women in the discovery cohort and 97 (41%) in the validation cohort. In a multivariable analysis, high TIL level (250 cells/mm2) was independently associated with ICI response in both the discovery (PFS: HR, 0.71; P = .006; OS: HR, 0.74; P = .03) and validation (PFS: HR = 0.80; P = .01; OS: HR = 0.75; P = .001) cohorts. Survival benefit was seen in both first- and subsequent-line ICI treatments in patients with NSCLC. In the discovery cohort, the combined models of TILs/PD-L1 or TMB/PD-L1 had additional specificity in differentiating ICI responders compared with PD-L1 alone. In the PD-L1 negative (<1%) subgroup, TIL levels had superior classification accuracy for ICI response (AUC = 0.77) compared with TMB (AUC = 0.65).
CONCLUSIONS AND RELEVANCE: In these cohorts, TIL levels were robustly and independently associated with response to ICI treatment. Patient TIL assessment is relatively easily incorporated into the workflow of pathology laboratories at minimal additional cost, and may enhance precision therapy.
JAMA Oncology
Bardia A, Konstantinopoulos PA
IMPORTANCE: Preclinical data suggest that poly(ADP-ribose) polymerase (PARP) inhibitors have synergistic activity when combined with immune checkpoint inhibitors (ICIs); however, it is unknown which tumor types or molecular subtypes may benefit from this combination.
OBJECTIVE: To investigate responses associated with the combination of avelumab and talazoparib in different tumor types and/or molecular subtypes.
DESIGN, SETTING, AND PARTICIPANTS: In this phase 1b and 2 basket nonrandomized controlled trial, patients with advanced solid tumors were enrolled in the following cohorts: non-small cell lung cancer (NSCLC); DNA damage response (DDR)-positive NSCLC; triple-negative breast cancer (TNBC); hormone receptor-positive, human epidermal growth factor receptor 2 (ERBB2)-negative, DDR-positive breast cancer; recurrent, platinum-sensitive ovarian cancer (OC); recurrent, platinum-sensitive, BRCA1/2-altered OC; urothelial cancer; metastatic castration-resistant prostate cancer (mCRPC); DDR-positive mCRPC; and BRCA1/2- or ATM-altered solid tumors. Data were analyzed between June 17, 2021, and August 6, 2021.
INTERVENTIONS: All patients in phases 1b and 2 received avelumab plus talazoparib.
MAIN OUTCOMES AND MEASURES: The phase 1b primary end point was dose-limiting toxic effects. The phase 2 primary end point was objective response, measured as objective response rate (ORR). Secondary end points included safety, time to response, duration of response (DOR), progression-free survival, time to prostate-specific antigen progression and PSA response of 50% or greater (for mCRPC), cancer antigen 125 response (for OC), pharmacokinetics, immunogenicity, and biomarkers.
RESULTS: A total of 223 patients (mean [SD] age, 63.2 [11.0] years; 117 [52.5%] men) were treated, including 12 patients in phase 1b and 211 patients in phase 2. The recommended phase 2 dose was avelumab 800 mg every 2 weeks plus talazoparib 1 mg once daily. In phase 2, the ORR was 18.2% (95% CI, 5.2%-40.3%) in patients with TNBC; 34.8% (95% CI, 16.4%-57.3%) in patients with HR-positive, ERBB2-negative, and DDR-positive BC; and 63.6% (95% CI, 30.8%-89.1%) in patients with platinum-sensitive, BRCA1/2-altered OC. Responses occurred more frequently in patients with BRCA1/2-altered tumors. Durable responses were observed in patients with TNBC (median [range] DOR, 11.1 [3.4-20.4] months); HR-positive, ERBB2-negative, and DDR-positive BC (median [range] DOR, 15.7 [3.9 to 20.6] months); and BRCA1/2-altered OC (median DOR not reached; range, 5.6 to 18.4 months). The most common grade 3 or greater treatment-related adverse events were anemia (75 patients [33.6%]), thrombocytopenia (48 patients [21.5%]), and neutropenia (31 patients [13.9%]).
CONCLUSIONS AND RELEVANCE: This nonrandomized controlled trial found that ORRs for avelumab plus talazoparib were comparable with those with PARP inhibitor or ICI monotherapy. Prolonged DOR in patients with TNBC; HR-positive, ERBB2-negative, and DDR-positive BC; and BRCA1/2-altered OC warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of ICI and PARP-inhibitor combinations.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03330405.
JAMA Oncology
Riaz IB, Ravi P, Duma N, Kehl KL, Kamran SC, Landman A, Van Allen E
IMPORTANCE: Prostate cancer (PCa) is marked by disparities in clinical outcomes by race, ethnicity, and age. Equitable enrollment in clinical trials is fundamental to promoting health equity.
OBJECTIVE: To evaluate disparities in the inclusion of racial and ethnic minority groups and older adults across PCa clinical trials.
DATA SOURCES: MEDLINE, Embase, and ClinicalTrials.gov were searched to identify primary trial reports from each database's inception through February 2021. Global incidence in age subgroups and US population-based incidence in racial and ethnic subgroups were acquired from the Global Burden of Disease and Surveillance, Epidemiology, and End Results 21 incidence databases respectively.
STUDY SELECTION: All phase 2/3 randomized PCa clinical trials were eligible for age disparity analyses. Trials recruiting exclusively from the US were eligible for primary racial and ethnic disparity analyses.
DATA EXTRACTION AND SYNTHESIS: This study was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Data were pooled using a random-effects model.
MAIN OUTCOMES AND MEASURES: Enrollment incidence ratios (EIRs), trial proportions (TPs) of participants 65 years or older or members of a racial and ethnic subgroup divided by global incidence in the corresponding age group, or US population-based incidence in the corresponding racial and ethnic subgroup, were calculated. Meta-regression was used to explore associations between trial characteristics and EIRs and trends in EIRs during the past 3 decades.
RESULTS: Of 9552 participants among trials reporting race, 954 (10.8%) were African American/Black, 80 (1.5%) were Asian/Pacific Islander, and 8518 (78.5) were White. Of 65 US trials, 45 (69.2%) reported race and only 9 (13.8%) reported data on all 5 US racial categories. Of 286 global trials, 75 (26.2%) reported the enrollment proportion of older adults. Outcomes by race and age were reported in 2 (3.1%) and 41 (15.0%) trials, respectively. Black (EIR, 0.70; 95% CI, 0.59-0.83) and Hispanic (EIR, 0.70; 95% CI, 0.59-0.83) patients were significantly underrepresented in US trials. There was no disparity in older adult representation (TP, 21‚ÄØ143 [71.1%]; EIR, 1.00; 95% CI, 0.95-1.05). The representation of Black patients was lower in larger trials (meta-regression coefficient, -0.06; 95% CI, -0.10 to -0.02; P = .002).
CONCLUSIONS AND RELEVANCE: The results of this meta-analysis suggest that Black and Hispanic men are underrepresented in trials compared with their share of PCa incidence. The representation of Black patients has consistently remained low during the past 2 decades.
Nature
Pre-T Cell Receptor Self-MHC Sampling Restricts Thymocyte Dedifferentiation
Duke-Cohan JS, Akitsu A, Mallis RJ, Messier CM, Lizotte PH, Aster JC, Reinherz EL
Programming T lymphocytes to distinguish self from non-self is a vital, multi-step process arising in the thymus. Signalling through the pre-T cell receptor (preTCR), a CD3-associated heterodimer comprising an invariant pTa chain and a clone-specific b chain, constitutes a critical early checkpoint in thymocyte development within the ab T-cell lineage. PreTCRs arrayed on double negative (DN) thymocytes, like ab TCRs appearing on double positive (DP) thymocytes, ligate peptides bound to MHC molecules (pMHC) on thymic stroma but via a different molecular docking strategy. Here we show the consequences of those distinctive interactions for thymocyte progression, using synchronized fetal thymic progenitor cultures differing in the presence or absence of pMHC on support stroma, determining single cell transcriptomes at key thymocyte developmental transitions. Although MHC negative stroma fosters ab T lymphocyte differentiation, the absence of pMHC-preTCR interplay leads to deviant thymocyte transcriptional programming associated with dedifferentiation. Highly proliferative DN and DP subsets with antecedent characteristics of T cell lymphoblastic and myeloid malignancies emerge. Compensatory upregulation of diverse MHC class Ib proteins in B2m/H2-Ab1 MHC knockout mice partially safeguards in vivo thymocyte progression although, with ageing, disseminated DP thymic tumours may develop. Thus, beyond fostering b chain repertoire broadening for subsequent ab TCR utilization, preTCR-pMHC interaction limits cellular plasticity to facilitate normal thymocyte differentiation and proliferation that, if absent, introduces developmental vulnerabilities.
Proceedings of the National Academy of Sciences of the U.S.A.
CCAR2 Functions Downstream of the Shieldin Complex to Promote Double-Strand Break End-Joining
Iyer DR, Harada N, Clairmont C, Jiang L, Martignetti D, Nguyen H, He YJ, Chowdhury D, D'Andrea AD
The 53BP1-RIF1 pathway restricts the resection of DNA double-strand breaks (DSBs) and promotes blunt end-ligation by non-homologous end joining (NHEJ) repair. The Shieldin complex is a downstream effector of the 53BP1-RIF1 pathway. Here, we identify a component of this pathway, CCAR2/DBC1, which is also required for restriction of DNA end-resection. CCAR2 co-immunoprecipitates with the Shieldin complex, and knockout of CCAR2 in a BRCA1-deficient cell line results in elevated DSB end-resection, RAD51 loading, and PARP inhibitor (PARPi) resistance. Knockout of CCAR2 is epistatic with knockout of other Shieldin proteins. The S1-like RNA-binding domain of CCAR2 is required for its interaction with the Shieldin complex and for suppression of DSB end-resection. CCAR2 functions downstream of the Shieldin complex, and CCAR2 knockout cells have delayed resolution of Shieldin complex foci. Forkhead-associated (FHA)-dependent targeting of CCAR2 to DSB sites re-sensitized BRCA1-/-SHLD2-/- cells to PARPi. Taken together, CCAR2 is a functional component of the 53BP1-RIF1 pathway, promotes the refill of resected DSBs, and suppresses homologous recombination.
Proceedings of the National Academy of Sciences of the U.S.A.
Fillmore NR, Szalat RE, La J, Branch-Elliman W, Monach PA, Nguyen V, Samur MK, Brophy MT, Do NV, Munshi NC
Solomon et al. identified an association between exposure to young children and lower risk of severe Coronavirus disease 2019 (COVID-19) in adults. The authors theorize that this protection may be due to higher rates of coronavirus immunity conferred by recent exposure to and subsequent infection with other human coronaviruses (HCoVs). Cross-protection is also supported by laboratory studies. Although laboratory and epidemiologic studies are suggestive, the clinical impact of HCoV infection on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility is not fully elucidated. Thus, the aim of this study was to measure the association between recent HCoV infection with common strains (HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1) and future risk of SARS-CoV-2 prior to widespread vaccination and immunity.
American Journal of Hematology
Bruton Tyrosine Kinase Inhibitors in the Management of Waldenström Macroglobulinemia
Castillo JJ, Sarosiek S, Treon SP
Annual Review of Immunology
Designing Cancer Immunotherapies That Engage T Cells and NK Cells
Kyrysyuk O, Wucherpfennig KW
Blood Advances
Amonoo HL, Johnson PC, Nelson AM, Clay MA, Daskalakis E, Newcomb RA, Deary EC, Mattera EF, Yang D, Cronin K, Boateng K, El-Jawahri A
Blood Advances
Merryman RW, Redd RA, Taranto E, Jeter E, McHugh KM, Brown JR, Crombie JL, Davids MS, Fisher DC, Freedman AS, Jacobsen ED, Jacobson CA, Kim AI, LaCasce AS, Ng SY, Odejide OO, Parry EM, Jacene H, Park H, Joyce R, Chen YB, Shipp MA, Armand P
BMC Public Health
Ramanadhan S, Mahtani SL, Minsky S, Viswanath K
Breast Cancer Research and Treatment
Rosenberg SM, Zheng Y, Gelber S, Poorvu P, Sella T, Wassermann J, Come S, Peppercorn J, Sepucha KR, Partridge AH
Cancer Immunology, Immunotherapy
Silk AW, Kaufman HL
Cancer Medicine
Plana D, Bitterman DS, Aerts HJWL, Kann BH
Cancer Research
Transcriptional Antagonism by CDK8 Inhibition Improves Therapeutic Efficacy of MEK Inhibitors
Malone CF, Kim M, Alexe G, Engel K, Forman AB, Robichaud A, Saur Conway A, Goodale A, Meyer A, Khalid D, Thayakumar A, Hatcher JM, Piccioni F, Stegmaier K
Cancer Research
JAK-STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States
Stevens LE, Peluffo G, Qiu X, Temko D, Fassl A, Li Z, Seehawer M, Jovanovic B, Aleckovic M, Wilde CM, Geck RC, Shu S, Harper NW, Pyke AL, Egri SB, Papanastasiou M, Clement K, Zhou N, Salas J, Jaffe JD, Sicinski P, Toker A, Michor F, Long HW, Overmoyer BA, Polyak K
Cancers
RAD51 Is Implicated in DNA Damage, Chemoresistance and Immune Dysregulation in Solid Tumors
Liao C, Talluri S, Zhao J, Mu S, Kumar S, Shi J, Buon L, Munshi NC, Shammas MA
Cell Systems
Somatic XIST Activation and Features of X Chromosome Inactivation in Male Human Cancers
Sadagopan A, Nasim IT, Li J, Achom M, Zhang CZ, Viswanathan SR
Journal of Cancer Survivorship
Medical Cannabis-Related Stigma: Cancer Survivors' Perspectives
Nayak MM, Revette A, Chai PR, Sannes T, Tung S, Braun IM
Journal of Pain and Symptom Management
US Immigrant Utilization and Perceptions of Palliative Care
Onyeaka HK, Sadang KG, Daskalakis E, Deary EC, Desir MC, Zambrano J, Francois J, Abrahm JL, Amonoo HL
JCO Oncology Practice
Patel AK, Glotzbecker B, Leblebjian H, Simmons J
Molecular Cancer Research
Yamashita N, Morimoto Y, Fushimi A, Ahmad R, Bhattacharya A, Daimon T, Haratake N, Ishikawa S, Yamamoto M, Hata T, Shapiro GI, Kufe D
Nature Reviews Clinical Oncology
Perioperative Immunotherapy for Renal Cell Carcinoma: Looking Beyond the Data
Labaki C, Choueiri TK
Neuro-Oncology
Gonzalez Castro LN, Liu I, Filbin M
Neuro-Oncology
Phase I Study of a Novel Glioblastoma Radiation Therapy Schedule Exploiting Cell-State Plasticity
Dean JA, Tanguturi SK, Cagney D, Shin KY, Youssef G, Aizer A, Rahman R, Hammoudeh L, Reardon D, Lee E, Dietrich J, Wickersham L, Wen PY, Catalano P, Haas-Kogan D, Alexander BM, Michor F
NPJ Breast Cancer
Sella T, Zheng Y, Tayob N, Freedman RA, Isakoff SJ, DeMeo M, Burstein HJ, Winer EP, Krop I, Partridge AH, Tolaney SM
Organic and Biomolecular Chemistry
Kang D, Wahl C, Kim J
PLoS Genetics
TGFb Pathway is Required for Viable Gestation of Fanconi Anemia Embryos
Rodriguez A, Filiatrault J, Velazquez M, Yang C, McQueen K, Sambel LA, Nguyen H, Iyer DR, Ayala-Zambrano C, Martignetti DB, Parmar K, D'Andrea AD
Scandinavian Journal of Medicine and Science in Sports
Gonzalo-Encabo P, Christopher CN, Yunker AG, Norris MK, Dieli-Conwright CM
Systematic Reviews
Kang DW, Wilson RL, Norris MK, Dieli-Conwright CM
Telemedicine J E Health
Onyeaka HK, Deary EC, Amonoo HL
Trends in Pharmacological Sciences
More Than One Route to Render Tumors Resistant to cGAS/STING Activation
Manokaran C, Roberts TM, Wang Y