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 July 1 through July 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.
For more about Dana-Farber science, tune in to our Unraveled podcast. The second season is now available at dana-farber.org/unraveled, or wherever you get your podcasts.
|
|
|
Blood
Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma: Final Analysis of KEYNOTE-170
Shipp MA, Armand P
Previous analyses of the phase 2 KEYNOTE-170 (NCT02576990) study demonstrated effective antitumor activity and acceptable safety of pembrolizumab 200 mg given every 3 weeks for up to 35 cycles (∼2 years) in patients with relapsed/refractory (R/R) primary mediastinal B-cell lymphoma (PMBCL) whose disease progressed after or who were ineligible for autologous stem cell transplantation. The end points included objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR) according to the investigator per 2007 Response Criteria; overall survival (OS); and safety. In this final analysis, median duration of follow-up was 48.7 months (range, 41.2-56.2). The ORR was 41.5% (complete response, 20.8%; partial response, 20.8%). The median DOR was not reached; no patients who achieved a complete response progressed at the data cutoff. The median PFS was 4.3 months; the 4-year PFS rate was 33.0%. The median OS was 22.3 months; the 4-year OS rate was 45.3%. At the data cutoff, 30 patients (56.6%) had any-grade treatment-related adverse events (AEs); the most common were neutropenia, asthenia, and hypothyroidism. Grade 3/4 treatment-related AEs occurred in 22.6% of the patients; no grade 5 AEs occurred. After 4 years of follow-up, pembrolizumab continued to provide durable responses, with promising trends for long-term survival and acceptable safety in R/R PMBCL.
|
Blood
Richter Syndrome: Novel Insights into the Biology of Transformation
Parry EM, Ten Hacken E, Wu CJ
Although the genetic landscape of chronic lymphocytic leukemia (CLL) has been broadly profiled by large-scale sequencing studies performed over the past decade, the molecular basis of the transformation of CLL into aggressive lymphoma, or Richter syndrome (RS), has remained incompletely characterized. Recent advances in computational methods of clonal deconvolution, as well as extensive sample collection efforts in this rapidly progressive malignancy, have now enabled comprehensive analysis of paired CLL and RS samples and have led to multiple new studies investigating the genetic, transcriptomic, and epigenetic origins of RS. In parallel, new genetically engineered and xenograft mouse models have provided the opportunity for gleaning fresh biological and mechanistic insights into RS development and stepwise evolution from antecedent CLL. Altogether, these studies have defined RS driver lesions and CLL risk lesions and identified pathways dysregulated in transformation. Moreover, unique molecular subtypes of RS have been revealed, including a disease marked by profound genomic instability with chromothripsis/chromoplexy and whole genome duplication. Novel profiling approaches, including single-cell DNA and transcriptome sequencing of RS biopsy specimens and cell-free DNA profiling of patient plasma, demonstrate promise for the timely identification of RS clones and may translate to noninvasive identification and early diagnosis of RS. This review summarizes the recent scientific advances in RS and supports the integrated study of human genomics with mouse modeling to provide an advanced understanding of the biological underpinnings of transformation. These recent studies have major implications for much-needed novel therapeutic strategies for this still largely incurable malignancy.
|
Journal of Clinical Oncology
Early Treatment Intensification in Metastatic Hormone-Sensitive Prostate Cancer
Wala J, Nguyen P, Pomerantz M
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 the Journal of Clinical Oncology, to patients seen in their own clinical practice. For generations, oncologists and urologists have used androgen deprivation therapy (ADT) to manage metastatic hormone-sensitive prostate cancer (mHSPC). Until recently, ADT monotherapy was standard. Within the past decade, a series of trials have clearly demonstrated improved outcomes with a more aggressive up-front approach. Doublet intensification therapy, involving either ADT plus docetaxel or ADT plus any of several second-generation oral androgen-receptor pathway inhibitors (ARPIs), provide considerable survival advantages compared with ADT alone. In 2022, two trials, PEACE-1 and ARASENS, demonstrated the potential of triplet therapy, adding an ARPI to an ADT-docetaxel doublet. In the Original Report that accompanies this article, the authors provide a post hoc analysis of ARASENS (ADT plus docetaxel, with or without darolutamide), identifying the subpopulations of patients with mHSPC who might benefit most from a triplet regimen. They segment the ARASENS cohort by disease volume and disease risk profile, finding that triplet therapy is associated with improved outcomes regardless of category (although with limited power in the low-volume cohort). Meanwhile, trials are ongoing examining the role of radiotherapy (RT) in mHSPC, a modality previously reserved for localized disease or isolated, symptomatic metastases. Here, we present a mHSPC case and discuss our approach to mHSPC considering recent studies. We recommend triplet therapy for patients who are suitable candidates for chemotherapy, especially for patients with high-volume disease. We also favor aggressive use of RT, when feasible, for patients with low-volume mHSPC.
|
Journal of Clinical Oncology
Quality Surgical Care and Outcomes for Patients with Non-Small-Cell Lung Cancer
Kehl KL, Jaklitsch MT
The curative potential of surgical resection for non–small-cell lung cancer (NSCLC) was established nearly a century ago, with pneumonectomy initially constituting the primary operative approach. As surgical techniques became more refined, lobectomy when feasible became the standard of care and less invasive techniques including video-assisted thoracic surgery and robotic-assisted thoracoscopic surgery have reduced surgical morbidity. Despite the evolving role of systemic therapy in the treatment of early-stage NSCLC, now including cytotoxic chemotherapy, targeted therapy, and immunotherapy, surgical resection still plays a critical role in curative treatment.
|
Journal of the National Cancer Institute
The "Scope" of Colorectal Cancer Screening in Lynch Syndrome: Is There an Optimal Interval?
Biller LH, Ng K
Lynch syndrome (LS) is one of the most common hereditary colorectal cancer (CRC) predisposition syndromes and is present in 1 out of 279 individuals in the general population and in approximately 3% of unselected cases of CRC. LS is caused by the autosomal dominant inheritance of a pathologic variant in 1 of 4 mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or deletions in the EPCAM gene (which lead to epigenetic silencing of MSH2). LS carriers are at increased risk of CRC as well as endometrial, ovarian, stomach, small intestine, pancreaticobiliary, urinary tract, and skin cancers, among an increasingly long list of other rarer cancer types. It is now well established that rather than being a singular entity, each individual LS gene phenotype is different with respect to cancer type and risk. MLH1 and MSH2 are highly penetrant, with a cumulative incidence of CRC by age 75 years in MLH1 of 48.3% women and 57.1% men and in MSH2 of 46.6% women and 51.4% men. Cumulative incidence of CRC for MSH6 carriers is less than that for MLH1 and MSH2, at 20.3% and 18.2% for women and men, respectively. PMS2 is the most prevalent LS gene but the least penetrant, with a cumulative CRC incidence of 10.4% in both sexes by age 75 years, and one large study suggested that PMS2 carriers are at increased risk of only CRC and endometrial cancer but not other LS-associated cancers. Across all genes, colonoscopy screening reduces the risk of CRC and improves overall survival among LS carriers and remains the mainstay of current risk reduction recommendations. What remain less clear are the optimal age at which to start screening and the best interval between colonoscopy screenings for LS carriers, such that many international professional society guidelines vary with respect to these recommendations.
|
Lancet
Atezolizumab Plus Cabozantinib Versus Cabozantinib Monotherapy for Patients with Renal Cell Carcinoma After Progression with Previous Immune Checkpoint Inhibitor Treatment (CONTACT-03): A Multicentre, Randomised, Open-Label, Phase 3 Trial
Choueiri TK
BACKGROUND: Immune checkpoint inhibitors are the standard of care for first-line treatment of patients with metastatic renal cell carcinoma, yet optimised treatment of patients whose disease progresses after these therapies is unknown. The aim of this study was to determine whether adding atezolizumab to cabozantinib delayed disease progression and prolonged survival in patients with disease progression on or after previous immune checkpoint inhibitor treatment.
METHODS: CONTACT-03 was a multicentre, randomised, open-label, phase 3 trial, done in 135 study sites in 15 countries in Asia, Europe, North America, and South America. Patients aged 18 years or older with locally advanced or metastatic renal cell carcinoma whose disease had progressed with immune checkpoint inhibitors were randomly assigned (1:1) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus cabozantinib (60 mg orally once daily) or cabozantinib alone. Randomisation was done through an interactive voice-response or web-response system in permuted blocks (block size four) and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk group, line of previous immune checkpoint inhibitor therapy, and renal cell carcinoma histology. The two primary endpoints were progression-free survival per blinded independent central review and overall survival. The primary endpoints were assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT04338269, and is closed to further accrual.
FINDINGS: From July 28, 2020, to Dec 27, 2021, 692 patients were screened for eligibility, 522 of whom were assigned to receive atezolizumab-cabozantinib (263 patients) or cabozantinib (259 patients). 401 (77%) patients were male and 121 (23%) patients were female. At data cutoff (Jan 3, 2023), median follow-up was 15·2 months (IQR 10·7-19·3). 171 (65%) patients receiving atezolizumab-cabozantinib and 166 (64%) patients receiving cabozantinib had disease progression per central review or died. Median progression-free survival was 10·6 months (95% CI 9·8-12·3) with atezolizumab-cabozantinib and 10·8 months (10·0-12·5) with cabozantinib (hazard ratio [HR] for disease progression or death 1·03 [95% CI 0·83-1·28]; p=0·78). 89 (34%) patients in the atezolizumab-cabozantinib group and 87 (34%) in the cabozantinib group died. Median overall survival was 25·7 months (95% CI 21·5-not evaluable) with atezolizumab-cabozantinib and was not evaluable (21·1-not evaluable) with cabozantinib (HR for death 0·94 [95% CI 0·70-1·27]; p=0·69). Serious adverse events occurred in 126 (48%) of 262 patients treated with atezolizumab-cabozantinib and 84 (33%) of 256 patients treated with cabozantinib; adverse events leading to death occurred in 17 (6%) patients in the atezolizumab-cabozantinib group and nine (4%) in the cabozantinib group.
INTERPRETATION: The addition of atezolizumab to cabozantinib did not improve clinical outcomes and led to increased toxicity. These results should discourage sequential use of immune checkpoint inhibitors in patients with renal cell carcinoma outside of clinical trials.
FUNDING: F Hoffmann-La Roche and Exelixis.
|
Nature
Author Correction: Clonal Haematopoiesis and Risk of Chronic Liver Disease
Wong W, Emdin C, Bick AG, Zekavat SM, Niroula A, Pirruccello JP, Dichtel L, Griffin G, Uddin MM, Gibson CJ, Kovalcik V, Lin AE, McConkey ME, Vromman A, Sellar RS, Kim PG, Agrawal M, Loh PR, McCarroll S, Chung RT, Corey K, Ebert BL, Natarajan P
Chronic liver disease is a major public health burden worldwide. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.
|
Nature
Heritable Transcriptional Defects from Aberrations of Nuclear Architecture
Papathanasiou S, Mynhier NA, Liu S, Brunette G, Stokasimov E, Jacob E, Li L, Comenho C, Buenrostro JD, Zhang CZ, Pellman D
Transcriptional heterogeneity due to plasticity of the epigenetic state of chromatin contributes to tumour evolution, metastasis and drug resistance. However, the mechanisms that cause this epigenetic variation are incompletely understood. Here we identify micronuclei and chromosome bridges, aberrations in the nucleus common in cancer as sources of heritable transcriptional suppression. Using a combination of approaches, including long-term live-cell imaging and same-cell single-cell RNA sequencing (Look-Seq2), we identified reductions in gene expression in chromosomes from micronuclei. With heterogeneous penetrance, these changes in gene expression can be heritable even after the chromosome from the micronucleus has been re-incorporated into a normal daughter cell nucleus. Concomitantly, micronuclear chromosomes acquire aberrant epigenetic chromatin marks. These defects may persist as variably reduced chromatin accessibility and reduced gene expression after clonal expansion from single cells. Persistent transcriptional repression is strongly associated with, and may be explained by, markedly long-lived DNA damage. Epigenetic alterations in transcription may therefore be inherently coupled to chromosomal instability and aberrations in nuclear architecture.
|
Nature Chemical Biology
Depletion of Creatine Phosphagen Energetics with a Covalent Creatine Kinase Inhibitor
Darabedian N, Lin S, Seo HS, Mills EL, Xiao H, Johnson JL, Che J, Cantley LC, Dhe-Paganon S, Stegmaier K, Chouchani ET
Creatine kinases (CKs) provide local ATP production in periods of elevated energetic demand, such as during rapid anabolism and growth. Thus, creatine energetics has emerged as a major metabolic liability in many rapidly proliferating cancers. Whether CKs can be targeted therapeutically is unknown because no potent or selective CK inhibitors have been developed. Here we leverage an active site cysteine present in all CK isoforms to develop a selective covalent inhibitor of creatine phosphagen energetics, CKi. Using deep chemoproteomics, we discover that CKi selectively engages the active site cysteine of CKs in cells. A co-crystal structure of CKi with creatine kinase B indicates active site inhibition that prevents bidirectional phosphotransfer. In cells, CKi and its analogs rapidly and selectively deplete creatine phosphate, and drive toxicity selectively in CK-dependent acute myeloid leukemia. Finally, we use CKi to uncover an essential role for CKs in the regulation of proinflammatory cytokine production in macrophages.
|
Nature Communications
Impact of TMB/PD-L1 Expression and Pneumonitis on Chemoradiation and Durvalumab Response in Stage III NSCLC
Alessi JV, Ricciuti B, Wang X, Pecci F, Di Federico A, Lamberti G, Rodig SJ, Johnson BE, Awad MM
Although concurrent chemoradiation (CRT) and durvalumab consolidation has become a standard treatment for stage III non-small cell lung cancer (NSCLC), clinicopathologic and genomic factors associated with its efficacy remain poorly characterized. Here, in a multi-institutional retrospective cohort study of 328 patients treated with CRT and durvalumab, we identify that very high PD-L1 tumor proportion score (TPS) expression (90%) and increased tumor mutational burden (TMB) are independently associated with prolonged disease control. Additionally, we identify the impact of pneumonitis and its timing on disease outcomes among patients who discontinue durvalumab: compared to patients who experienced early-onset pneumonitis (< months) leading to durvalumab discontinuation, patients with late-onset pneumonitis had a significantly longer PFS (12.7 months vs not reached; HR 0.24 [95% CI, 0.10 to 0.58]; P = 0.001) and overall survival (37.2 months vs not reached; HR 0.26 [95% CI, 0.09 to 0.79]; P = 0.017). These findings suggest that opportunities exist to improve outcomes in patients with lower PD-L1 and TMB levels, and those at highest risk for pneumonitis.
|
Nature Communications
Multi-batch Single-Cell Comparative Atlas Construction by Deep Learning Disentanglement
Lynch AW, Brown M, Meyer CA
Cell state atlases constructed through single-cell RNA-seq and ATAC-seq analysis are powerful tools for analyzing the effects of genetic and drug treatment-induced perturbations on complex cell systems. Comparative analysis of such atlases can yield new insights into cell state and trajectory alterations. Perturbation experiments often require that single-cell assays be carried out in multiple batches, which can introduce technical distortions that confound the comparison of biological quantities between different batches. Here we propose CODAL, a variational autoencoder-based statistical model which uses a mutual information regularization technique to explicitly disentangle factors related to technical and biological effects. We demonstrate CODAL's capacity for batch-confounded cell type discovery when applied to simulated datasets and embryonic development atlases with gene knockouts. CODAL improves the representation of RNA-seq and ATAC-seq modalities, yields interpretable modules of biological variation, and enables the generalization of other count-based generative models to multi-batched data.
|
Proceedings of the National Academy of Sciences of the U.S.A.
Harnessing ab T Cell Receptor Mechanobiology to Achieve the Promise of Immuno-Oncology
Reinherz EL
T cell receptors (TCR) on cytolytic T lymphocytes (CTLs) recognize "foreign" antigens bound in the groove of major histocompatibility complex (MHC) molecules (H-2 in mouse and HLA in human) displayed on altered cells. These antigens are peptide fragments of proteins derived either from infectious pathogens or cellular transformations during cancer evolution. The conjoint ligand formed by the foreign peptide and MHC, termed pMHC, marks an aberrant cell as a target for CTL-mediated destruction. Recent data have provided compelling evidence that adaptive protection is achieved in a facile manner during immune surveillance when mechanical load consequent to cellular motion is applied to the bond formed between an ab TCR and its pMHC ligand arrayed on a disease-altered cell. Mechanobiology maximizes both TCR specificity and sensitivity in comparison to receptor ligation in the absence of force. While the field of immunotherapy has made advances to impact the survival of cancer patients, the latest information relevant to T cell targeting and mechanotransduction has yet to be applied for T cell monitoring and treatment of patients in the clinic. Here we review these data, and challenge scientists and physicians to apply critical biophysical parameters of TCR mechanobiology to the medical oncology field, broadening treatment success within and among various cancer types. We assert that TCRs with digital ligand-sensing performance capability directed at sparsely as well as luminously displayed tumor-specific neoantigens and certain tumor-associated antigens can improve effective cancer vaccine development and immunotherapy paradigms.
|
Blood Advances
Effect of BMI on Toxicities and Survival Among Adolescents and Young Adults Treated on DFCI Consortium ALL Trials
Flamand Y, Place AE, Silverman LB, Vrooman LM, Brunner AM, Sallan SE, Stone RM, Wadleigh M, Neuberg DS, DeAngelo DJ, Luskin MR
|
Cancer Research
Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor-Positive Breast Cancer
Hermida-Prado F, Xie Y, Sherman S, Nagy Z, Russo D, Akhshi T, Campisi M, Chen M, Nardone A, Guarducci C, Lim K, Font-Tello A, Agudo J, Huang Y, Jin Q, Tayob N, Mittendorf EA, Tolaney SM, Qiu X, Long H, Lin JR, Santagata S, Richardson ET, Oliveira G, Wu CJ, Barbie D, Metzger O, Jeselsohn R
|
Clinical Cancer Research
ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma
Blandin AF, Giglio R, Garcia G, Malinowski S, Woods JK, Ramkissoon S, Ramkissoon L, Dubois F, Schoolcraft K, Tsai J, Wang D, Jones R, Vogelzang J, Pelton K, Becker S, Watkinson F, Sinai C, Cohen EF, Booker MA, Tolstorukov MY, Wright K, Fehnel K, Reardon D, Charest A, Ligon AH, Dubuc A, Wen PY, Alexander BM, Chi S, Alexandrescu S, Bandopadhayay P, Beroukhim R, Ligon KL
|
Clinical Cancer Research
Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non-Small Cell Lung Cancer
Ricciuti B, Alessi J, Wang X, Li Y, Gupta H, Bertram AA, Pecci F, Lamberti G, Di Federico A, Barrichello A, Vaz VR, Gandhi M, Lee E, Shapiro GI, Park H, Nishino M, Lindsay J, Felt KD, Sharma B, Cherniack AD, Rodig S, Rakaee M, Janne PA, Sholl LM, Awad MM, Cheng ML
|
Clinical Cancer Research
Clonal Hematopoiesis in Young Women Treated for Breast Cancer
Gibson CJ, Fell G, Sella T, Sperling AS, Snow C, Kirkner G, Patel A, Dillon D, Neuberg D, Partridge AH, Miller PG
|
Journal of Applied Clinical Medical Physics
Comparison of MR-Soft Tissue Based Versus Biliary Stent Based Alignment for Image Guidance in Pancreatic SBRT
Han Z, Sudhyadhom A, Hsu SH, Hu YH, Mak RH, Huynh MA, van Dams RR, Tanguturi S, Venkatachalam V, Mancias JD, Mamon HJ, Martin NE, Lam MB, Leeman JE
|
Leukemia Research
Incidence and Predictors of Anthracycline-Related Left Ventricular Dysfunction in Acute Myeloid Leukemia
Stahl M, Liu Y, Winer ES, Garcia JS, Chen E, Wadleigh M, Ling K, Lindsley RC, Shimony S, Copson K, Charles A, DeAngelo DJ, Stone RM, Nohria A, Luskin MR
|
Neuro-Oncology
Telomerase Inhibition is an Effective Therapeutic Strategy in TERT Promoter-Mutant Glioblastoma Models with Low Tumor Volume
Aquilanti E, Kageler L, Watson J, Szegletes ZM, Doench JG, Strathdee CA, Figueroa JRMF, Ligon KL, Beck M, Wen PY, Meyerson M
|
Oncologist
Adjuvant Olaparib for Germline BRCA Carriers with HER2-Negative Early Breast Cancer: Evidence and Controversies
Morganti S, Bychkovsky BL, Poorvu PD, Garrido-Castro AC, Block CC, Partridge AH, Tung NM, Lin NU, Garber JE, Tolaney SM, Lynce F
|
Transplantation and Cellular Therapy
Clinical Features of Acute Kidney Injury in the Early Post-Transplantation Period Following Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation
Vergara-Cadavid J, Johnson PC, Kim HT, Yi A, Sise ME, Leaf DE, Hanna PE, Ho VT, Cutler CS, Antin JH, Gooptu M, Kelkar AH, Wells SL, Nikiforow S, Koreth J, Romee R, Soiffer RJ, Shapiro RM, Gupta S
|
Transplantation and Cellular Therapy
Positive Psychological Well-Being in Hematopoietic Stem Cell Transplantation Survivors
Amonoo HL, Daskalakis E, Deary EC, Celano C, Onyeaka HK, Newcomb R, Barata A, Horick N, Cutler C, Pirl WF, Huffman JC, El-Jawahri A
|
|
|
Manage your preferences | Opt Out using TrueRemove™
Got this as a forward? Sign up to receive our future emails.
View this email online.
|
450 Brookline Ave OS300 | Boston, MA 02215 US
|
|
|
This email was sent to pr@americantowns.com.
To continue receiving our emails, add us to your address book.
|
| |
|
|
