Read more about the 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.
August 15, 2021
Blood
Gooptu M, Romee R, Antin JH, Soiffer RJ
Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.
Blood
Munshi NC
We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible newly diagnosed multiple myeloma (TIE NDMM) using data from four phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD-negativity rates and reduced the risk of disease progression or death by approximately half versus standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response (CR) or better with MRD-negative status, and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10 threshold). Patient-level data were pooled from all four studies, and for patients with TIE NDMM plus patients with RRMM who received 2 prior lines of therapy (2PL). PFS was evaluated by response and MRD status. Median follow-up (months) was: POLLUX, 54.8; CASTOR, 50.2; ALCYONE, 40.1; and MAIA, 36.4. Patients who achieved CR and MRD negativity had improved PFS versus those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM 2PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.ClinicalTrials.gov: NCT02076009/NCT02136134/NCT02195479/NCT02252172.
Cancer Cell
TRIM8 Modulates the EWS/FLI Oncoprotein to Promote Survival in Ewing Sarcoma
Seong BKA, Dharia NV, Lin S, Donovan KA, Robichaud A, Conway A, Hamze A, Ross L, Alexe G, Adane B, Nabet B, Ferguson FM, Stolte B, Wang EJ, Sun J, Piccioni F, Gray NS, Fischer ES, Stegmaier K
Fusion-transcription factors (fusion-TFs) represent a class of driver oncoproteins that are difficult to therapeutically target. Recently, protein degradation has emerged as a strategy to target these challenging oncoproteins. The mechanisms that regulate fusion-TF stability, however, are generally unknown. Using CRISPR-Cas9 screening, we discovered tripartite motif-containing 8 (TRIM8) as an E3 ubiquitin ligase that ubiquitinates and degrades EWS/FLI, a driver fusion-TF in Ewing sarcoma. Moreover, we identified TRIM8 as a selective dependency in Ewing sarcoma compared with >700 other cancer cell lines. Mechanistically, TRIM8 knockout led to an increase in EWS/FLI protein levels that was not tolerated. EWS/FLI acts as a neomorphic substrate for TRIM8, defining the selective nature of the dependency. Our results demonstrate that fusion-TF protein stability is tightly regulated and highlight fusion oncoprotein-specific regulators as selective therapeutic targets. This study provides a tractable strategy to therapeutically exploit oncogene overdose in Ewing sarcoma and potentially other fusion-TF-driven cancers.
Journal of Clinical Oncology
Tolaney SM, Tayob N, Isakoff SJ, Faggen M, Mulvey T, Hu J, Weckstein D, Constantine M, Briccetti F, Tung N, Zheng Y, Rosenberg SM, Gelber RD, Trippa L, Barry W, DeMeo M, Burstein H, Partridge A, Winer EP, Krop I
PURPOSE: The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). METHODS: Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m2 IV with H once every week ?ó 12 weeks (4 mg/kg load 2 mg/kg), followed by H ?ó 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1. RESULTS: The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH (P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis (P < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH. CONCLUSION: Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH.
Journal of Clinical Oncology
Burstein HJ
Journal of Clinical Oncology Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update Burstein HJ PURPOSE: To update recommendations of the ASCO systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline. METHODS: An Expert Panel conducted a systematic review to identify new, potentially practice-changing data. RESULTS: Fifty-one articles met eligibility criteria and form the evidentiary basis for the recommendations. RECOMMENDATIONS: Alpelisib in combination with endocrine therapy (ET) should be offered to postmenopausal patients, and to male patients, with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, ABC, or MBC following prior endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. Clinicians should use next-generation sequencing in tumor tissue or cell-free DNA in plasma to detect PIK3CA mutations. If no mutation is found in cell-free DNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with PIK3CA mutations. There are insufficient data at present to recommend routine testing for ESR1 mutations to guide therapy for HR-positive, HER2-negative MBC. For BRCA1 or BRCA2 mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered in the 1st-line through 3rd-line setting. A nonsteroidal aromatase inhibitor (AI) and a CDK4/6 inhibitor should be offered to postmenopausal women with treatment-nave HR-positive MBC. Fulvestrant and a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with AIs (or who develop a recurrence within 1 year of adjuvant AI therapy) with or without one line of prior chemotherapy for metastatic disease, or as first-line therapy. Treatment should be limited to those without prior exposure to CDK4/6 inhibitors in the metastatic setting. Additional information can be found at www.asco.org/breast-cancer-guidelines.
Journal of Clinical Oncology
US Trends in Opioid Access Among Patients with Poor Prognosis Cancer Near the End-of-Life
Enzinger AC, Keating NL, Cutler DM, Landrum MB, Wright AA
PURPOSE: Heightened regulations have decreased opioid prescribing across the United States, yet little is known about trends in opioid access among patients dying of cancer. METHODS: Among 270,632 Medicare fee-for-service decedents with poor prognosis cancers, we used part D data to examine trends from 2007 to 2017 in opioid prescription fills and opioid potency (morphine milligram equivalents per day [MMED]) near the end-of-life (EOL), defined as the 30 days before death or hospice enrollment. We used administrative claims to evaluate trends in pain-related emergency department (ED) visits near EOL. RESULTS: Between 2007 and 2017, the proportion of decedents with poor prognosis cancers receiving ‚â• 1 opioid prescription near EOL declined 15.5% (relative percent difference [RPD]), from 42.0% (95% CI, 41.4 to 42.7) to 35.5% (95% CI, 34.9 to 36.0) and the proportion receiving ‚â• 1 long-acting opioid prescription declined 36.5% (RPD), from 18.1% (95% CI, 17.6 to 18.6) to 11.5% (95% CI, 11.1 to 11.9). Among decedents receiving opioids near EOL, the mean daily dose fell 24.5%, from 85.6 MMED (95% CI, 82.9 to 88.3) to 64.6 (95% CI, 62.7 to 66.6) MMED. Overall, the total amount of opioids prescribed per decedent near EOL (averaged across those who did and did not receive an opioid) fell 38.0%, from 1,075 morphine milligram equivalents per decedent (95% CI, 1,042 to 1,109) to 666 morphine milligram equivalents per decedent (95% CI, 646 to 686). Simultaneously, the proportion of patients with pain-related ED visits increased 50.8% (RPD), from 13.2% (95% CI, 12.7 to 13.6) to 19.9% (95% CI, 19.4 to 20.4). Sensitivity analyses demonstrated similar declines in opioid utilization in the 60 and 90 days before death or hospice, and suggested that trends in opioid access were not confounded by secular trends in hospice utilization. CONCLUSION: Opioid use among patients dying of cancer has declined substantially from 2007 to 2017. Rising pain-related ED visits suggests that EOL cancer pain management may be worsening.
Molecular Cell
Solenoid Architecture of HUWE1 Contributes to Ligase Activity and Substrate Recognition
Hunkeler M, Jin CY, Ma MW, Overwijn D, Fischer ES
HECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors, including Mcl1, p53, DDIT4, and Myc. Although mutations in HUWE1 and related HECT ligases are widely implicated in human disease, our molecular understanding remains limited. Here we present a comprehensive investigation of full-length HUWE1, deepening our understanding of this class of enzymes. The N-terminal 3,900 amino acids of HUWE1 are indispensable for proper ligase function, and our cryo-EM structures of HUWE1 offer a complete molecular picture of this large HECT ubiquitin ligase. HUWE1 forms an alpha solenoid-shaped assembly with a central pore decorated with protein interaction modules. Structures of HUWE1 variants linked to neurodevelopmental disorders as well as of HUWE1 bound to a model substrate link the functions of this essential enzyme to its three-dimensional organization.
Nature
Phenotype, Specificity and Avidity of Antitumour CD8(+) T Cells in Melanoma
Oliveira G, Stromhaug K, Klaeger S, Kula T, Frederick DT, Le PM, Forman J, Huang T, Li S, Zhang W, Cieri N, Clauser KR, Shukla SA, Neuberg D, MacBeath G, Carr SA, Fritsch EF, Hacohen N, Sade-Feldman M, Livak KJ, Boland GM, Ott PA, Keskin DB, Wu CJ
Interactions between T cell receptors (TCRs) and their cognate tumour antigens are central to antitumour immune responses1-3; however, the relationship between phenotypic characteristics and TCR properties is not well elucidated. Here we show, by linking the antigenic specificity of TCRs and the cellular phenotype of melanoma-infiltrating lymphocytes at single-cell resolution, that tumour specificity shapes the expression state of intratumoural CD8+ T cells. Non-tumour-reactive T cells were enriched for viral specificities and exhibited a non-exhausted memory phenotype, whereas melanoma-reactive lymphocytes predominantly displayed an exhausted state that encompassed diverse levels of differentiation but rarely acquired memory properties. These exhausted phenotypes were observed both among clonotypes specific for public overexpressed melanoma antigens (shared across different tumours) or personal neoantigens (specific for each tumour). The recognition of such tumour antigens was provided by TCRs with avidities inversely related to the abundance of cognate targets in melanoma cells and proportional to the binding affinity of peptide-human leukocyte antigen (HLA) complexes. The persistence of TCR clonotypes in peripheral blood was negatively affected by the level of intratumoural exhaustion, and increased in patients with a poor response to immune checkpoint blockade, consistent with chronic stimulation mediated by residual tumour antigens. By revealing how the quality and quantity of tumour antigens drive the features of T cell responses within the tumour microenvironment, we gain insights into the properties of the anti-melanoma TCR repertoire.
Nature Communications
Structure of PDE3A-SLFN12 Complex Reveals Requirements for Activation of SLFN12 RNase
Garvie CW, Wu X, Papanastasiou M, Lee S, Schnitzler GR, Horner SW, Baker A, Mullahoo JP, Westlake L, Hoyt SH, Toetzl M, Ranaghan MJ, de Waal L, McGaunn J, Kaplan B, Piccioni F, Yang X, Raymond D, Lewis TA, Carr SA, Cherniack AD, Lemke CT, Meyerson M, Greulich H
DNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies.
Proceedings of the National Academy of Science of the U.S.A.
Sritharan D, Wang S, Hormoz S
Most high-dimensional datasets are thought to be inherently low-dimensional-that is, data points are constrained to lie on a low-dimensional manifold embedded in a high-dimensional ambient space. Here, we study the viability of two approaches from differential geometry to estimate the Riemannian curvature of these low-dimensional manifolds. The intrinsic approach relates curvature to the Laplace-Beltrami operator using the heat-trace expansion and is agnostic to how a manifold is embedded in a high-dimensional space. The extrinsic approach relates the ambient coordinates of a manifold's embedding to its curvature using the Second Fundamental Form and the Gauss-Codazzi equation. We found that the intrinsic approach fails to accurately estimate the curvature of even a two-dimensional constant-curvature manifold, whereas the extrinsic approach was able to handle more complex toy models, even when confounded by practical constraints like small sample sizes and measurement noise. To test the applicability of the extrinsic approach to real-world data, we computed the curvature of a well-studied manifold of image patches and recapitulated its topological classification as a Klein bottle. Lastly, we applied the extrinsic approach to study single-cell transcriptomic sequencing (scRNAseq) datasets of blood, gastrulation, and brain cells to quantify the Riemannian curvature of scRNAseq manifolds.
AIDS
Multimorbidity Networks Associated with Frailty Among Middle Aged and Older People with HIV
Lorenz DR, Mukerji SS, Misra V, Uno H, Gelman BB, Moore DJ, Singer EJ, Morgello S, Gabuzda D
American Journal of Clinical Nutrition
Bioorthogonal Hydroamination of Push-Pull-Activated Linear Alkynes
Kang D, Cheung ST, Kim J
Annals of Surgical Oncology
Kantor O, Wang ML, Freedman RA, King TA, Mittendorf EA
Biomaterials
Wan Z, Shelton SE, Campisi M, Sundararaman SK, Barbie DA
Brain
Uncomfortably Numb: How Nav1.7 Mediates Paclitaxel-Induced Peripheral Neuropathy
Names
Breast Cancer Research and Treatment
Balch SM, Vaz-Luis I, Li T, Tayob N, Jain E, Helvie K, Buendia-Buendia JE, Shannon E, Isakoff SJ, Tung NM, Krop IE, Lin NU, Wagle N, Freedman RA
Cell Death and Disease
Dynamic BH3 Profiling Identifies Active BH3 Mimetic Combinations in Non-Small Cell Lung Cancer
Potter DS, Du R, Bhola P, Bueno R, Letai A
Cell Reports
SMAD4 Represses FOSL1 Expression and Pancreatic Cancer Metastatic Colonization
Dai C, Rennhack JP, Arnoff TE, Thaker M, Younger ST, Doench JG, Huang AY, Yang A, Aguirre AJ, Wang B, Mun E, O'Connell JT, Huang Y, Labella K, Talamas JA, Li J, Ilic N, Giacomelli AO, Gjoerup O, Root DE, Hahn WC
Clinical Cancer Research
Xing L, Wang S, Liu J, Chen H, Wen K, Lin L, Hsieh PA, Munshi N, Anderson KC, Tai YT
Clinical Cancer Research
Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration
Anderson KC, Ghobrial IM, Lightbody ED, Lomas OC, Munshi NC, O'Donnell EK
Clinical Cancer Research
Cleary JM, Wolpin BM, Dougan SK, Raghavan S, Singh H, Huffman B, Sethi NS, Nowak JA, Shapiro GI, Aguirre AJ, D'Andrea AD
European Journal of Haematology
Griffin JD
Expert Review of Hematology
Selinexor for the Treatment of Patients with Previously Treated Multiple Myeloma
Mo CC, Richardson P
Head and Neck
Epidemiologic Distinctions Between Base of Tongue and Tonsil Oropharyngeal Carcinomas
Margalit DN, Dey T, Rettig EM
HemaSphere
Kofides A, Hunter ZR, Xu L, Tsakmaklis N, Demos MG, Munshi M, Liu X, Guerrera ML, Leventoff CR, White TP, Flynn CA, Meid K, Patterson CJ, Yang G, Branagan AR, Sarosiek S, Castillo JJ, Treon SP, Gustine JN
Hematology/Oncology Clinics of North America
Cutaneous Malignancies of the Head and Neck
Silk AW
Human Mutation
Heeney MM, Berhe S, Campagna DR, Shanap MA, Antin JH, Shimamura A, Fleming MD
Journal of the American Medical Informatics Association
Huang K, Gray TF, Romero-Brufau S, Tulsky JA, Lindvall C
Journal of Medicinal Chemistry
Structure-Guided Design of a "Bump-and-Hole" Bromodomain-Based Degradation Tag
Nowak RP, Xiong Y, Kirmani N, Kalabathula J, Donovan KA, Eleuteri NA, Yuan JC, Fischer ES
Journal of Pain and Symptom Management
Parent and Adolescent Perspectives on the Impact of COVID on the Care of Seriously Ill Children
Beight LJ, Helton G, Avery M, Dussel V, Wolfe J
Leukemia
Yang J, Weisberg EL, Liu X, Magin RS, Chan WC, Hu B, Schauer NJ, Zhang S, Lamberto I, Doherty L, Meng C, Sattler M, Cabal-Hierro L, Winer E, Stone R, Marto JA, Griffin JD, Buhrlage SJ
Lung Cancer
Kozono DE
NPJ Breast Cancer
Treatment-Related Amenorrhea in a Modern, Prospective Cohort Study of Young Women with Breast Cancer
Poorvu PD, Hu J, Zheng Y, Gelber SI, Peppercorn JM, Come SE, Rosenberg SM, Partridge AH
Nucleic Acids Research
Bedwell GJ, Jang S, Li W, Singh PK, Engelman AN
Oncogene
He S, Zimmerman MW, Layden HM, Berezovskaya A, Etchin J, Martel MW, Thurston G, Jing CB, Rodig SJ, Mansour MR, Look AT
STAR Protocols
Liu S, Nguyen M, Hormoz S
Urologic Oncology
Yang DD, D'Amico AV