This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from November 1 through November 15.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing ericd_schuller@dfci.harvard.edu.
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Annals of Oncology
Is There a Role for Continuation of CDK4/6 Inhibition After Progression on a Prior CDK4/6 Inhibitor in HR+/HER2- Metastatic Breast Cancer?
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.
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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.
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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.
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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.
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Journal of Clinical Oncology
Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial
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.
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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.
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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.
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Journal of the National Cancer Institute
Tazemetostat for Tumors Harboring SMARCB1/SMARCA4 or EZH2 Alterations: Results From NCI-COG Pediatric MATCH APEC1621C
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.
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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.
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Nature Communications
Inadequate Structural Constraint on Fab Approach Rather than Paratope Elicitation Limits HIV-1 MPER Vaccine Utility
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.
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Nature Medicine
Publisher Correction: Machine Learning for Genetics-Based Classification and Treatment Response Prediction in Cancer of Unknown Primary
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.
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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
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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
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Clinical Cancer Research
Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
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
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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
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Journal of Clinical Investigation
A Narrow T Cell Receptor Repertoire Instructs Thymic Differentiation of MHC Class Ib-Restricted CD8+ Regulatory T-Cells
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
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Journal of Clinical Investigation
Hyperphosphorylation of BCL-2 Family Proteins Underlies Functional Resistance to Venetoclax in Lymphoid Malignancies
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
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Journal of Thoracic Oncology
Impact of Aneuploidy and Chromosome 9p Loss on Tumor Immune Microenvironment and Immune Checkpoint Inhibitor Efficacy in NSCLC
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
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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
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JCO Oncology Practice
Pretest Video Education Versus Genetic Counseling for Patients with Prostate Cancer: ProGen, A Multisite Randomized Controlled Trial
Rana HQ, Stopfer JE, Weitz M, Kipnis L, Koeller DR, Culver S, Mercado J, Gelman RS, Underhill-Blazey M, McGregor BA, Sweeney CJ, Vatnick DR, Silver R, Kilbridge KE, Pomerantz MM, Wei XX, Choudhury AD, Sonpavde GP, Kozyreva O, Lathan C, Garber JE, Taplin ME
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Molecular Cancer Therapeutics
Combination Therapies to Improve the Efficacy of Immunotherapy in Triple-negative Breast Cancer
Alečković 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
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Pediatric Blood and Cancer
Loss of Heterozygosity does not Occur in BRCA1/2 Mutant Pediatric Solid and Central Nervous System Tumors
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
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Practical Radiation Oncology
Prospective Evaluation of the Clinical Benefits of a Novel Tattoo-less Workflow for Non-Spine Bone Stereotactic Body Radiation Therapy (SBRT): Integrating Surface-Guidance with Triggered Imaging Reduces Treatment Time and Eliminates the Need for Tattoos
Zhou AZ, Conway L, Bartlett S, Marques A, Physic M, Czerminska M, Spektor A, Killoran JH, Friesen S, Bredfeldt J, Huynh MA
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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
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