Welcome to Dana-Farber's Research News
November 15, 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.
Blood
Jacobson CA
Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 CAR T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel in patients with R/R indolent non-Hodgkin lymphoma (iNHL; N=104), including FL and marginal zone lymphoma (MZL). In the primary analysis (17.5 months median follow-up), overall response rate (ORR) was 92% (74% complete response rate). Here we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ?2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2×106 CAR T cells/kg). The primary endpoint was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n=127) and 31.8 months in MZL (n=31), ORR was comparable to the primary analysis (94% in FL; 77% in MZL). Median progression-free survival was 40.2 months in FL and not yet reached in MZL. Medians of overall survival were not reached in either disease type. Grade ?3 adverse events of interest occurring since the prior analysis were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL. The ZUMA-5 study is registered at ClinicalTrials.gov (NCT NCT03105336).
Cell
A Disordered Region Controls cBAF Activity Via Condensation and Partner Recruitment
Patil A, Paulo JA, Collings CK, Sankar A, Cervantes KS, Wauer T, St Laurent JD, Xu G, Gygi SP, Kadoch C
Intrinsically disordered regions (IDRs) represent a large percentage of overall nuclear protein content. The prevailing dogma is that IDRs engage in non-specific interactions because they are poorly constrained by evolutionary selection. Here, we demonstrate that condensate formation and heterotypic interactions are distinct and separable features of an IDR within the ARID1A/B subunits of the mSWI/SNF chromatin remodeler, cBAF, and establish distinct "sequence grammars" underlying each contribution. Condensation is driven by uniformly distributed tyrosine residues, and partner interactions are mediated by non-random blocks rich in alanine, glycine, and glutamine residues. These features concentrate a specific cBAF protein-protein interaction network and are essential for chromatin localization and activity. Importantly, human disease-associated perturbations in ARID1B IDR sequence grammars disrupt cBAF function in cells. Together, these data identify IDR contributions to chromatin remodeling and explain how phase separation provides a mechanism through which both genomic localization and functional partner recruitment are achieved.
Journal of Clinical Oncology
Mack JW, Cernik C, Uno H, Fisher L, Lakin JR
PURPOSE: Adolescents and young adults (AYAs) with cancer receive high rates of medically intensive measures at the end of life. This study aimed to characterize the prevalence and timing of conversations about goals of care and advance care planning among AYAs at the end of life as one potential influence on care received.
METHODS: This was a review of electronic health data and medical records for 1,929 AYAs age 12-39 years who died after receiving care at one of three sites between 2003 and 2019, including documented conversations about goals of care and advance care planning, and care received.
RESULTS: A majority of AYAs were female (54%) and White (61%); 12% were Asian, 8% Black, and 27% Hispanic. Most patients had documented discussions about prognosis (86%), goals of care (83%), palliative care (79%), hospice (79%), and preferred location of death (64%). When last documented goals of care were evaluated, 69% of patients wanted care focused on palliation; however, 29% of those with palliative goals spent time in the intensive care unit (ICU) in the last month of life, and 32% had multiple emergency room (ER) visits. When goals-of-care discussions happened earlier, >30 days before death, AYAs were less likely to receive chemotherapy in the last 14 days of life (P = .001), ICU care (P < .001), ER visits (P < .001), and hospitalizations in the last month (P < .001).
CONCLUSION: High rates of medically intensive measures among AYAs near the end of life do not appear to be the result of a lack of discussions about goals of care and advance care planning. Although some interventions may be used to support palliative goals, earlier discussions have potential to reduce late-life intensive measures.
Journal of Clinical Oncology
Germline EGFR Mutations and Familial Lung Cancer
Oxnard GR, Chen R, Pharr JC, Koeller DR, Bertram AA, Dahlberg SE, Rainville I, Sholl LM, Jänne PA, Garber JE
PURPOSE: The genomic underpinnings of inherited lung cancer risk are poorly understood. This prospective study characterized the clinical phenotype of patients and families with germline EGFR pathogenic variants (PVs).
METHODS: The Investigating Hereditary Risk from T790M study (ClinicalTrials.gov identifier: NCT01754025) enrolled patients with lung cancer whose tumor profiling harbored possible germline EGFR PVs and their relatives, either in person or remotely, providing germline testing and follow-up.
RESULTS: A total of 141 participants were enrolled over a 5-year period, 100 (71%) remotely. Based upon previous genotyping, 116 participants from 59 kindreds were tested for EGFR T790M, demonstrating a pattern of Mendelian inheritance with variable lung cancer penetrance. In confirmed or obligate carriers of a germline EGFR PV from 39 different kindreds, 50/91 (55%) were affected with lung cancer with 34/65 (52%) diagnosed by age 60 years. Somatic testing of lung cancers in carriers revealed that 35 of 37 (95%) had an EGFR driver comutation. Among 36 germline carriers without a cancer diagnosis, 15 had computed tomography (CT) imaging and nine had lung nodules, including a 28-year-old with >10 lung nodules. Given geographic enrichment of germline EGFR T790M in the southeast United States, genome-wide haplotyping of 46 germline carriers was performed and identified a 4.1-Mb haplotype shared by 41 (89%), estimated to originate 223-279 years ago.
CONCLUSION: To our knowledge, this is the first prospective description of familial EGFR-mutant lung cancer, identifying a recent founder germline EGFR T790M variant enriched in the Southeast United States. The high prevalence of EGFR-driver lung adenocarcinomas and lung nodules in germline carriers supports effort to identify affected patients and family members for investigation of CT-based screening for these high-risk individuals.
Journal of Clinical Oncology
Palliative Care in Adolescents and Young Adults with Cancer
Rosenberg AR
Palliative care (PC) aims to improve quality of life (QOL) for patients with serious illness and their families by recognizing and alleviating the physical, emotional, social, existential, and spiritual suffering of patients and their communities. Because adolescents and young adults (AYAs, age 15-39 years) with cancer commonly report distress across all these domains and because that distress translates to their QOL during and after their cancers, PC is particularly relevant for this population. Here, we review the evidence for PC among AYAs with cancer, including its rationale, gaps, opportunities, and implications for care delivery. For example, nearly 90% of AYAs with cancer report distressing symptoms during their treatment, those who survive report ongoing unmet psychosocial and physical health needs, and those who die from their cancers are highly likely to receive medically intense care that is discordant with their goals and values. AYA communication and decision making can be challenging because of ethical and developmental considerations regarding the patient's autonomy and competing priorities of patients and caregivers. PC interventions (including primary PC delivered by oncologists, routine PC subspecialty care, symptom tracking, advance care planning, and psychosocial programs promoting AYA resilience) are all associated with improved patient-centered outcomes. However, PC is inconsistently integrated into AYA oncology care, and access to PC programs is not equitable; marginalized groups continue to experience poorer outcomes. Ongoing and future research and clinical initiatives must continue to bridge these gaps. Improving the QOL of AYAs with cancer is a shared goal of the larger clinical oncology community, and including PC in AYA cancer care delivery can help attain that goal.
Journal of Clinical Oncology
Quality of End-of-Life Care Among Adolescents and Young Adults with Cancer
Mack JW, Cernik C, Uno H, Fisher L, Cooper RM
Adolescents and young adults (AYAs) receive high rates of medically intensive measures at the end of life, but less is known about other measures of quality cancer care, such as use of palliative care and hospice, symptom management, and psychological support. We conducted a review of electronic health data and medical records for 1,929 AYAs age 12-39 years who died after receiving cancer care at one of three sites (Dana-Farber Cancer Institute, Kaiser Permanente Northern California, and Kaiser Permanente Southern California) between 2003 and 2019, including medical care and treatment, assessment and management of physical and psychological symptoms, and support of psychosocial and spiritual needs. We found that AYAs frequently received medically intensive measures, including late-life emergency room visits (25% with two or more in the last month) and intensive care unit (ICU) admissions (31%). However, most also received palliative care (73%) and hospice (62%). Just over half (58%) received psychosocial care in the last 90 days of life, and 49% received spiritual care, with an additional 7% declining spiritual care. Nearly all patients had pain assessed in the last 90 days of life, but only 34% had assessment for depression and 40% for anxiety. In summary, this study found that AYAs often receive medically intensive measures at the end of life, including ICU care in nearly a third, but most also receive palliative care and hospice. Suboptimal rates of psychosocial and spiritual care and assessment of psychological symptoms offer an opportunity to better address emotional and spiritual distresses at the end of life in this young population.
Lancet
Bardia A, Tolaney SM
BACKGROUND: Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ and HER2-) metastatic breast cancer with limited treatment options. Here, we report the protocol-specified final analysis of overall survival and endpoints by trophoblast cell-surface antigen 2 (Trop-2) expression and other variables.
METHODS: In this randomised, open-label, multicentre, phase 3 trial, which took place in 91 centres across North America (the USA and Canada) and Europe (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK), patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR+ and HER2- locally recurrent inoperable or metastatic breast cancer and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease. The primary endpoint was progression-free survival (previously reported and not included in this analysis), and secondary endpoints included overall survival, objective response rate (ORR), and patient-reported outcomes. Overall survival was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry. In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if overall survival was significant. This study is registered with ClinicalTrials.gov, NCT03901339.
FINDINGS: At the data cutoff date of July 1, 2022, 543 of 776 screened patients were randomly assigned between May 30, 2019, and April 5, 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12·5-month (IQR 6·4-18·8) median follow-up, 390 deaths occurred among 543 patients. Overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14·4 months [95% CI 13·0-15·7] vs 11·2 months [10·1-12·7]; hazard ratio [HR] 0·79, 95% CI 0·65-0·96; p=0·020); survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy (57 [21%] patients vs 38 [14%]; odds ratio 1·63 [95% CI 1·03-2·56]; p=0·035), as was time to deterioration of global health status and quality of life (median 4·3 months vs 3·0 months; HR 0·75 [0·61-0·92]; p=0·0059) and fatigue (median 2·2 months vs 1·4 months; HR 0·73 [0·60-0·89]; p=0·0021). The safety profile of sacituzumab govitecan was consistent with previous studies (including the TROPiCS-02 primary analysis and the ASCENT trial). One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment.
INTERPRETATION: Sacituzumab govitecan demonstrated statistically significant and clinically meaningful benefit over chemotherapy, with a 3·2-month median overall survival improvement and a manageable safety profile. These data support sacituzumab govitecan as a new treatment option for patients with pretreated, endocrine-resistant HR+ and HER2- metastatic breast cancer.
FUNDING: Gilead Sciences.
Molecular Cell
Fork Restart: Unloading FANCD2 to Travel Ahead
Iyer DR, D'Andrea AD
In this issue of Molecular Cell, Brunner et al.1 reveal that eliminating FANCD2 from stalled forks via FBXL12-mediated degradation enables cells to tolerate oncogene-induced replication stress, making FBXL12 a promising target for cancer treatment.
Nature Chemical Biology
Targeting ROS Production Through Inhibition of NADPH Oxidases
Reis J, Gorgulla C, Törner R, Cox H 3rd, Viennet T, Yang MH, Ronan MM, Rees MG, Roth JA, Arthanari H
NADPH oxidases (NOXs) are transmembrane enzymes that are devoted to the production of reactive oxygen species (ROS). In cancers, dysregulation of NOX enzymes affects ROS production, leading to redox unbalance and tumor progression. Consequently, NOXs are a drug target for cancer therapeutics, although current therapies have off-target effects: there is a need for isoenzyme-selective inhibitors. Here, we describe fully validated human NOX inhibitors, obtained from an in silico screen, targeting the active site of Cylindrospermum stagnale NOX5 (csNOX5). The hits are validated by in vitro and in cellulo enzymatic and binding assays, and their binding modes to the dehydrogenase domain of csNOX5 studied via high-resolution crystal structures. A high-throughput screen in a panel of cancer cells shows activity in selected cancer cell lines and synergistic effects with KRAS modulators. Our work lays the foundation for the development of inhibitor-based methods for controlling the tightly regulated and highly localized ROS sources.
Nature Communication
Spisak S, Tisza V, Nuzzo PV, Seo JH, Sztupinszki Z, Bell C, Rohanizadegan M, Stillman DR, Alaiwi SA, Bartels AH, Shetty A, Pomerantz M, Baca S, Szallasi Z, Gusev A, Freedman ML
To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21?bp short allele), a single copy knock-in of the 47?bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.
Nature Communications
Spirohn K, Hao T, Hill DE, Vidal M, Fuxman Bass JI
Cooperativity and antagonism between transcription factors (TFs) can drastically modify their binding to regulatory DNA elements. While mapping these relationships between TFs is important for understanding their context-specific functions, existing approaches either rely on DNA binding motif predictions, interrogate one TF at a time, or study individual TFs in parallel. Here, we introduce paired yeast one-hybrid (pY1H) assays to detect cooperativity and antagonism across hundreds of TF-pairs at DNA regions of interest. We provide evidence that a wide variety of TFs are subject to modulation by other TFs in a DNA region-specific manner. We also demonstrate that TF-TF relationships are often affected by alternative isoform usage and identify cooperativity and antagonism between human TFs and viral proteins from human papillomaviruses, Epstein-Barr virus, and other viruses. Altogether, pY1H assays provide a broadly applicable framework to study how different functional relationships affect protein occupancy at regulatory DNA regions.
Nature Medicine
Liquid Biopsy Epigenomic Profiling for Cancer Subtyping
Baca SC, Seo JH, Davidsohn MP, Fortunato B, Semaan K, Sotudian S, Lakshminarayanan G, Diossy M, Qiu X, El Zarif T, Savignano H, Canniff J, Madueke I, Saliby RM, Zhang Z, Li R, Jiang Y, Taing L, Awad M, DeCaprio JA, Hata AN, Hodi FS, Hughes ME, Ligon KL, Lin N, Ng K, Oser MG, Meador C, Parsons HA, Pomerantz MM, Ritz J, Thakuria M, Tolaney SM, Wen PY, Long H, Berchuck JE, Szallasi Z, Choueiri TK, Freedman ML
Although circulating tumor DNA (ctDNA) assays are increasingly used to inform clinical decisions in cancer care, they have limited ability to identify the transcriptional programs that govern cancer phenotypes and their dynamic changes during the course of disease. To address these limitations, we developed a method for comprehensive epigenomic profiling of cancer from 1?ml of patient plasma. Using an immunoprecipitation-based approach targeting histone modifications and DNA methylation, we measured 1,268 epigenomic profiles in plasma from 433 individuals with one of 15 cancers. Our assay provided a robust proxy for transcriptional activity, allowing us to infer the expression levels of diagnostic markers and drug targets, measure the activity of therapeutically targetable transcription factors and detect epigenetic mechanisms of resistance. This proof-of-concept study in advanced cancers shows how plasma epigenomic profiling has the potential to unlock clinically actionable information that is currently accessible only via direct tissue sampling.
Annals of Hematology
Merryman RW, Redd RA, Freedman AS, Ahn IE, Brown JR, Crombie JL, Davids MS, Fisher DC, Jacobsen ED, Kim AI, LaCasce AS, Ng S, Odejide OO, Parry EM, Kuntz TM, Wolff J, Rodig SJ, Armand P, Jacobson CA
Annals of Surgical Oncology
Kantor O, King TA, Jones A, Glass C, Leonard SJ, Ogayo ER, Mayer EL, Freedman RA, Mittendorf EA
Annals of Surgical Oncology
Minami CA, Jin G, Freedman RA, Schonberg MA, King TA, Mittendorf EA
Blood Advances
AMPK Activation Induces Immunogenic Cell Death in AML
Mondesir J, Bossong RA, Lane AA
Blood Advances
More Intensive Therapy has a Better Effect for Frail Parents with Multiple Myeloma
DuMontier C, La J, Bihn J, Corrigan J, Yildirim C, Dharne M, Abel GA, Gaziano JM, Do NV, Brophy M, Kim DH, Munshi NC, Fillmore NR, Driver JA
BMC Cancer
Regulation of HHLA2 Expression in Kidney Cancer and Myeloid Cells
Shigemura T, Perrot N, Huang Z, Bhatt RS, Sheshdeh AB, Ahmar NE, Ghandour F, Signoretti S, McDermott DF, Freeman GJ, Mahoney KM
Cancer
Sorouri K, Sella T, Loucks M, Kirkner G, Snow C, Gelber SI, Peppercorn JM, Come SE, Partridge AH
Cancer
Mullen EA
Cancer
Florez N, Kiel L, Meza K, Wei Z, Mazzola E, Franco I
Cancer Medicine
Nayak MM, Chai PR, Tung S, Tulsky JA, Hammer M, Andrade N, Braun IM
Cell Chemical Biology
HATS Off to KAT6A/B Inhibitors: A New Way to Target Estrogen-Receptor-Positive Breast Cancer
Jeselsohn R, Polyak K
Clinical Cancer Research
Tolaney SM
Expert Opinion on Drug Safety
Midha S, Hartley-Brown MA, Mo CC, Hossain S, Nadeem O, O'Donnell EK, Bianchi G, Sperling AS, Laubach JP, Richardson PG
Expert Review of Hematology
Maurer K, Soiffer RJ
Future Oncology
Choueiri TK
Gut Microbes
The Microbiome and Rise of Early-Onset Cancers: Knowledge Gaps and Research Opportunities
Ugai T, Ogino S
Gynecologic Oncology
Matulonis UA
Gynecologic Oncology
Konstantinopoulos PA
Haematologica
BH3 Profiling as Pharmacodynamic Biomarker for the Activity of BH3 Mimetics
Pan RA, Villalobos-Ortiz M, Ryan J, Halilovic E, Letai A
Hepatology Communications
Pepe-Mooney BJ, Smith CJ, Sherman MS, North TE, Padera RF Jr, Goessling W
Journal of Adolescent and Young Adult Oncology
Morris SE, Ryan AK, Malinowski P, Pozo-Kaderman C, Fasciano KM
Journal of Hospital Medicine
Things We Do for No Reason™: Opioid Infusions as Initial Therapy for Symptoms at the End of Life
Gelfand SL, Drutchas A, Rosenberg LB
Journal of Virology
Anang S, Zhang S, Madani N, Sodroski J
Pediatric Blood and Cancer
Gikandi A, DuBois SG
Therapeutic Advances in Vaccines and Immunotherapy
Cancer Vaccine Strategies for the Treatment of Diffusely Infiltrating Gliomas
Dumont S, Pooley C, Gonzalez Castro LN
Transplantation and Cellular Therapy
Jacobson CA