Welcome to Dana-Farber's Research News
December 01, 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.
Annals of Oncology
Giordano A, Lin NU, Tolaney SM, Mayer EL
Cyclin-dependent kinase 4 (CDK4) and CDK6 interact with cyclin D1 to hyperphosphorylate the retinoblastoma (RB1) gene product pRb early in the G1 phase of the cell cycle. This results in pRb inactivation and release of transcription factors that allow progression to the S phase. Cyclin D1 and CDK4 play particularly important roles in mammary gland biology and breast cancer and numerous molecular features suggest that the cyclin D-CDK4/6 pathway can be hyperactivated in human hormone receptor (HR)-positive breast cancers. The CDK4/6 inhibitors (CDK4/6i) palbociclib (Pfizer, Collegeville, PA), ribociclib (Novartis East, Hanover, NJ), and abemaciclib (Eli Lilly, Indianapolis, IN) are currently approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) in either the first-line or pre-treated setting in combination with endocrine therapy (ET, aromatase inhibitors or fulvestrant) for HR-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC). They all are ATP competitive kinase inhibitors that bind to the hinge region of CDK4/6 and inhibit phosphorylation of downstream substrates. Recently, abemaciclib received EMA and FDA approval for node-positive, high-risk, early-stage breast cancer in combination with adjuvant aromatase inhibitor, and positive data for ribociclib in the adjuvant setting have been reported.
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.
Blood
Causes and Consequences of Clonal Hematopoiesis
Weeks LD, Ebert BL
Clonal hematopoiesis (CH) describes the outsized contribution of expanded clones of hematopoietic stem and progenitor cells (HSPCs) to blood cell production. The prevalence of CH increases dramatically with age. CH can be caused by somatic mutations in individual genes or by gains and or losses of larger chromosomal segments. CH is a premalignant state; the somatic mutations detected in CH are the initiating mutations for hematologic malignancies, and CH is a strong predictor for the development of blood cancers. Moreover, CH is associated with non-malignant disorders and increased overall mortality. The somatic mutations that drive clonal expansion of HSPCs can alter the function of terminally differentiated blood cells, including release of elevated levels of inflammatory cytokines. These cytokines may then contribute to a broad range of inflammatory disorders that increase in prevalence with age. Detection of specific somatic mutations in the peripheral blood, in coordination with blood count parameters, can powerfully predict the development of hematologic malignancies and overall mortality. In this review we summarize the current understanding of CH nosology and origins. We provide an overview of available tools for risk stratification and discuss management strategies for patients presenting to hematology clinics with CH.
Blood
Myeloma Heterogeneity at Cell Resolution
Samur MK
In this issue of Blood, Poos et al show how integrative multiomics at the single-cell level can track and characterize distinct subclones at single-cell resolution to study the emergence of resistance and identify new targets. The authors combined bulk whole genome sequencing data with single-cell RNA and assay for transposase-accessible chromatin sequencing (ATAC-seq) data with longitudinal samples from 15 patients with relapsed/refractory disease to reconstruct the clonal structures at multiple time points.
Blood
Toward Rational Therapy for Mantle Cell Lymphoma
Murakami MA
Clinical and biological heterogeneity challenges the development of curative treatment for mantle cell lymphoma (MCL). In their timely article in this issue of Blood, Decombis et al describe a targetable mechanism of acquired resistance to combined inhibition of Bruton tyrosine kinase (BTK), BCL2, and CD20 — a clinical strategy currently under intensive clinical investigation — and animate the development of biologically informed therapy to overcome this resistance.
Journal of Clinical Oncology
Jänne PA
PURPOSE: Trastuzumab deruxtecan (T-DXd) 5.4 and 6.4 mg/kg showed robust antitumor activity in multiple cancer indications; however, T-DXd 5.4 mg/kg has not been evaluated in patients with previously treated human epidermal growth factor receptor 2-mutant (HER2m; defined as single-nucleotide variants and exon 20 insertions) metastatic non-small-cell lung cancer (mNSCLC).
METHODS: DESTINY-Lung02, a blinded, multicenter, phase II study, investigated T-DXd 5.4 mg/kg once every 3 weeks for the first time in previously treated (platinum-containing therapy) patients with HER2m mNSCLC and further assessed T-DXd 6.4 mg/kg once every 3 weeks in this population. The primary end point was confirmed objective response rate (ORR) per RECIST v1.1 by blinded independent central review.
RESULTS: One hundred fifty-two patients were randomly assigned 2:1 to T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. As of December 23, 2022, the median duration of follow-up was 11.5 months (range, 1.1-20.6) with 5.4 mg/kg and 11.8 months (range, 0.6-21.0) with 6.4 mg/kg. Confirmed ORR was 49.0% (95% CI, 39.0 to 59.1) and 56.0% (95% CI, 41.3 to 70.0) and median duration of response was 16.8 months (95% CI, 6.4 to not estimable [NE]) and NE (95% CI, 8.3 to NE) with 5.4 and 6.4 mg/kg, respectively. Median treatment duration was 7.7 months (range, 0.7-20.8) with 5.4 mg/kg and 8.3 months (range, 0.7-20.3) with 6.4 mg/kg. Grade ? 3 drug-related treatment-emergent adverse events occurred in 39 of 101 (38.6%) and 29 of 50 (58.0%) patients with 5.4 and 6.4 mg/kg, respectively. 13 of 101 (12.9%) and 14 of 50 (28.0%) patients had adjudicated drug-related interstitial lung disease (2.0% grade ? 3 in each arm) with 5.4 and 6.4 mg/kg, respectively.
CONCLUSION: T-DXd demonstrated clinically meaningful responses at both doses. Safety profile was acceptable and generally manageable, favoring T-DXd 5.4 mg/kg.
Journal of Clinical Oncology
Treatment Approaches for Platinum-Resistant Ovarian Cancer
St Laurent J, Liu JF
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
Journal of the National Cancer Institute
Are Linchpin Oncologists Keeping the Wheels from Falling off Cancer Care?
Manz CR, Barnett ML
Medical, radiation, and surgical oncologists, like other clinicians, are practicing in increasingly complex professional networks. Expanding subspecialization, increased use of advanced practice clinicians, and an increasingly part-time work force all contribute to a more interconnected, yet diffuse health-care system than in previous decades. This complexity can be bewildering to patients and physicians. Further complicating the matter is the tremendous variation across the country in the structure of oncology care networks. Particularly in resource-limited settings, clinicians specializing in medical, radiation, and surgical oncology may be in short supply, which could constrain timely patient access to more advanced treatment. The connections of these more isolated oncology clinicians to other clinicians, which constitute a complex and intricate network of referrals, could also be quite important for ensuring high-quality, multidisciplinary care that optimizes patient outcomes.
Journal of the National Cancer Institute
Chi SN, Janeway KA
BACKGROUND: National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice assigns patients aged 1-21?years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of predefined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat.
METHODS: Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate; secondary endpoints included progression-free survival and tolerability of tazemetostat.
RESULTS: Twenty patients (median age = 5?years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (n?=?8) and malignant rhabdoid tumor (n?=?4). Actionable alterations consisted of SMARCB1 loss (n?=?16), EZH2 mutation (n?=?3), and SMARCA4 loss (n?=?1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200?mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n?=?2), atypical teratoid rhabdoid tumor (n?=?1), and renal medullary carcinoma (n?=?1). Six-month progression-free survival was 35% (95% confidence interval [CI] = 15.7% to 55.2%) and 6-month overall survival was 45% (95% CI = 23.1% to 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports.
CONCLUSIONS: Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (objective response rate = 5%, 90% CI = 1% to 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of 6?months and over (range = 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.
Nature Communications
Automated Temporalis Muscle Quantification and Growth Charts for Children Through Adulthood
Zapaishchykova A, Liu KX, Saraf A, Ye Z, Catalano PJ, Benitez V, Ravipati Y, Jain A, Huang J, Hayat H, Likitlersuang J, Vajapeyam S, Chopra RB, Mak RH, Cooney TM, Haas-Kogan DA, Poussaint TY, Aerts HJWL, Kann BH
Lean muscle mass (LMM) is an important aspect of human health. Temporalis muscle thickness is a promising LMM marker but has had limited utility due to its unknown normal growth trajectory and reference ranges and lack of standardized measurement. Here, we develop an automated deep learning pipeline to accurately measure temporalis muscle thickness (iTMT) from routine brain magnetic resonance imaging (MRI). We apply iTMT to 23,876 MRIs of healthy subjects, ages 4 through 35, and generate sex-specific iTMT normal growth charts with percentiles. We find that iTMT was associated with specific physiologic traits, including caloric intake, physical activity, sex hormone levels, and presence of malignancy. We validate iTMT across multiple demographic groups and in children with brain tumors and demonstrate feasibility for individualized longitudinal monitoring. The iTMT pipeline provides unprecedented insights into temporalis muscle growth during human development and enables the use of LMM tracking to inform clinical decision-making.
Nature Communications
Chen J, Kaku Y, Wang Y, Donius L, Khan RA, Li X, Richter H, Seaman MS, Reinherz EL, Kim M
Broadly neutralizing antibodies (bnAbs) against HIV-1 target conserved envelope (Env) epitopes to block viral replication. Here, using structural analyses, we provide evidence to explain why a vaccine targeting the membrane-proximal external region (MPER) of HIV-1 elicits antibodies with human bnAb-like paratopes paradoxically unable to bind HIV-1. Unlike in natural infection, vaccination with MPER/liposomes lacks a necessary structure-based constraint to select for antibodies with an adequate approach angle. Consequently, the resulting Abs cannot physically access the MPER crawlspace on the virion surface. By studying naturally arising Abs, we further reveal that flexibility of the human IgG3 hinge mitigates the epitope inaccessibility and additionally facilitates Env spike protein crosslinking. Our results suggest that generation of IgG3 subtype class-switched B cells is a strategy for anti-MPER bnAb induction. Moreover, the findings illustrate the need to incorporate topological features of the target epitope in immunogen design.
Nature Medicine
Moon I, LoPiccolo J, Baca SC, Sholl LM, Kehl KL, Hassett MJ, Liu D, Gusev A
In the version of the article initially published, in Table 1, five cancer types were mistakenly placed under incorrect groups. Invasive breast carcinoma (BRCA), Colorectal adenocarcinoma (COADREAD), Prostate adenocarcinoma (PRAD), Melanoma (MEL) and Gastrointestinal stromal tumor (GIST) now stand as individual cancer groups. In the fifth paragraph of the introduction, the fifth sentence has been updated to read “We applied this classifier, named OncoNPC, to 971 tumor samples from patients with CUP with clinical follow-up at Dana-Farber Cancer Institute (DFCI).” Additionally, Supplementary Data 3 and 5 were interchanged. These changes have been made in the HTML and PDF versions of the article.
Annals of Emergency Medicine
Ouchi K, Bowman J, Block SD
Annals of Surgical Oncology
ASO Visual Abstract: Genomic Characterization of Aggressive Breast Cancer in Younger Women
Franco I, Punglia R
Annals of Surgical Oncology
Genomic Characterization of Aggressive Breast Cancer in Younger Women
Franco I, Punglia R
Annals of Surgical Oncology
Hersh EH, Minami CA, Weiss A, King TA
Arthritis and Rheumatology
Somatic TET2 Mutations are Associated with Giant Cell Arteritis
Robinette ML, Weeks LD, Kramer RJ, Agrawal M, Gibson CJ, Yu Z, Sekar A, Mehta A, Niroula A, Brown JT, McDermott GC, Reshef ER, Lu JE, Liou VD, Chiou CA, Natarajan P, Freitag SK, Rao DA, Ebert BL
Blood Advances
Jacobson CA, Arnason J
Blood Advances
DHODH: A Promising Target in the Treatment of T-Cell Acute Lymphoblastic Leukemia
Sexauer AN, Alexe G, Gustafsson K, Zanetakos E, Milosevic J, Pikman Y, Stegmaier K, Sykes DB
Blood Advances
Feraco AM, Friedmann A, Weinstein HJ
Blood Advances
Fillmore NR, La J, Corrigan JK, Branch-Elliman W, Monach P, Brophy MT, Do NV, Munshi NC
Blood Advances
Monoallelic Deletion of BCMA is a Frequent Feature in Multiple Myeloma
Samur MK, Aktas Samur A, Lannes R, Shah P, Anderson K, Munshi N
Blood Cancer Discovery
Ritz J
Cancer
Meyerhardt J, Ng K, Partridge AH, George S
Cancer
Lost in the Shadow of Giants: The Neglected Treatment Modalities in Oncologic Trials
Mohammadi H, Schoenfeld JD
Cancer
Mullen EA
Cancer Epidemiology, Biomarkers, and Prevention
Effects of KRAS Genetic Interactions on Outcomes in Cancers of the Lung, Pancreas, and Colorectum
Grabski IN, Kehl KL, Irizarry RA, Haigis KM
Cancer Immunology Research
EDIL3 as an Angiogenic Target of Immune Exclusion Following Checkpoint Blockade
Tabasum S, Thapa D, Giobbie-Hurder A, Weirather JL, Campisi M, Li X, Li J, Yoon CH, Manos MP, Barbie DA, Hodi FS
Cancer Medicine
Kearney G, Orio PF, Nguyen PL, D'Amico AV, Sayan M
Cancer Research Communications
Cheng YC, Stein S, Nardone A, Liu W, Ma W, Cohen G, Guarducci C, McDonald TO, Jeselsohn R, Michor F
Clinical Cancer Research
Paolino J, Dimitrov B, Ocasio-Martinez N, Tsai HK, Li Y, Robichaud AL, Khalid D, Hatton C, Gillani R, Gotti G, Kavanagh J, Adhav AA, Gow S, Tsai J, Li Y, Ebert BL, Van Allen EM, Bledsoe J, Kim AS, Luskin MR, Harris MH, Stegmaier K, Place AE, Pikman Y
Clinical Cancer Research
Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer
Singh H, Keller RB, Kapner KS, Dilly J, Raghavan S, Yuan C, Cohen EF, Tolstorukov M, Andrews E, Brais LK, da Silva A, Perez K, Rubinson DA, Surana R, Giannakis M, Ng K, Clancy TE, Yurgelun MB, Schlechter BL, Clark JW, Shapiro GI, Rosenthal MH, Hornick JL, Nardi V, Li YY, Gupta H, Cherniack AD, Meyerson M, Cleary JM, Nowak JA, Wolpin BM, Aguirre AJ
Clinical Cancer Research
Choy E, Merriam P, Barker E, George S
Clinical Lung Cancer
Heist R, Awad MM
Current Neurology and Neuroscience Reports
Advances in Treatment of Diffuse Midline Gliomas
Wright KD
Current Oncology Reports
Gonzalo-Encabo P, Wilson RL, Kang DW, Ficarra S, Dieli-Conwright CM
Current Oncology Reports
Opportunities and Challenges for a Histology-Agnostic Utilization of Trastuzumab Deruxtecan
Tolaney SM, Tarantino P
Endocrine-Related Cancer
IGF-1 Axis Changes with ADT and Docetaxel in Metastatic Prostate Cancer
Ravi P, Wang V, Fichorova RN, McGregor B, Wei XX, Basaria S
Genome Research
De Novo Reconstruction of Satellite Repeat Units from Sequence Data
Zhang Y, Chu J, Cheng H, Li H
Haematologica
Richardson PG, Raje N, Munshi N, Laubach JP, O'Donnell E, Anderson KC
Harvard Review of Psychiatry
Toward a Psychological Model of Chemical Coping with Opioids in Cancer Care
Yusufov M, Pirl WF, Braun IM, Sannes T, McHugh RK
Hepatology Communications
Pepe-Mooney BJ, Smith CJ, Sherman MS, North TE, Padera RF Jr, Goessling W
Journal of the American Academy of Dermatology
Jfri A, Virgen CA, Tawa M, Giobbie-Hurder A, Kupper TS, Fisher DC, LeBoeuf NR, Larocca C
Journal of Cancer Survivorship
Chevalier LL, Michaud A, Fine E, Recklitis CJ
Journal of Clinical Investigation
Kim HJ, Nakagawa H, Choi JY, Che X, Divris A, Liu Q, Wight AE, Zhang H, Saad A, Solhjou Z, Deban C, Azzi JR, Cantor H
Journal of Clinical Investigation
Genomic Insights into the Mechanisms of FGFR1 Dependency in Squamous Cell Lung Cancer
Mäkinen N, Meyerson M
Journal of Clinical Investigation
Chong SJF, Zhu F, Dashevsky O, Mizuno R, Hackett L, Ryan CE, Collins MC, Iorgulescu JB, Guièze R, Penailillo J, Carrasco R, Wu CJ, Mitsiades CS, Davids MS
Journal of Hospital Medicine
Sleep and Circadian Disruptors: Unhealthy Noise and Light Levels for Hospitalized Pediatric Patients
Waitt J, Lehmann LE, Solet JM, Duffy JF, Zhou ES
Journal for Immunotherapy of Cancer
Alessi JV, Ricciuti B, Wang X, Pecci F, Di Federico A, Gandhi MM, Johnson BE, Awad MM
Journal of the National Cancer Institute Monographs
Population Simulation Modeling of Disparities in US Breast Cancer Mortality
Stout NK, Huang H, Stein S, Lee SJ
Journal of Oncology Pharmacy Practice
McBride P, Degar B
Journal of Pain and Symptom Management
Forms or Free-Text? Measuring Advance Care Planning Activity Using Electronic Health Records
Zupanc SN, Lakin JR, Volandes AE, Moseley ET, Gundersen DA, Das S, Penumarthy A, Tulsky JA, Lindvall C
Journal of Palliative Medicine
Mendoza K, Killeen K, Lakin JR, Leiter RE, Sciacca KR, Gelfand SL
Journal of Palliative Medicine
Morris SE, Littlefield M, Mendu ML
Journal of Thoracic Oncology
Alessi JV, Wang X, Ricciuti B, Li YY, Gupta H, Luo J, Pecci F, Lamberti G, Recondo G, Venkatraman D, Di Federico A, Gandhi MM, Vaz VR, Nishino M, Sholl LM, Cherniack AD, Lindsay J, Sharma B, Turner MM, Pfaff KL, Felt KD, Rodig SJ, Lin X, Meyerson ML, Johnson BE, Christiani DC, Awad MM
Journal of Thoracic Oncology
Muc1-C Is a Common Driver of Acquired Osimertinib Resistance in Non-Small Cell Lung Cancer
Haratake N, Ozawa H, Morimoto Y, Yamashita N, Daimon T, Bhattacharya A, Wang K, Nakashoji A, Isozaki H, Hata AN, Kufe D
JAMA Network Open
Kwak L, Xie W, Ravi P, D'Amico AV
JCO Oncology Practice
Kelkar AH, Hantel A, Koranteng E, Cutler CS, Hammer MJ, Abel GA
JCO Oncology Practice
When Cancer Centers Snooze, Patients Lose: It is Time to Make Insomnia a Priority for Survivors
Zhou ES, Recklitis CJ, Partridge AH
Kidney Medicine
Conservative Kidney Management in the United States: What It Is and What It Could Be
Gelfand SL
Molecular Cancer Therapeutics
Combination Therapies to Improve the Efficacy of Immunotherapy in Triple-negative Breast Cancer
Ale?kovi? M, Li Z, Zhou N, Qiu X, Lulseged B, Foidart P, Huang XY, Garza K, Shu S, Kesten N, Li R, Lim K, Garrido-Castro AC, Guerriero JL, Qi J, Long HW, Polyak K
Nature Reviews Clinical Oncology
A New Era for Glioma Therapy - Targeting Mutant IDH
Reardon DA, Cahill DP
Neuro-Oncology
"LOGGIC" of RNA-Sequencing in Enhancing Diagnoses of Pediatric Low-Grade Gliomas
Apfelbaum A, Bandopadhayay P
Neuro-Oncology
The INDIGO Trial: Precision Medicine Finally Comes to Glioma
Shi DD, Kaelin WG
Oncologist
Xie W, Jegede O, Choueiri TK
Pediatric Blood and Cancer
Olsen HE, Liu KX, Frazier AL, O'Neill AF, Janeway KA, DuBois SG, Shulman DS
Pediatric Blood and Cancer
Flamand Y, Stevenson KE, Neuberg DS, Place AE, Sallan SE, Silverman LB, Vrooman LM
Pediatric Blood and Cancer
Ward A, Li YY, Lazo de la Vega L, Nag A, Forrest SJ, Gupta HV, Thorner AR, Meyerson M, Kamihara J, Cherniack AD, Janeway KA
PLoS One
von Hippel C, Dibble KE, Rosenberg SM, Partridge AH
Practical Radiation Oncology
Zhou AZ, Conway L, Bartlett S, Marques A, Physic M, Czerminska M, Spektor A, Killoran JH, Friesen S, Bredfeldt J, Huynh MA
RSC Chemical Biology
Development of a Covalent cereblon-Based PROTAC Employing a Fluorosulfate Warhead
Nowak RP, Ragosta L, Huerta F, Liu H, Ficarro SB, Cruite JT, Metivier RJ, Donovan KA, Marto JA, Fischer ES, Zerfas BL, Jones LH
Science Translational Medicine
Targeting DNA Methylation and B7-H3 in RB1-Deficient and Neuroendocrine Prostate Cancer
Yamada Y, Venkadakrishnan VB, Mizuno K, Bakht M, Ku SY, Garcia MM, Beltran H
Transplantation and Cellular Therapy
Sarosiek S, Quillen K
World Journal of Urology
MR-Guided Prostate SBRT in Prostate Cancer Patients with Low-Volume Metastatic Disease
Moningi S, Choudhury AD, Martin NE, Nguyen PL, D'Amico AV, Cagney DN, Leeman JE