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Management of patients with advanced-stage HER2-positive breast cancer: current evidence and future perspectives (vol 21, pg 185, 2024)

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NATURE REVIEWS CLINICAL oncology 2024年第9期21卷 701-701页

作者： Marra, Antonio Chandarlapaty, Sarat Modi, Shanu Division of New Drugs and Early Drug Development European Institute of Oncology IRCCS Milan Italy Human Oncology and Pathogenesis Program (HOPP) Memorial Sloan Kettering Cancer Center New York NY USA Breast Medicine Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA Weill Cornell Medical College New York NY USA

Amplification and/or overexpression of ERBB2, the gene encoding HER2, can be found in 15–20% of invasive breast cancers and is associated with an aggressive phenotype and poor clinical outcomes. Relentless research efforts in molecular biology and drug development have led to the implementation of several HER2-targeted therapies, including monoclonal antibodies, tyrosine-kinase inhibitors and antibody–drug conjugates, constituting one of the best examples of bench-to-bedside translation in oncology. Each individual drug class has improved patient outcomes and, importantly, the combinatorial and sequential use of different HER2-targeted therapies has increased cure rates in the early stage disease setting and substantially prolonged survival for patients with advanced-stage disease. In this Review, we describe key steps in the development of the modern paradigm for the treatment of HER2-positive advanced-stage breast cancer, including selecting and sequencing new-generation HER2-targeted therapies, and summarize efficacy and safety outcomes from pivotal studies. We then outline the factors that are currently known to be related to resistance to HER2-targeted therapies, such as HER2 intratumoural heterogeneity, activation of alternative signalling pathways and immune escape mechanisms, as well as potential strategies that might be used in the future to overcome this resistance and further improve patient outcomes.

关键词： Breast cancer Targeted therapies Tumour biomarkers

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Defining 2 biologically and clinically distinct groups in acute leukemia with a mixed phenotype

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Blood 2025年第18期145卷 2056-2069页

作者： Galera, Pallavi Dilip, Deepika Derkach, Andriy Chan, Alexander Zhang, Yanming Persaud, Sonali Mishra, Tanmay Kramer, Kyle Kathpalia, Mahak Liu, Ying Famulare, Christopher Gao, Qi Mata, Douglas A. Arcila, Maria Geyer, Mark B. Stein, Eytan Dogan, Ahmet Roshal, Mikhail Levine, Ross L. Glass, Jacob Xiao, Wenbin Hematopathology Service Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY United States Center for Epigenetics Research Memorial Sloan Kettering Cancer Center New York NY United States Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY United States Department of Pathology and Laboratory Medicine Cytogenetics Laboratory Memorial Sloan Kettering Cancer Center New York NY United States Molecular Cancer Medicine Service Human Oncogenesis and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY United States Department of Pathology and Laboratory Medicine Diagnostic Molecular Laboratory Memorial Sloan Kettering Cancer Center New York NY United States Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY United States Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY United States Cell Therapy Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY United States

A mixed phenotype (MP) is a characteristic of de novo MP acute leukemia (MPAL), but it can also be found in other leukemias. It poses substantial classification and management dilemmas. Herein, we report a large cohort of acute leukemia with MP and define acute myeloid leukemia with MP (AML-MP) and MPAL as 2 distinct groups by characterizing clinical, genetic, and transcriptomic features. Clinically, patients with AML-MP and MPAL were both treated with either AML- or acute lymphoblastic leukemia (ALL)–directed induction regimens. AML-MP has inferior responses (hazard ratio, 12.5;95% confidence interval, 2.72-57.8;P = .001), whereas MPAL has better responses to ALL-directed treatment. Genetically, AML-MP harbors more frequent RUNX1 (23/52 [44%]) and TP53 (12/52 [23.1%]) mutations. In contrast, RUNX1 mutations are less frequent in MPAL (8/35 [23%];P = .01 vs AML-MP) and TP53 mutations as a driver are virtually absent in MPAL. Transcriptionally, AML-MP shows enrichment for stemness signatures and a relative deficit of transcription factors critical for myeloid and lymphoid differentiation. Furthermore, AML-MP rarely switches to a lymphoid immunophenotype after treatment, in contrast to MPAL (1/40 [2.5%] vs 10/28 [35.7%];P = .0003). Last, a genomic classification framework is proposed for future studies. Together, these data support the designation of AML-MP as a diagnosis distinct from MPAL and provide novel insights into the pathogenesis and therapies of acute leukemia with MP. © 2025 American Society of Hematology

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

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Signal Transduction and Targeted Therapy 2024年第8期9卷 3519-3532页

作者： Alvaro Quintanal-Villalonga Kenta Kawasaki Esther Redin Fathema Uddin Swanand Rakhade Vidushi Durani Amin Sabet Moniquetta Shafer Wouter R.Karthaus Samir Zaidi Yingqian A.Zhan Parvathy Manoj Harsha Sridhar Dennis Kinyua Hong Zhong Barbara P.Mello Metamia Ciampricotti Umesh K.Bhanot Irina Linkov Juan Qiu Radhika A.Patel Colm Morrsey Sanjoy Mehta Jesse Barnes Michael C.Haffner Nichlas D.Socci Richard P.Koche Elisa de Stanchina Sonia Molina-Pinelo Sohrab Salehi Helena A.Yu Joseph M.Chan Charles M.Rudin Department of Medicine Thoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Cancer Biology and Genetics Program Sloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Vagelos College of Physicians and Surgeons Columbia UniversityNew YorkNYUSA Weill Cornell Graduate School of Medical Sciences Weill Cornell MedicineNew YorkNYUA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Center for Epigenetics Research Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Pathology Core Facilty Department of Pathology and Laboratory MedicineMSKCCNew YorkNYUSA Antitumor Assessment Core Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Divisionsof Human Biology and Clinical Research Fred Hutchinon Cancer CenterSeattleWAUSA Deparmentof Urology University of WashingtonSeattleWAUSA Gene Editing&Screening Core Facility Memorial Sloan Kettering Cancer Center New YorkNYUSA Department of Laboratory Medicine and Pathology University of WashingtonSeattleWAUSA Bioinfomatics CoreFacility Memorial Soan Kettering Cancer CenterNew YorkNYUSA Institute of Biomedicine of Seille(Bis) HURCSCUniversidad de SevillaSevilleSpain Computational Oncology Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Well Cornell Medical College New York NYUSA Present address:Swiss Institute for Experimental Cancer Research(ISREC) School of Life SciencesEPFLLausanneSwitzerland

Neuroendocrine(NE)transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor *** to date,even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53(TP53)and Retinoblastoma Transcriptional Corepressor 1(RB1)mutations in their tumors,no therapeutic strategies are available to prevent or delay histological *** of the cell cycle kinase Cell Division Cycle 7(CDC7)occurred in tumors during the initial steps of NE transformation,already after TP53/RB1 co-inactivation,leading to induced sensitivity to the CDC7 inhibitor ***7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen(MYC),implicated in stemness and histological *** overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy,even in the presence of ***7 inhibition also markedly extended response to standard cytotoxics(cisplatin,irinotecan)in lung and prostate small cell carcinoma *** results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity,as well as to effectively treat NE tumors de novo or after *** simurosertib clinical efficacy trials are ongoing,this concept could be readily translated for patients at risk oftransformation.

关键词： tumors markedly transformation

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LSD1 Inhibitor CPI-482 Shows Efficacy and Prolongs Survival in Mouse Models of AML and Post-MPN AML in the Context of Constitutive JAK-STAT Pathway Activation

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BLOOD 2020年 136卷 50-51页

作者： Rampal, Raajit K. McGrath, John P. Krishnan, Aishwarya Li, Bing Xiao, Wenbin Nikom, David Wang, Jing Levine, Ross L. Trojer, Patrick Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY Translational Sciences Constellation Pharmaceuticals Cambridge MA Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY Department of Pathology Memorial Sloan Kettering Cancer Center New York NY Constellation Pharmaceuticals Cambridge MA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Department of Medicine Leukemia Service Memorial Sloan Kettering Cancer Center New York NY

Several novel mechanism-based therapeutic modalities are currently being clinically investigated for the treatment of patients with acute myelogenous leukemia (AML), including agents that exploit genomic vulnerabilities, attenuate leukemia stem cell populations and/or or synergize with anti-leukemic cytotoxic/epigenetic therapies. Lysine-specific demethylase 1 (LSD1) is an enzyme that functions in transcriptional repression by catalyzing the removal of histone H3 lysine 4 methylation, a histone modification associated with transcriptionally competent gene enhancers and transcriptional start sites. Small molecule mediated inhibition of LSD1 alters the chromatin state and the transcriptional output of LSD1 target genes. Transcriptional ‘reprogramming’ by LSD1 inhibitors either causes a direct impact on cell fate and/or renders malignant cells more susceptible to the treatment with other cancer therapeutic agents. LSD1 inhibitors have shown encouraging phenotypic effects in myelogenous leukemia (AML) models but the key molecular determinants governing LSD1 inhibitor sensitivity remain to be further investigated. Here, we explored the in vitro sensitivity of 350 cancer cell lines to our LSD1 inhibitor CPI-482 to identify potential hyper-responder cell contexts. Four AML cell lines showed high sensitivity with low nanomolar concentration GI 50 s, each of which contained either a JAK2 V617F mutation or a genetic aberration that resulted in JAK-STAT pathway activation. Oral administration of LSD1 inhibitor CPI-482 on a once daily or a once weekly dosing schedule resulted in significant tumor growth inhibition in SET-2 and HEL 92.1.7 JAK2 mutant AML xenograft mouse models. Given the unmet need and poor prognosis in post-MPN secondary AML (sAML) we then explored CPI-482 in a tertiary transplant post-MPN AML retroviral transduction murine model ( Jak2 V617F retrovirus transduced into Tp53 null bone marrow). Jak2 V617F/ Tp53 null spleen cells were transplanted into lethally ir

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Venetoclax Therapy for Relapsed and Treatment Refractory AML: Clinical Outcomes and Molecular Predictors

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BLOOD 2020年 136卷 47-48页

作者： Stahl, Maximilian Menghrajani, Kamal Derkach, Andriy Chan, Alexander Xiao, Wenbin Glass, Jacob L. King, Amber C. Daniyan, Anthony Famulare, Christopher Cuello, Bernadette M. Abdel-Wahab, Omar Levine, Ross L. Viny, Aaron D. Stein, Eytan M. Roshal, Mikhail Tallman, Martin S. Goldberg, Aaron D. Department of Medicine Leukemia Service Memorial Sloan Kettering Cancer Center New York NY Weill Cornell Medical College New York NY Department of Biostatistics and Epidemiology Memorial Sloan Kettering Cancer Center New York NY Department of Pathology Memorial Sloan Kettering Cancer Center New York NY Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York Center for Epigenetics Research Memorial Sloan Kettering Cancer Center New York NY Department of Pharmacy Memorial Sloan Kettering Cancer Center New York NY Department of Medicine Leukemia Service Memorial Sloan Kettering Cancer Center NY NY Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Memorial Sloan-Kettering Cancer Center New York NY Department of Medicine Leukemia Service Memorial Sloan-Kettering Cancer Center New York NY

Background: Venetoclax combined with azacitidine (aza/ven), decitabine (dec/ven), and low-dose cytarabine (LDAC/ven) is commonly used off-label in relapsed/refractory (RR)-AML patients; however, predictors of response and survival are incompletely understood. Objectives: To report clinical outcomes of RR-AML patients (pts) treated with venetoclax combination therapy and to analyze molecular predictors of these outcomes. Methods: All pts with RR-AML, who received treatment with aza/ven, dec/ven or LDAC/ven from 08/2016 to 02/2020 at Memorial Sloan Kettering Cancer Center in New York City were included. The best response to therapy was determined using the 2017 European leukemiaNet (ELN) response criteria. The overall response rate (ORR) was defined as the combination of the complete response (CR) + complete response with incomplete count recovery (CRi) + morphologic leukemia free state (MLFS) rate. Measurable residual disease (MRD) was assessed by multiparameter flow cytometric analysis of bone marrow aspirate samples and any level of residual disease was considered MRD+. Overall survival (OS) was calculated from cycle 1 day 1 of therapy until death or time of last follow-up. Results: A total of 86 pts were treated with venetoclax-based combination therapy ( A ). Median age was 67 years. More than half of the pts had received prior HMA therapy, 17% had received a prior allogeneic stem cell transplant. The majority of pts received aza/ven (41%) while 23% and 31% received dec/ven and LDAC/ven, respectively. Treatment trajectories of all patients are shown in the Swimmers' plot in panel ( B ). While the ORR was 31% and 24% of patients achieved a CR/CRi, 60% of pts were refractory to venetoclax therapy; 45% of responding pts eventually relapsed with a median follow up of 12 months ( B, C ). Oncoprint showing associations between molecular patterns and response to venetoclax combination therapy is shown in panel ( D ). Mutations in NPM1 (CR/CRi 46%, ORR 62%; OR 4.53, 95%

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ZRSR2 Mutation Induced Minor Intron Retention Drives MDS and Diverse Cancer Predisposition Via Aberrant Splicing of LZTR1

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BLOOD 2020年 136卷 10-11页

作者： Inoue, Daichi Polaski, Jacob T. Taylor, Justin Castel, Pau Chen, Sisi Kobayashi, Susumu Hogg, Simon J. Hayashi, Yasutaka Pineda, Jose Mario Bello Penson, Alexander V. El Marabti, Ettaib Erickson, Caroline Fukumoto, Miki Yamazaki, Hiromi Fukui, Chie Lu, Sydney X. Durham, Benjamin H. Liu, Bo Mehta, Sanjoy Zakheim, Daniel Garippa, Ralph Chew, Guo-Liang McCormick, Frank Bradley, Robert K. Abdel-Wahab, Omar Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Department of Hematology-Oncology Institute of Biomedical Research and Innovation Foundation for Biomedical Research and Innovation at Kobe Kobe Japan Public Health Sciences and Basic Sciences Divisions Fred Hutchinson Cancer Research Center Seattle Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center Miami FL Helen Diller Family Comprehensive Cancer Center University of California San Francisco San Francisco Foundation for Biomedical Research and Innovation at Kobe Kobe Japan Department of Genome Sciences University of Washington Seattle Memorial Sloan Kettering Cancer Center New York Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York Myeloma Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY Gene Editing & Screening Facility Memorial Sloan Kettering Cancer Center New York

Mutations in RNA splicing factors are amongst the most common genetic alterations in myeloid malignancies. Mutations in the splicing factors SF3B1 , SRSF2 , and U2AF1 occur as heterozygous, missense mutations and have been shown to confer a change-of-function. In contrast, the X chromosome encoded ZRSR2 is enriched in nonsense/frameshift mutations in males, consistent with loss of function. To date however, we do not understand the basis for enrichment of ZRSR2 mutations in leukemia. Moreover, ZRSR2 is the only one of these factors that primarily functions in the minor spliceosome. While most introns are spliced by the major spliceosome, a small subset (<1%) of introns are recognized by a separate complex, the minor spliceosome. Although minor (or “U12”) introns are present in only ~800 genes in humans, their sequences and positions are highly evolutionarily conserved - more so than their U2 counterparts. The high conservation of minor introns suggests key regulatory roles yet few functional roles for the minor spliceosome in regulating biological phenotypes are known. The rarity and conservation of minor introns offered a unique opportunity to investigate splicing factor mutations and identify potential tissue-specific roles of the minor spliceosome. Modeling loss-of-function mutations in ZRSR2 via a mouse model for induced deletion of Zrsr2 revealed strikingly enhanced self-renewal of Zrsr2 -deficient male and female hematopoietic cells ( Fig. A-C ). This was in stark contrast to the effects of hotspot mutations in Sf3b1 and Srsf2 and similar to those of Tet2 loss on increasing self-renewal and numbers of HSCs. Zrsr2 loss was also associated increased myeloid cells in the blood and long-term hematopoietic stem cells (HSCs) in the marrow ( Fig. C ). To understand the mechanistic basis by which ZRSR2 loss causes aberrant HSC self-renewal, we quantified transcriptome-wide splicing patterns in MDS patients. ZRSR2 -mutant samples had widespread, dysfunctional recogniti

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Fundamental immuneoncogenicity trade-offs define driver mutation fitness (vol 606, pg 172, 2022)

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NATURE 2022年第7914期606卷 E5-E5页

作者： Hoyos, David Zappasodi, Roberta Schulze, Isabell Sethna, Zachary de Andrade, Kelvin Cesar Bajorin, Dean F. Bandlamudi, Chaitanya Callahan, Margaret K. Funt, Samuel A. Hadrup, Sine R. Holm, Jeppe S. Rosenberg, Jonathan E. Shah, Sohrab P. Vazquez-Garcia, Ignacio Weigelt, Britta Wu, Michelle Zamarin, Dmitriy Campitelli, Laura F. Osborne, Edward J. Klinger, Mark Robins, Harlan S. Khincha, Payal P. Savage, Sharon A. Balachandran, Vinod P. Wolchok, Jedd D. Hellmann, Matthew D. Merghoub, Taha Levine, Arnold J. Luksza, Marta Greenbaum, Benjamin D. Computational Oncology Department of Epidemiology & Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA Swim Across America Laboratory and Ludwig Collaborative Immunology Program Parker Institute for Cancer Immunotherapy Memorial Sloan Kettering Cancer Center New York NY USA Department of Medicine Weill Cornell Medical College New York NY USA Parker Institute for Cancer Immunotherapy Memorial Sloan Kettering Cancer Center New York NY USA Immunology and Microbial Pathogenesis Program Weill Cornell Graduate School of Medical Sciences New York NY USA Hepatopancreatobiliary Service Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA Division of Cancer Epidemiology and Genetics Clinical Genetics Branch National Cancer Institute National Institutes of Health Rockville MD USA Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA Kravis Center for Molecular Oncology Memorial Sloan Kettering Cancer Center New York NY USA Experimental and Translational Immunology Health Technology Technical University of Denmark Lyngby Denmark Physiology Biophysics & Systems Biology Weill Cornell Medicine Weill Cornell Medical College New York NY USA Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA Adaptive Biotechnologies Seattle WA USA David M. Rubenstein Center for Pancreatic Cancer Research Memorial Sloan Kettering Cancer Center New York NY USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY USA Thoracic Oncology Service Memorial Sloan Kettering Cancer Center New York NY USA Simons Center for Systems Biology Institute for Advanced Study Princeton NJ USA Department of Oncological Sciences Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA

Missense driver mutations in cancer are concentrated in a few hotspots1. Various mechanisms have been proposed to explain this skew, including biased mutational processes2, phenotypic differences3,4,5,6 and immunoediting of neoantigens7,8; however, to our knowledge, no existing model weighs the relative contribution of these features to tumour evolution. We propose a unified theoretical ‘free fitness’ framework that parsimoniously integrates multimodal genomic, epigenetic, transcriptomic and proteomic data into a biophysical model of the rate-limiting processes underlying the fitness advantage conferred on cancer cells by driver gene mutations. Focusing on TP53, the most mutated gene in cancer1, we present an inference of mutant p53 concentration and demonstrate that TP53 hotspot mutations optimally solve an evolutionary trade-off between oncogenic potential and neoantigen immunogenicity. Our model anticipates patient survival in The Cancer Genome Atlas and patients with lung cancer treated with immunotherapy as well as the age of tumour onset in germline carriers of TP53 variants. The predicted differential immunogenicity between hotspot mutations was validated experimentally in patients with cancer and in a unique large dataset of healthy individuals. Our data indicate that immune selective pressure on TP53 mutations has a smaller role in non-cancerous lesions than in tumours, suggesting that targeted immunotherapy may offer an early prophylactic opportunity for the former. Determining the relative contribution of immunogenicity and oncogenic function to the selective advantage of hotspot mutations thus has important implications for both precision immunotherapies and our understanding of tumour evolution.

关键词： Computational models Evolutionary theory Tumour immunology Tumour-suppressor proteins

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Redifferentiation therapy in unresectable or metastatic radioactive iodine refractory thyroid cancer: an International Thyroid oncology Group statement

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The Lancet Diabetes and Endocrinology 2025年第6期13卷 516-527页

作者： Leboulleux, Sophie Boucai, Laura Busaidy, Naifa Durante, Cosimo Fagin, James A Fazeli, Sasan Gianoukakis, Andrew G Haugen, Bryan R Kang, Hyunseok Konda, Bhavana Laetsch, Theodore W Locati, Laura Ryder, Mabel Spitzweg, Christine Worden, Francis P Wirth, Lori Ho, Alan Department of Medicine Endocrinology and Diabetology Service Geneva University Hospitals and Univerisity of Geneva Geneva Switzerland Department of Medicine Endocrinology Service Memorial Sloan Kettering Cancer Center New York NY United States Department of Endocrine Neoplasia and Hormonal Disorders The University of Texas MD Anderson Cancer Center Houston TX United States Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy Department of Medicine Memorial Sloan Kettering Cancer Center New York NY United States Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY United States Department of Clinical Diabetes Endocrinology & Metabolism City of Hope Comprehensive Cancer Center Duarte CA United States Division of Endocrinology Diabetes and Metabolism David Geffen School of Medicine at UCLA Harbor-UCLA Medical Center Los Angeles CA United States Division of Endocrinology Metabolism and Diabetes University of Colorado School of Medicine Aurora CO United States Department of Medicine University of California at San Francisco San Francisco CA United States Division of Medical Oncology Department of Internal Medicine The Ohio State University Comprehensive Cancer Center Columbus OH United States Center for Childhood Cancer Research Children's Hospital of Philadelphia Philadelphia PA United States Medical Oncology Unit Istituti Clinici Scientifici Maugeri IRCCS Pavia Italy Division of Endocrinology Diabetes Metabolism and Nutrition Mayo Clinic Rochester MN United States Department of Internal Medicine IV LMU Munich Germany Division of Endocrinology Diabetes Metabolism and Nutrition Mayo Clinic Rochester Minnesota United States Department of Internal Medicine Division of Hematology and Oncology University of Michigan Rogel Cancer Center Ann Arbor MI United States Harvard Medical School Boston MA United States Center for Head and Neck Cancers Massachusetts General Hospital

In patients with follicular cell-derived thyroid cancer that have distant metastases and no iodine uptake, redifferentiation—ie, the restoration of tumoural 131I uptake with systemic therapy—is now possible. The use...

In patients with follicular cell-derived thyroid cancer that have distant metastases and no iodine uptake, redifferentiation—ie, the restoration of tumoural ¹³¹I uptake with systemic therapy—is now possible. The use of mitogen-activated protein kinase (MAPK) inhibitors for a short period of time before the administration of high activity ¹³¹I shows promising results with iodine uptake restoration and tumour response. Redifferentiation has been used in patients with BRAF-mutated and RAS-mutated tumours in prospective trials and in the case of patients with RET or NTRK fusions. The iodine uptake restoration ranges from 33% to 95%, and tumour response rates from 11% to 80%. There is substantial variability between trials with regards to inclusion criteria, duration of redifferentiation drug therapy, activity of radioactive iodine, and use of dosimetry. Randomised studies are missing to clearly establish the effectiveness and applicability of redifferentiation. Thus, long-term studies are needed to establish the most effective redifferentiation protocols. The objectives of this Review are to: (1) provide a comprehensive review of the available results from prospective trials and case reports, including results regarding the restoration of radioiodine uptake and treatment efficacy (morphological and biological);(2) describe the differences in redifferentiation trial design between studies and discuss their potential impact on treatment efficacy;(3) describe the implications and limitations of dosimetry;and (4) outline the key questions to be addressed in future redifferentiation trials. © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

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Regional and intratumoral adoptive T-cell therapy

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Immuno-oncology and Technology 2024年 24卷 100715-100715页

作者： Olivera, I. Etxeberria, I. Luri-Rey, C. Molero-Glez, P. Melero, I. Program of Immunology and Immunotherapy Cima Universidad de Navarra Pamplona Navarra Institute for Health Research (IDISNA) Pamplona Spain Human Oncology and Pathogenesis Program (HOPP) Immuno-Oncology Service Memorial Sloan Kettering Cancer Center New York Parker Institute for Cancer Immunotherapy New York United States Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) Madrid Department of Immunology and Immunotherapy Clínica Universidad de Navarra Pamplona Department of Oncology Clínica Universidad de Navarra Madrid Centro del Cancer de la Universidad de Navarra (CCUN) Pamplona Spain Nuffield Department of Medicine (NDM) University of Oxford Oxford United Kingdom

Adoptive T-cell therapies (ACTs) including tumor-infiltrating lymphocytes and engineered T cells (transgenic T-cell receptor and chimeric antigen receptor T cells), have made an important impact in the field of cancer treatment over the past years. Most of these therapies are typically administered systemically in approaches that facilitate the elimination of hematologic malignancies. Therapeutical efficacy against solid tumors, however, with the exception of tumor-infiltrating lymphocytes against melanoma, remains limited due to several barriers preventing lymphocyte access to the tumor bed. Building upon the experience of regional administration in other immunotherapies, the regional administration of adoptive cell therapies is being assessed to overcome this challenge, granting a first round of access of the transferred T cells to the tumor niche and thereby ensuring their activation and expansion. Intralesional and intracavitary routes of delivery have been tested with promising antitumor objective responses in preclinical and clinical studies. Additionally, several strategies are being developed to further improve T-cell activity after reinfusing them back to the patient such as combinations with other immunotherapy agents or direct engineering of the transferred T cells, achieving long-term immune memory. Clinical trials testing different regional adoptive T-cell therapies are ongoing but some issues related to methodology of administration and correct selection of the target antigen to avoid on-target/off-tumor side-effects need to be further evaluated and improved. Herein, we discuss the current preclinical and clinical landscape of intratumoral and locoregional delivery of adoptive T-cell therapies. © 2024

关键词： CAR cell therapies regional TCR TIL

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Lineage plasticity in cancer: a shared pathway of therapeutic resistance (Mar, 10.1038/s41571-020-0340-z, 2020)

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NATURE REVIEWS CLINICAL oncology 2020年第6期17卷 382-382页

作者： Quintanal-Villalonga, Alvaro Chan, Joseph M. Yu, Helena A. Pe'er, Dana Sawyers, Charles L. Sen, Triparna Rudin, Charles M. Department of Medicine Thoracic Oncology Service Memorial Sloan Kettering Cancer Center New York NY USA Program for Computational and Systems Biology Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA Parker Institute for Cancer Immunotherapy Memorial Sloan Kettering Cancer Center New York NY USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY USA Howard Hughes Medical Institute Chevy Chase MD USA

Lineage plasticity, the ability of cells to transition from one committed developmental pathway to another, has been proposed as a source of intratumoural heterogeneity and of tumour adaptation to an adverse tumour microenvironment including exposure to targeted anticancer treatments. Tumour cell conversion into a different histological subtype has been associated with a loss of dependency on the original oncogenic driver, leading to therapeutic resistance. A well-known pathway of lineage plasticity in cancer — the histological transformation of adenocarcinomas to aggressive neuroendocrine derivatives — was initially described in lung cancers harbouring an EGFR mutation, and was subsequently reported in multiple other adenocarcinomas, including prostate cancer in the presence of antiandrogens. Squamous transformation is a subsequently identified and less well-characterized pathway of adenocarcinoma escape from suppressive anticancer therapy. The increased practice of tumour re-biopsy upon disease progression has increased the recognition of these mechanisms of resistance and has improved our understanding of the underlying biology. In this Review, we provide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumours. We discuss the current understanding of the molecular drivers of this phenomenon, emerging management strategies and open questions in the field.

关键词： Epithelial–mesenchymal transition Mechanisms of disease Prostate cancer Small-cell lung cancer

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