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 September 16 through September 30.
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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Cancer Cell
ZNF683 Marks a CD8(+) T Cell Population Associated with Anti-Tumor Immunity Following Anti-PD-1 Therapy for Richter Syndrome
Parry EM, Lemvigh CK, Deng S, Dangle N, Ruthen N, Knisbacher BA, Zhang W, Johnson C, Long JM, Yin S, Werner L, Anandappa A, Purroy N, Gohil S, Oliveira G, Huang T, Livak KJ, Getz G, Neuberg D, Kharchenko P, Wu CJ
Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyze single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 patients with RS. Response is associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlaps with that of tumor-infiltrating populations from anti-PD-1 responsive solid tumors. ZNF683 is found to directly target key T cell genes (TCF7, LMO2, CD69) and impact pathways of T cell cytotoxicity and activation. Analysis of pre-treatment peripheral blood from 10 independent patients with RS treated with anti-PD-1, as well as patients with solid tumors treated with anti-PD-1, supports an association of ZNF683high T cells with response.
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Cancer Discovery
Formate Supplementation Enhances Anti-Tumor CD8+ T Cell Fitness and Efficacy of PD-1 Blockade
Rowe JH, Shahid O, Gaudiano EF, Sifnugel NE, Johnson S, Reynolds AG, Fung ME, Joshi S, LaFleur MW, Park JS, Freeman GJ, Haigis MC, Sharpe AH
The tumor microenvironment (TME) restricts anti-tumor CD8+ T cell function and immunotherapy responses. Cancer cells compromise metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate one carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T cell fitness and anti-tumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for the enhanced tumor control. Our data demonstrate formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T cell function.
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Journal of Clinical Oncology
Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization
Rahman R, Trippa L, Lee EQ, Arrillaga-Romany I, Fell G, Touat M, McCluskey C, Wiley J, Gaffey S, Chukwueke UN, Beroukhim R, Nayak L, McFaline-Figueroa JR, Batchelor TT, Rinne ML, Bi WL, Arnaout O, Peruzzi PP, Haas-Kogan D, Tanguturi S, Aizer A, Doherty L, Lavallee M, Fisher-Longden B, Dowling S, Geduldig J, Watkinson F, Pisano W, Malinowski S, Ramkissoon S, Santagata S, Meredith DM, Chiocca EA, Reardon DA, Alexander BM, Ligon KL, Wen PY
PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design.
PATIENTS AND METHODS: Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov identifier: NCT02977780.
RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05).
CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.
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Journal of Clinical Oncology
RANO 2.0: Update to the Response Assessment in Neuro-Oncology Criteria for High- and Low-Grade Gliomas in Adults
Wen PY, Youssef G, Huang R, Rahman R, Reardon DA
PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria.
METHODS: Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0).
RESULTS: We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment.
CONCLUSION: The revised RANO 2.0 criteria refine response assessment in gliomas.
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JAMA Oncology
Medical Travel for Immigrant Patients with Cancer-Returning Home
Florez N
Many people with cancer desire to return home, spending their time with loved ones in familiar environments. For immigrants, home can be thousands of miles away in their native country. Over 40 million people living in the US were born in another country, accounting for 13.7% of the US population and one-fifth of the world’s migrants. To better meet the needs of this growing community, we explore travel to the patient’s country of origin during their cancer journey, highlight barriers to achieving these goals, and outline potential steps forward.
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Molecular Cell
eIF3d Controls the Persistent Integrated Stress Response
Mukhopadhyay S, Amodeo ME, Lee ASY
Cells respond to intrinsic and extrinsic stresses by reducing global protein synthesis and activating gene programs necessary for survival. Here, we show that the integrated stress response (ISR) is driven by the non-canonical cap-binding protein eIF3d that acts as a critical effector to control core stress response orchestrators, the translation factor eIF2α and the transcription factor ATF4. We find that during persistent stress, eIF3d activates the translation of the kinase GCN2, inducing eIF2α phosphorylation and inhibiting general protein synthesis. In parallel, eIF3d upregulates the m6A demethylase ALKBH5 to drive 5' UTR-specific demethylation of stress response genes, including ATF4. Ultimately, this cascade converges on ATF4 expression by increasing mRNA engagement of translation machinery and enhancing ribosome bypass of upstream open reading frames (uORFs). Our results reveal that eIF3d acts in a life-or-death decision point during chronic stress and uncover a synergistic signaling mechanism in which translational cascades complement transcriptional amplification to control essential cellular processes.
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Nature Genetics
Systematic Profiling of Conditional Pathway Activation Identifies Context-Dependent Synthetic Lethalities
Chang L, Jung NY, Atari A, Rodriguez DJ, Kesar D, Song TY, Rees MG, Ronan M, Li R, Ruiz P, Chaturantabut S, Ito T, van Tienen LM, Tseng YY, Roth JA, Sellers WR
The paradigm of cancer-targeted therapies has focused largely on inhibition of critical pathways in cancer. Conversely, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been deeply characterized. In this study, we sought to systematically identify context-specific gene-activation-induced lethalities in cancer. To this end, we developed a method for gain-of-function genetic perturbations simultaneously across ~500 barcoded cancer cell lines. Using this approach, we queried the pan-cancer vulnerability landscape upon activating ten key pathway nodes, revealing selective activation dependencies of MAPK and PI3K pathways associated with specific biomarkers. Notably, we discovered new pathway hyperactivation dependencies in subsets of APC-mutant colorectal cancers where further activation of the WNT pathway by APC knockdown or direct β-catenin overexpression led to robust antitumor effects in xenograft and patient-derived organoid models. Together, this study reveals a new class of conditional gene-activation dependencies in cancer.
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New England Journal of Medicine
Skin Cancer after Ruxolitinib or Belumosudil
Cutler C
Lee and colleagues (July 13 issue) describe two patients with chronic graft-versus-host-disease (GVHD) in whom aggressive cutaneous squamous-cell carcinoma developed while they received treatment that included ruxolitinib or belumosudil, recently approved drugs for the management of chronic GVHD. These two patients had multiple risk factors for cutaneous squamous-cell carcinoma, including previous premalignant or malignant skin tumors, the use of ultraviolet B phototherapy, and prolonged immunosuppression in the context of cutaneous chronic GVHD. Among long-term survivors of hematopoietic-cell transplantation (HCT), the risk of secondary solid tumors is increased by a factor of 2 or 3 and the risk of cutaneous squamous-cell carcinoma is increased by a factor of more than 4.
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Blood Advances
Effect of BMI on Toxicities and Survival Among Adolescents and Young Adults Treated on DFCI Consortium ALL Trials
Shimony S, Flamand Y, Place AE, Silverman LB, Vrooman LM, Brunner AM, Sallan SE, Stone RM, Wadleigh M, Neuberg DS, DeAngelo DJ, Luskin MR
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Blood Advances
FLT3-ITD Does not Predict Inferior Prognosis in Acute Myeloid Leukemia Patients Aged ≥60 Years
Shimony S, Fell G, Chen EC, Tsai HK, Wadleigh M, Winer ES, Garcia JS, Luskin MR, Stahl M, Neuberg DS, DeAngelo DJ, Lindsley RC, Stone RM
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Cell Chemical Biology
Screening in Serum-Derived Medium Reveals Differential Response to Compounds Targeting Metabolism
Ali A, Ferreira R, Cheah JH, Soule CK, Deik A, Schmidt DR, Hsu PP, Gramatikov IMT, Clish CB, Rees MG, Roth JA, Vander Heiden MG
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Cell Reports Medicine
Spatially Aware Deep Learning Reveals Tumor Heterogeneity Patterns that Encode Distinct Kidney Cancer States
Nyman J, Denize T, Bakouny Z, Labaki C, Titchen BM, Bi K, Hari SN, Rosenthal J, Mehta N, Jiang B, Sharma B, Felt K, Umeton R, Rodig S, Choueiri TK, Signoretti S, Van Allen EM
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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
PD-1 Blockade Induces Reactivation of Non-Productive T Cell Responses Characterized by NF-kB Signaling in Patients with Pancreatic Cancer
Ali LR, Lenehan PJ, Cardot-Ruffino V, Dias Costa A, Nowak JA, Wolpin BM, Abrams TA, Patel A, Clancy TE, Wang J, Mancias JD, Rahma OE, Dougan SK
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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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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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Pediatric Blood and Cancer
Phase 1 Study of Cabozantinib in Combination with Topotecan-Cyclophosphamide for Patients with Relapsed Ewing Sarcoma or Osteosarcoma
Campbell K, Posner A, Chen N, Cavanaugh K, Bhushan K, Janeway KA, Shulman DS, George S, Klega K, Crompton B, London WB, DuBois SG
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Science Advances
Intertumoral Lineage Diversity and Immunosuppressive Transcriptional Programs in Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors
Hoffman SE, Bi K, Titchen B, Johri S, DelloStritto L, Patel M, Mackichan C, Inga S, Chen J, Grimaldi G, Napolitano S, Wakiro I, Wu J, Yeung J, Rotem A, Sicinska E, Shannon E, Clancy T, Wang J, Denning S, Brais L, Besson NR, Pfaff KL, Huang Y, Kao KZ, Rodig S, Hornick JL, Vigneau S, Park J, Chan J, Van Allen EM
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Science Translational Medicine
TP63 Fusions Drive Multicomplex Enhancer Rewiring, Lymphomagenesis, and EZH2 Dependence
Wu G, Yoshida N, Liu J, Zhang X, Xiong Y, Heavican-Foral TB, Mandato E, Liu H, Nelson GM, Donovan KA, Jones MK, Xu R, Nirmal AJ, Jain S, Leahy C, Jones KL, Stevenson KE, Wu WC, Louissaint A, Debaize L, Yoon H, Dal Cin P, Ho Sui SJ, Ng SY, Adelman K, Fischer ES, Weinstock DM, Brown M
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