Welcome to Dana-Farber's Research News
July 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.
Cell
cGLRs are a Diverse Family of Pattern Recognition Receptors in Innate Immunity
Li Y, Slavik KM, Toyoda HC, Morehouse BR, Mears KS, Liu J, Kranzusch PJ
Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2'3'-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila, we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.
Journal of Clinical Oncology
Tolaney SM
PURPOSE: Amcenestrant (oral selective estrogen receptor degrader) demonstrated promising safety and efficacy in earlier clinical studies for endocrine-resistant, estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (aBC).
PATIENTS AND METHODS: In AMEERA-3 (ClinicalTrials.gov identifier: NCT04059484), an open-label, worldwide phase II trial, patients with ER+/HER2- aBC who progressed in the (neo)adjuvant or advanced settings after not more than two previous lines of endocrine therapy (ET) were randomly assigned 1:1 to amcenestrant or single-agent endocrine treatment of physician's choice (TPC), stratified by the presence/absence of visceral metastases, previous/no treatment with cyclin-dependent kinase 4/6 inhibitor, and Eastern Cooperative Oncology Group performance status (0/1). The primary end point was progression-free survival (PFS) by independent central review, compared using a stratified log-rank test (one-sided type I error rate of 2.5%).
RESULTS: Between October 22, 2019, and February 15, 2021, 290 patients were randomly assigned to amcenestrant (n = 143) or TPC (n = 147). PFS was numerically similar between amcenestrant and TPC (median PFS [mPFS], 3.6 v 3.7 months; stratified hazard ratio [HR], 1.051 [95% CI, 0.789 to 1.4]; one-sided P = .643). Among patients with baseline mutated ESR1; (n = 120 of 280), amcenestrant numerically prolonged PFS versus TPC (mPFS, 3.7 v 2.0 months; stratified HR, 0.9 [95% CI, 0.565 to 1.435]). Overall survival data were immature but numerically similar between groups (HR, 0.913; 95% CI, 0.595 to 1.403). In amcenestrant versus TPC groups, treatment-emergent adverse events (any grade) occurred in 82.5% versus 76.2% of patients and grade ?3 events occurred in 21.7% versus 15.6%.
CONCLUSION: AMEERA-3 did not meet its primary objective of improved PFS with amcenestrant versus TPC although a numerical improvement in PFS was observed in patients with baseline ESR1 mutation. Efficacy and safety with amcenestrant were consistent with the standard of care for second-/third-line ET for ER+/HER2- aBC.
Journal of Clinical Oncology
Sarosiek S, Treon SP, Branagan AR, Castillo JJ
In the recent publication “Bortezomib-Dexamethasone, Rituximab, and Cyclophosphamide as First-Line Treatment for Waldenström's Macroglobulinemia: A Prospectively Randomized Trial of the European Consortium for Waldenström's Macroglobulinemia” by Buske et al, 202 patients with Waldenström's macroglobulinemia (WM) were randomly assigned to receive dexamethasone-rituximab-cyclophosphamide (DRC) versus bortezomib-DRC (B-DRC). Buske et al should be commended on successfully conducting this large, randomized trial in a rare disease. The effort to focus on the development of a finite, combination therapy with the goal of achieving a prolonged progression-free survival (PFS) is greatly appreciated.
Journal of Clinical Oncology
Warren KE
PURPOSE: Children with low-grade glioma often require long-term therapy and suffer from treatment morbidity. Although targeted agents are promising, tumor targets often encompass normal developmental pathways and long-term effects of inhibition are unknown. Lenalidomide is an immunomodulatory agent with wide-ranging properties. Phase I studies indicated greater tolerability of lenalidomide in children compared with adults and a potential dose-response effect.
PATIENTS AND METHODS: We performed a phase II trial of lenalidomide in children with pilocytic astrocytomas and optic pathway gliomas who failed initial therapy. Primary objectives included determination of objective response rate of children randomly assigned to regimen A, low-dose (20 mg/m2/dose), or regimen B, high-dose (115 mg/m2/dose) lenalidomide, and assessment for early progression. Secondary objectives included estimation of event-free survival, overall survival, incidence of toxic events, and assessment of plasma lenalidomide concentrations. Lenalidomide was administered once daily × 21 days of each 28-day cycle for each regimen.
RESULTS: Seventy-four eligible patients were enrolled (n = 37, each arm). The predefined activity level of interest was achieved for both arms. Four objective responses were observed in each arm, and the number of early progressors was low. Eighteen patients completed 26 cycles of therapy (regimen A, n = 12; regimen B, n = 6). The median number of cycles was 14 (range, 2-26) for regimen A and 11 for regimen B (range, 1-26). Of 74 eligible patients who received study drug, 30 required dose reduction for toxicity (regimen A, n = 6; regimen B, n = 24) and 16 discontinued because of toxicity (regimen A, n = 2; regimen B, n = 14).
CONCLUSION: Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration. Low-dose (20 mg/m2/dose administered once daily × 21 days of each 28-day cycle) lenalidomide appears to have better tolerability with comparable activity.
Journal of Clinical Oncology
Mullen EA
PURPOSE: The safety of reintroducing chemotherapy in the pediatric renal tumor setting after severe hepatopathy (SH), including sinusoidal obstruction syndrome (SOS), is uncertain. We describe the incidence, severity, outcomes, and impact on subsequent treatment for patients with SH from National Wilms Tumor Study (NWTS) protocols 3-5.
PATIENTS AND METHODS: Archived charts for patients enrolled on NWTS 3-5 who met study inclusion criteria for SH by using established hepatopathy grading scales and clinical criteria were reviewed for demographics, tumor characteristics, radio- and chemotherapy details, SH-related dose modifications, and oncologic outcomes. Genomic analysis for candidate polymorphisms associated with SH was performed in 14 patients.
RESULTS: Seventy-one of 8,862 patients (0.8%) met study inclusion criteria. The median time from therapy initiation to SH was 51 days (range, 2-293 days). Sixty percent received radiotherapy, and 56% had right-sided tumors. Grade 1-4 thrombocytopenia was noted in 70% at initial occurrence of SH (median 22,000/microliter). Among 69 of 71 children with SH occurring before the end of therapy (EOT) and post-SH treatment information available, chemotherapy was delayed posthepatopathy for 65% (69% of these at a reduced dose), continued without delay for 20% (57% of these at reduced dose), and stopped completely for 15% (4 of 10 of whom died of SH). Overall, 42% of patients with dose reductions achieved full dose by EOT. The five-year post-SH event-free survival for patients who continued therapy was 89% (95% CI, 81 to 98), with no significant differences by whether delay or dose reduction occurred. We identified no SH-associated pharmacogenomic polymorphism.
CONCLUSION: The incidence of SH on NWTS 3-5 was low; many had associated severe thrombocytopenia. Careful reintroduction of chemotherapy appeared to be feasible for the majority of patients who developed severe chemotherapy- and/or radiotherapy-induced liver toxicity.
Journal of Clinical Oncology
Burstein HJ
ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options. See the Appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only).
JAMA Oncology
Enhancing Patient Retention in Clinical Trials-Strategies for Success
Florez N
Clinical trials are crucial for the advancement of oncology treatments. They offer access to novel and potentially effective therapies, provide an extra layer of support for patients through research nurses or coordinators who help them navigate the complex health care system, and can narrow or eliminate disparities in cancer by providing standardized care to all participants regardless of their backgrounds. Clinical trials over the past 3 decades have led to considerable treatment breakthroughs and the improvement of overall survival for patients with cancer globally. However, clinical research has been historically performed on patients rather than with them, leading to the design of complex studies with frequent visits and mandatory biopsies, increasing the burden on patients and decreasing their interest in trial participation. These practices are changing, and patients are now active partners in the research infrastructure, including in the planning and implementation of studies. Without patients’ consent and participation, clinical trials would not be possible.
JAMA Oncology
Leveraging Goals of Care Interventions to Deliver Personalized Care Near the End of Life
Manz CR
Patients with cancer often receive costly care near the end of life that is not aligned with their preferences. Interventions facilitating discussions about patients’ goals and preferences contribute to patient-centered care while resulting in less intensive care near the end of life. However, many patients with cancer die without having goals of care conversations (GOCCs) and few health systems use interventions to prompt these discussions. The effectiveness of interventions to increase GOCCs and change cancer care near the end of life may vary based on context, population, and implementation approaches. Herein we provide recommendations that can enable successful GOCCs and associated personalized high-quality care near the end of life.
Nature
Cancer Aneuploidies are Shaped Primarily by Effects on Tumour Fitness
Shih J, Sarmashghi S, Zhang S, Hoyt SH, Cuoco MS, Gao GF, Spurr LF, Berger AC, Ha G, Rendo V, Meyerson M, Cherniack AD, Taylor AM, Beroukhim R
Aneuploidies-whole-chromosome or whole-arm imbalances-are the most prevalent alteration in cancer genomes. However, it is still debated whether their prevalence is due to selection or ease of generation as passenger events. Here we developed a method, BISCUT, that identifies loci subject to fitness advantages or disadvantages by interrogating length distributions of telomere- or centromere-bounded copy-number events. These loci were significantly enriched for known cancer driver genes, including genes not detected through analysis of focal copy-number events, and were often lineage specific. BISCUT identified the helicase-encoding gene WRN as a haploinsufficient tumour-suppressor gene on chromosome 8p, which is supported by several lines of evidence. We also formally quantified the role of selection and mechanical biases in driving aneuploidy, finding that rates of arm-level copy-number alterations are most highly correlated with their effects on cellular fitness1,2. These results provide insight into the driving forces behind aneuploidy and its contribution to tumorigenesis.
Proceedings of the National Academy of Sciences of the U.S.A.
Harnessing ?? 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 ?? 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.
Advances in Therapy
Bispecific Monoclonal Antibodies in Multiple Myeloma: Data from ASH 2022: A Podcast
Nadeem O
Annual Review of Virology
CBASS to cGAS-STING: The Origins and Mechanisms of Nucleotide Second Messenger Immune Signaling
Slavik KM, Kranzusch PJ
Blood Advances
Olesinski EA, Garcia JS, Letai A
Blood Advances
Stahl M, Kutchroo V, Hasserjian RP, Brunner AM
Blood Advances
Nelarabine: When, Where and How to Use it When Treating T-cell Acute Lymphoblastic Leukemia
Shimony S, DeAngelo DJ, Luskin MR
BMC Medical Research Methodology
Vanderbeek AM, Redd RA, Trippa L
Clinical Cancer Research
George S
Clinical Trials
Onyeaka H, Weber DB, Amonoo HL
Contemporary Clinical Trials
Amonoo HL, Daskalakis E, Deary EC, Celano CM, Ghanime PM, Healy BC, Cutler C, Pirl WF, Park ER, El-Jawahri A, Huffman JC
European Urology
Regan MM, McDermott DF
Hematology/Oncology Clinics of North America
Saad E, Saliby RM, Labaki C, Xu W, Viswanathan SR, Bakouny Z
Hematology/Oncology Clinics of North America
State of Cancer Control in South America: Challenges and Advancement Strategies
Abuali I, Florez N
Journal of Pain and Symptom Management
Palliative Care for All? An Assessment of Racial and Ethnic Disparities Research with Solutions
Collons D, Florez N, Petrillo L, Gray TF
Journal of Pediatric Nursing
Broden EG, Mazzola E, DeCourcey DD, Blume ED, Wolfe J, Snaman JM
Journal of Virology
Zhou R, Zhang S, Nguyen HT, Sodroski JG
JAMA Pediatrics
Poor Mental Health Among Survivors of Childhood Cancer-Risk Factors and a Call for Intervention
Rosenberg AR, Muriel AC
JCO Oncology Practice
Evolution of the Oncologist Clinician Educator
Kiel L, Florez N
JCO Oncology Practice
Impact of a Biopsychosocial Screening Program on Clinical and Hospital-Based Outcomes in Cancer
Florez N
JCO Oncology Practice
Horiguchi M, Abuali I, Florez N
Nature Protocols
Yang L, Wang J, Altreuter J, Jhaveri A, Wong CJ, Song L, Fu J, Taing L, Bodapati S, Sahu A,
Tokheim C, Zhang Y, Zeng Z, Bai G, Tang M, Qiu X, Long HW, Michor F, Liu Y, Liu XS
Pediatric Blood and Cancer
Wachter F, Hebert K, Pikman Y, Yang J, Shah B, Bledsoe J, Shimamura A, Neuberg DS, Pollard JA, Lehmann LE
Physics in Medicine and Biology
Impact of a Novel Multilayer Imager on Metal Artifacts in MV-CBCT
Harris TC, Jacobson MW, Myronakis ME, Ozoemelam I, Hu YH, Ferguson D, Berbeco RI
Science Advances
Sequential Apoptotic and Multiplexed Proteomic Evaluation of Single Cancer Cells
Lecky E, Mukherji A, German R, Antonellis G, Lin JR, Yorsz M, McQueeney KE, Ryan J, Ng K,
Sicinska E, Sorger PK, Letai A, Bhola PD
Transplantation and Cellular Therapy
Ho VT
Trends in Cell Biology
The Bidirectional Relationship Between Metabolism and Cell Cycle Control
Vander Heiden MG