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 May 16 through May 31.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing [email protected].
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Blood
CRISPR-Cas13d Functional Transcriptomics Reveals Widespread Isoform-Selective Cancer Dependencies on lncRNAs
Aktas Samur A, Maisano D, Gao C, Favasuli VK, Liu N, Folino P, Vreux L, Cumerlato M, Chen L, Fulciniti M, Anderson KC, Samur MK, Munshi NC
Long noncoding RNAs (lncRNAs) are a significant yet largely uncharted component of the cancer transcriptome, with their isoform-specific functions remaining poorly understood. In this study, we employed RNA-targeting CRISPR-Cas13d to uncover and characterize hundreds of tumor-essential (te)-lncRNA isoforms with clinical relevance. Focusing on multiple myeloma (MM), we targeted the lncRNA transcriptome expressed in tumor cells from MM patients and revealed both MM-specific and pan-cancer dependencies across diverse cancer cell lines, which we further validated in animal models. Additionally, we mapped the subcellular localization of these te-lncRNAs, identifying over 30 cytosolic isoforms that proved essential when targeted by cytosol-localized Cas13d. Notably, a specific isoform of SNHG6, enriched in the endoplasmic reticulum, interacts with heat shock proteins to maintain cellular proteostasis. We also integrated functional and clinical data into the publicly accessible LongDEP Portal, providing a valuable resource for the research community. Our study offers a comprehensive characterization of te-lncRNAs, underscoring their oncogenic roles and therapeutic potential.
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JAMA Oncology
Expression of Membrane Targets for Therapeutics in RET-Positive Non-Small Cell Lung Cancer
Rotow JK, Jänne PA, Aldea M
IMPORTANCE: Patients with advanced RET fusion-positive (RET+) non-small cell lung cancer (NSCLC) who experience disease progression following treatment with RET inhibitors (RETis) have limited treatment options. Identifying membrane protein targets may support the assessment of novel therapies, such as antibody-drug conjugates and bispecific antibodies.
OBJECTIVE: To evaluate membrane target expression in RET+ NSCLC.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study used centralized immunohistochemistry (IHC) on archival tissue samples and whole transcriptome sequencing (WTS) in an independent cohort. Tissue samples were collected from 12 European centers, and WTS was performed on globally sourced patient samples submitted for molecular profiling. This study included samples from patients with RET+ NSCLC and RET-wild-type (RET-wt) adenocarcinoma controls that were analyzed by IHC and 203 RET+ and 19 579 RET-wt samples analyzed by WTS.
EXPOSURES: Membrane protein expression of MET, ERBB2 (formerly HER2), epidermal growth factor receptor (EGFR), human epidermal growth factor 3 (HER3), and trophoblastic cell surface antigen 2 (TROP2) was evaluated using IHC, with samples scored on a scale of 0 to 3. Scores of 2 or greater were considered positive. Target expression as analyzed by WTS was expressed as median transcript per million scores.
MAIN OUTCOMES AND MEASURES: Biomarker positivity, coexpression of biomarkers, dynamic changes in paired biopsies, and clinical correlates with survival outcomes.
RESULTS: A total of 189 patients were included in the study (among 81 patients with RET+ NSCLC, the median [IQR] age was 62 [55-70] years, and there were 49 female individuals [60%]). In 93 samples from 81 patients with RET+ NSCLC, positive IHC scores were observed for MET in 51 of 86 (59%), ERBB2 in 3 of 84 (3.6%), EGFR in 24 of 84 (29%), HER3 in 31 of 82 (38%), and TROP2 in 59 of 65 (91%). Compared with RET-wt adenocarcinoma (n = 112), RET+ tumors showed higher MET (59% vs 43%; P = .03) and lower ERBB2 expression (3.6% vs 15%; P = .01). The WTS analysis from the independent cohort confirmed these results. Of 61 evaluable samples, 59 of 61 (97%) had at least 1 positive biomarker, 60 of 77 (78%) when excluding TROP2. MET/EGFR coexpression occurred in 17 of 79 evaluable samples (21.5%). Dynamic change in biomarker expression was observed in paired biopsy specimens. No significant survival differences based on target expression emerged in patients treated with RETi in the IHC and the WTS cohorts.
CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that RET+ NSCLC tumors frequently express MET and TROP2, with MET positivity enriched vs RET-wt controls. Coexpression and biomarker dynamics highlight the need for membrane target screening and novel therapeutic strategies for this population.
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JAMA Oncology
Neoadjuvant PD-1 and PD-L1 Blockade with Chemotherapy for Borderline Resectable and Unresectable Stage III Non-Small Cell Lung Cancer
Ricciuti B, Garbo E, Pecci F, Aldea M, Wang X, Sholl LM, Nishino M, Di Federico A, Santo V, Ugalde Figueroa PA, Shaw AT, Awad MM
IMPORTANCE: Patients with borderline resectable or unresectable stage III non-small cell lung cancer (NSCLC) with T4 and/or N2-N3 involvement face limited treatment options and poor outcomes. Neoadjuvant chemoimmunotherapy has shown promise in improving resectability and pathological responses.
OBJECTIVE: To evaluate the efficacy of neoadjuvant programmed cell death 1 protein (PD-1) or programmed cell death 1 ligand 1 (PD-L1) blockade combined with chemotherapy in enhancing surgical outcomes and pathological responses in patients with T4 and/or N2-N3 stage III NSCLC.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study analyzed data from patients treated between February 2018 and January 2024 with neoadjuvant PD-1/PD-L1 inhibitors plus chemotherapy at academic and tertiary care centers across the US and Italy. Pathological and survival outcomes were assessed. Patients with stage III NSCLC and T4 and/or N2-N3 involvement were included. Data were collected from February 2018 to January 2024.
EXPOSURES: Neoadjuvant PD-1/PD-L1 blockade combined with platinum-based chemotherapy.
MAIN OUTCOMES AND MEASURES: Pathological complete response (pCR), major pathological response, surgical resectability, and event-free survival (EFS).
RESULTS: Of 112 patients, 58 (51.8%) were female, and the median (range) age was 66 (41-84) years. A total of 84(75.0%) underwent surgical resection, achieving a pCR rate of 29.0% (24 of 83 with available final pathology) and a major pathological response rate of 42.2% (35 of 83). Patients with both PD-L1 expression of 50% or more and high tumor mutational burden achieved the highest pCR rate (4 of 9 [44.4%]; P = .03). Conversely, covariants in KRAS/STK11 or KRAS/KEAP1 were associated with lack of pCR. Patients with single-station or multistation N2/N3 disease exhibited comparable pathological outcomes. The median EFS for all resected patients was 52.6 months (95% CI, 27.8 to not reached), and this was significantly longer in patients with pCR (not reached vs 27.8 months [95% CI, 19.5 to not reached]; P < .001).
CONCLUSIONS AND RELEVANCE: In this study, neoadjuvant PD-1/PD-L1 blockade combined with chemotherapy resulted in high pathological response rates and surgical resectability in patients with T4 and/or N2-N3 stage III NSCLC. This approach offers a viable treatment option for patients with borderline resectable or unresectable NSCLC but requires further validation through prospective studies.
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Journal of the National Cancer Institute
Rising Incidence of Early-Onset Colorectal Cancer: Impact of Anatomy and Histology
Char SK, Chan JA, Ng K
The incidence of early-onset colorectal cancer (EO-CRC) – defined as CRC diagnosed in adults younger than age 50 – has been steadily increasing over the past several decades. Although the steepest rise has been seen among adults aged 20-29 years, EO-CRC incidence is highest in adults aged 45-49 years, with an age-adjusted incidence rate of 33.4 per 100 000 between 2015 and 2019. EO-CRC is currently the leading cause of cancer-related death in men age <50 years and the second leading cause among women age <50 years. In response to these trends, the United States Preventative Services Task Force (USPSTF) formally recommended lowering the age at which to start CRC screening from 50 to 45 years for average-risk individuals in 2021.
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Lancet
The Missing Link in the NCD Agenda: Girls and Young Women Remain Overlooked
Sana H, Viswanath K
An update to the original 2016 Commission, this second iteration of The Lancet Commission on adolescent health and wellbeing presents crucial data on the challenges faced by adolescents and shares a call for rapid investment in adolescent health and wellbeing. The Commission reports non-existent progress on non-communicable disease (NCD)-related mortality and disability-adjusted life-years (DALYs) for adolescents, with especially poorer performance for NCD DALYs for adolescent girls across all regions. Here we argue for a gender disaggregated lens for shaping NCD prevention, diagnosis, and management strategies.
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Nature Cancer
Cellular Hierarchies of Embryonal Tumors with Multilayered Rosettes are Shaped by Oncogenic MicroRNAs and Receptor-Ligand Interactions
Beck A, Gabler-Pamer L, Alencastro Veiga Cruzeiro G, Lambo S, Englinger B, Shaw ML, Hack OA, Liu I, Haase RD, de Biagi CAO Jr, Baumgartner A, Nascimento Silva AD, Baird LC, Yang E, Chi SN, Alexandrescu S, Hovestadt V, Filbin MG
Embryonal tumor with multilayered rosettes (ETMR) is a pediatric brain tumor with dismal prognosis. Characteristic alterations of the chromosome 19 microRNA cluster (C19MC) are observed in most ETMR; however, the ramifications of C19MC activation and the complex cellular architecture of ETMR remain understudied. Here we analyze 11 ETMR samples from patients using single-cell transcriptomics and multiplexed spatial imaging. We reveal a spatially distinct cellular hierarchy that spans highly proliferative neural stem-like cells and more differentiated neuron-like cells. C19MC is predominantly expressed in stem-like cells and controls a transcriptional network governing stemness and lineage commitment, as resolved by genome-wide analysis of microRNA-mRNA binding. Systematic analysis of receptor-ligand interactions between malignant cell types reveals fibroblast growth factor receptor and Notch signaling as oncogenic pathways that can be successfully targeted in preclinical models and in one patient with ETMR. Our study provides fundamental insights into ETMR pathobiology and a powerful rationale for more effective targeted therapies.
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Nature Genetics
Genomic Landscape of Multiple Myeloma and Its Precursor Conditions
Alberge JB, Dutta AK, Poletti A, Coorens THH, Lightbody ED, Toenges R, Loinaz X, Wallin S, Dunford A, Priebe O, Dagan J, Boehner CJ, Horowitz E, Su NK, Barr H, Hevenor L, Towle K, Beesam R, Beckwith JB, Perry J, Cordas Dos Santos DM, Bertamini L, Kübler K, Hess J, Sklavenitis-Pistofidis R, Stewart C, Getz G, Ghobrial IM
Reliable strategies to capture patients at risk of progression from precursor stages of multiple myeloma (MM) to overt disease are still missing. We assembled a comprehensive collection of MM genomic data comprising 1,030 patients (218 with precursor conditions) that we used to identify recurrent coding and non-coding candidate drivers as well as significant hotspots of structural variation. We used those drivers to define and validate a simple 'MM-like' score, which we could use to place patients' tumors on a gradual axis of progression toward active disease. Our MM precursor genomic map provides insights into the time of initiation and cell-of-origin of the disease, order of acquisition of genomic alterations and mutational processes found across the stages of transformation. Taken together, we highlight here the potential of genome sequencing to better inform risk assessment and monitoring of MM precursor conditions.
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Cell Reports Medicine
Dissecting the Immune Landscape in Pediatric High-Grade Glioma Reveals Cell State Changes Under Therapeutic Pressure
LaBelle JJ, Haase RD, Haase J, Jiang L, Oliveira de Biagi CA Jr, Neyazi S, Englinger B, Liu I, Trissal M, Jeong D, Hack OA, Nascimento A, Shaw ML, Nguyen CM, Castellani S, Mathewson ND, Ashenberg O, Veiga Cruzeiro GA, Rosenberg T, Vogelzang JR, Pyrdol J, Marx S, Luomo AM, Godicelj A, Baumgartner A, Rozowsky JS, Yeo KK, Cooney T, Ligon K, Lidov H, Alexandrescu S, Baird LC, Gojo J, Wucherpfennig KW, Filbin MG
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Clinical Cancer Research
Clinicogenomic Characterization of Inflammatory Breast Cancer
Priedigkeit N, Harrison B, Hughes ME, Li Y, Lebrón-Torres A, Kirkner GJ, Spurr LF, Remolano MC, Strauss S, Files J, Feeney AM, Grant L, Mohammed-Abreu A, Garrido-Castro A, Barroso Bychkovsky B, Nakhlis F, Bellon JR, King TA, Winer EP, Johnson BE, Sholl L, Dillon D, Overmoyer B, Tolaney SM, Cherniack AD, Lin NU, Lynce F
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Contemporary Clinical Trials
Exercise to Enhance Cardiovascular Health Among Black Men with Prostate Cancer with Androgen Deprivation Therapy (The POWER Trial): A Study Protocol
Kang DW, Ficarra S, Wilson RL, Morgans AK, Nguyen PL, Rebbeck TR, Einstein DJ, Uno H, Mossanen M, Hill DM, Gonzalo-Encabo P, Norris MK, Gardiner J, Greer J, Dieli-Conwright CM
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Gynecologic Oncology
Phase 2, Two-Stage Study of Avelumab and Axitinib in Patients with Mismatch Repair Proficient Recurrent or Persistent Endometrial Cancer
Lee EK, Xiong N, Krasner C, Polak M, Campos S, Wright AA, Liu JF, Shea M, Yeku O, Castro C, Porter R, Stover EH, Koppermann L, Smith J, Sawyer H, Hayes M, Zhou N, Cheng SC, Bouberhan S, Pfaff KL, Rodig SJ, Jones S, Penson RT, Matulonis UA, Konstantinopoulos PA
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Journal of Geriatric Oncology
Patterns of Presentation, Treatment, and Survival Among Older Adults with Metastatic Breast Cancer: Results from a Large Prospective Registry
Newman AB, Martin AR, Hughes ME, Higgins A, Kirkner GJ, Files J, Skeffington M, Moore M, Strauss S, Kuhnly N, Crowley L, Tolaney SM, Lin NU, Freedman RA
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Neuro-Oncology
Clinical, Molecular and Radiological Predictors of Prognosis in Newly Diagnosed Astrocytoma, IDH-Mutant, WHO Grade 4
Lasica AB, Lan Z, Miller JJ, Jiao A, Pan I, Aker L, Prabhakar P, Japo J, Russ A, Westergaard C, Aquilanti E, Chukwueke U, Gonzalez Castro LN, Lee EQ, Nayak L, Beroukhim R, Batchelor TT, Cahill DP, Nakhate V, Lanman T, Pablo Ospina J, Stec N, Patel RV, Meredith DM, Bi WL, Reardon DA, Ligon KL, Huang RY, Wen PY, Youssef G
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